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Novel drug approvals of 2020
In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.
No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
Anti-infectives
Artesunate (384)
The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.
Ebanga (ansuvimab) (147,000)
Studies on its use in pregnant animals have not been conducted.
Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)
Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.
Veklury (remdesivir) (603)
Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.
Antineoplastics
Ayvakit (avapritinib) (499)
The drug may cause fetal harm. The drug was teratogenic in animals.
Blenrep (belantamab mafodotin-blmf) (152,000)
A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.
Danyelza (naxitamab-gqgk) (144,000)
This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.
Gavreto (pralsetinib) (534)
Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.
Inqovi (cedazuridine + decitabine) (268,228)
The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.
Margenza (margetuximab-cmkb) (149,000)
Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.
Monjuvi (tafasitamab-cxix) (150,000)
This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.
Pemazyre (pemigatinib) (488)
It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.
Qinlock (ripretinib) (510)
This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.
Retevmo (selpercatinib) (526)
This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.
Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.
Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.
Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.
Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.
Tukysa (tucatinib) (481)
Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.
Zeposia (ozanimod) (441)
Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.
Zepzelca (lurbinectedin) (785)
This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
Antiemetics
Barhemsys (amisulpride) (369)
This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.
Antimigraine
Nurtec (rimegepant) (611)
Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.
Vyepti (eptinezumab-jjmr) (143,000)
A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
CNS
Byfavo (remimazolam) (493 – free base)
This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
Diagnostics
Cerianna (fluoroestradiol F 18) (289)
It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.
Detectnet (copper CU-64 dotatate) (1,497)
All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals
Miscellaneous
Dojolvi (triheptanoin) (429)
This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.
Enspryng (satralizumab-mwge) (143,000)
It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.
Evrysdi (risdiplam) (401)
This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.
Gemtesa (vibegron) (445)
Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.
Imcivree (setmelanotide) (1,117)
This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.
Isturisa (osilodrostat) (325)
Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.
Klisyri (tirbanibulin) (431)
Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.
Koselugo (selumetinib) (556)
This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.
Nexletol (bempedoic acid) (344)
Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.
Olinvyk (oliceridine) (503)
Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.
Ongentys (opicapone) (413)
Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.
Orladeyo (berotralstat) (635)
This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.
Oxlumo (lumasiran) (17,286)
Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.
Pizensy (lactitol) (344)
Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.
Rukobia (fostemsavir) (705; 584 for free acid)
This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.
Sogroya (somapacitan-beco) (23,305)
This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.
Tepezza (teprotumumab-trbw) (148,000)
Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.
Tauvid (flortaucipir F-18) (262)
This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.
Uplizna (inebilizumab-cdon) (149,000)
Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.
Winlevi (clascoterone) (403)
This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.
Xeglyze (abametapir) (1,840)
Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.
Zokinvy (lonafarnib) (639)
Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.
No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
Anti-infectives
Artesunate (384)
The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.
Ebanga (ansuvimab) (147,000)
Studies on its use in pregnant animals have not been conducted.
Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)
Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.
Veklury (remdesivir) (603)
Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.
Antineoplastics
Ayvakit (avapritinib) (499)
The drug may cause fetal harm. The drug was teratogenic in animals.
Blenrep (belantamab mafodotin-blmf) (152,000)
A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.
Danyelza (naxitamab-gqgk) (144,000)
This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.
Gavreto (pralsetinib) (534)
Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.
Inqovi (cedazuridine + decitabine) (268,228)
The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.
Margenza (margetuximab-cmkb) (149,000)
Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.
Monjuvi (tafasitamab-cxix) (150,000)
This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.
Pemazyre (pemigatinib) (488)
It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.
Qinlock (ripretinib) (510)
This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.
Retevmo (selpercatinib) (526)
This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.
Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.
Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.
Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.
Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.
Tukysa (tucatinib) (481)
Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.
Zeposia (ozanimod) (441)
Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.
Zepzelca (lurbinectedin) (785)
This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
Antiemetics
Barhemsys (amisulpride) (369)
This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.
Antimigraine
Nurtec (rimegepant) (611)
Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.
Vyepti (eptinezumab-jjmr) (143,000)
A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
CNS
Byfavo (remimazolam) (493 – free base)
This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
Diagnostics
Cerianna (fluoroestradiol F 18) (289)
It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.
Detectnet (copper CU-64 dotatate) (1,497)
All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals
Miscellaneous
Dojolvi (triheptanoin) (429)
This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.
Enspryng (satralizumab-mwge) (143,000)
It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.
Evrysdi (risdiplam) (401)
This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.
Gemtesa (vibegron) (445)
Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.
Imcivree (setmelanotide) (1,117)
This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.
Isturisa (osilodrostat) (325)
Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.
Klisyri (tirbanibulin) (431)
Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.
Koselugo (selumetinib) (556)
This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.
Nexletol (bempedoic acid) (344)
Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.
Olinvyk (oliceridine) (503)
Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.
Ongentys (opicapone) (413)
Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.
Orladeyo (berotralstat) (635)
This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.
Oxlumo (lumasiran) (17,286)
Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.
Pizensy (lactitol) (344)
Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.
Rukobia (fostemsavir) (705; 584 for free acid)
This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.
Sogroya (somapacitan-beco) (23,305)
This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.
Tepezza (teprotumumab-trbw) (148,000)
Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.
Tauvid (flortaucipir F-18) (262)
This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.
Uplizna (inebilizumab-cdon) (149,000)
Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.
Winlevi (clascoterone) (403)
This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.
Xeglyze (abametapir) (1,840)
Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.
Zokinvy (lonafarnib) (639)
Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.
No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
Anti-infectives
Artesunate (384)
The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.
Ebanga (ansuvimab) (147,000)
Studies on its use in pregnant animals have not been conducted.
Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)
Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.
Veklury (remdesivir) (603)
Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.
Antineoplastics
Ayvakit (avapritinib) (499)
The drug may cause fetal harm. The drug was teratogenic in animals.
Blenrep (belantamab mafodotin-blmf) (152,000)
A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.
Danyelza (naxitamab-gqgk) (144,000)
This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.
Gavreto (pralsetinib) (534)
Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.
Inqovi (cedazuridine + decitabine) (268,228)
The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.
Margenza (margetuximab-cmkb) (149,000)
Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.
Monjuvi (tafasitamab-cxix) (150,000)
This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.
Pemazyre (pemigatinib) (488)
It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.
Qinlock (ripretinib) (510)
This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.
Retevmo (selpercatinib) (526)
This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.
Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.
Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.
Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.
Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.
Tukysa (tucatinib) (481)
Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.
Zeposia (ozanimod) (441)
Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.
Zepzelca (lurbinectedin) (785)
This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
Antiemetics
Barhemsys (amisulpride) (369)
This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.
Antimigraine
Nurtec (rimegepant) (611)
Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.
Vyepti (eptinezumab-jjmr) (143,000)
A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
CNS
Byfavo (remimazolam) (493 – free base)
This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
Diagnostics
Cerianna (fluoroestradiol F 18) (289)
It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.
Detectnet (copper CU-64 dotatate) (1,497)
All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals
Miscellaneous
Dojolvi (triheptanoin) (429)
This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.
Enspryng (satralizumab-mwge) (143,000)
It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.
Evrysdi (risdiplam) (401)
This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.
Gemtesa (vibegron) (445)
Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.
Imcivree (setmelanotide) (1,117)
This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.
Isturisa (osilodrostat) (325)
Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.
Klisyri (tirbanibulin) (431)
Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.
Koselugo (selumetinib) (556)
This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.
Nexletol (bempedoic acid) (344)
Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.
Olinvyk (oliceridine) (503)
Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.
Ongentys (opicapone) (413)
Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.
Orladeyo (berotralstat) (635)
This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.
Oxlumo (lumasiran) (17,286)
Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.
Pizensy (lactitol) (344)
Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.
Rukobia (fostemsavir) (705; 584 for free acid)
This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.
Sogroya (somapacitan-beco) (23,305)
This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.
Tepezza (teprotumumab-trbw) (148,000)
Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.
Tauvid (flortaucipir F-18) (262)
This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.
Uplizna (inebilizumab-cdon) (149,000)
Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.
Winlevi (clascoterone) (403)
This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.
Xeglyze (abametapir) (1,840)
Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.
Zokinvy (lonafarnib) (639)
Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].
New targeted treatments are major advances for HER2-positive breast cancer
Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.
Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.
Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.
The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
Trastuzumab deruxtecan
Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.
Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).
Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
DESTINY-Breast 01 trial
In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.
Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.
The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.
The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.
The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.
The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
Tucatinib
Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.
The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m2 given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
HER2CLIMB trial
The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.
The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.
The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).
The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.
The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.
The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
Tucatinib in patients with brain involvement
A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.
There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.
The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P < .0001).
The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.
The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.
There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.
Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
Neratinib
Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.
Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.
In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
NALA trial
The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.
Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m2 orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m2 orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The primary endpoints were PFS and OS by blinded, independent, central review.
The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.
The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.
Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043).
The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
Margetuximab-cmkb
Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.
Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.
In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.
The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
SOPHIA trial
SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.
Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.
Co–primary outcome measures were PFS by blinded, independent, central review and OS.
At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).
At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).
Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.
The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.
The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.
Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.
In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
Take-home messages
There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.
The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).
When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.
Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.
Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.
The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
Trastuzumab deruxtecan
Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.
Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).
Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
DESTINY-Breast 01 trial
In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.
Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.
The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.
The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.
The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.
The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
Tucatinib
Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.
The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m2 given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
HER2CLIMB trial
The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.
The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.
The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).
The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.
The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.
The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
Tucatinib in patients with brain involvement
A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.
There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.
The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P < .0001).
The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.
The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.
There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.
Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
Neratinib
Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.
Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.
In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
NALA trial
The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.
Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m2 orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m2 orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The primary endpoints were PFS and OS by blinded, independent, central review.
The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.
The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.
Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043).
The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
Margetuximab-cmkb
Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.
Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.
In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.
The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
SOPHIA trial
SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.
Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.
Co–primary outcome measures were PFS by blinded, independent, central review and OS.
At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).
At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).
Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.
The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.
The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.
Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.
In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
Take-home messages
There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.
The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).
When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.
Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.
Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.
The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
Trastuzumab deruxtecan
Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.
Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).
Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
DESTINY-Breast 01 trial
In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.
Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.
The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.
The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.
The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.
The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
Tucatinib
Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.
The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m2 given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
HER2CLIMB trial
The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.
The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.
The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).
The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.
The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.
The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
Tucatinib in patients with brain involvement
A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.
There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.
The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P < .0001).
The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.
The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.
There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.
Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
Neratinib
Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.
Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.
In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
NALA trial
The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.
Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m2 orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m2 orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The primary endpoints were PFS and OS by blinded, independent, central review.
The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.
The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.
Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043).
The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
Margetuximab-cmkb
Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.
Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.
In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.
The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
SOPHIA trial
SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.
Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.
Co–primary outcome measures were PFS by blinded, independent, central review and OS.
At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).
At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).
Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.
The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.
The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.
Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.
In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
Take-home messages
There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.
The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).
When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Polycystic ovary syndrome: It’s not just about fertility
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at [email protected].
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at [email protected].
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at [email protected].
Addressing today’s racial health inequities requires understanding their roots
The health disparities seen in today’s high rates of Black infant and maternal morbidity and mortality are rooted in health inequities and generational stress dating back centuries in the United States, but today’s obstetricians can make changes in their own practices to address this inequity, according to Haywood L. Brown, MD, professor of ob.gyn. and associate dean of diversity at the Morsani College of Medicine and vice president of institutional equity at the University of South Florida, Tampa.
Dr. Brown delivered his remarks during the Benson and Pamela Harer Seminar on History at the annual meeting of the American College of Obstetricians and Gynecologists on May 2. His talk focused on the origins of perinatal and maternal health inequities and how those original factors play out today in increased maternal and neonatal morbidity and mortality among Black women and their babies.
“Racial and ethnic disparities and inequity in maternal and child health are prevalent and persistent. We have to move beyond the documentation,” Dr. Brown told attendees. “We have to adopt uniform care standards, recognizing our own biases and understanding that the contribution of social determinants of health are important in the care and outcome of women. And we have to work on decreasing the stress of women who give birth.”
Evelyn Nicole Mitchell, MD, faculty chair of the ob.gyn. diversity and inclusion committee at the University of Southern California, found Dr. Brown’s talk compelling and hopes it opens the eyes of others who attended.
“You really have to understand the why behind the problems we have, and it really goes back to slavery and this historical distrust that’s been here from the beginning,” Dr. Mitchell said in an interview. “I hope this allows people to open their eyes and think about this situation from their patients’ shoes, to really put their guard down and explore, ‘how can I contribute to fixing this system that has been here from the beginning?’ I think a lot of people get defensive and think: ‘Oh, I’m not a racist. I just don’t want to talk about this,’ but it’s about a system being racist.” The question then, Dr. Mitchell said, is: “So how do I contribute to that system?”
Dr. Brown frequently returned to the theme of high stress levels in Black mothers contributing to poorer outcomes, such as preterm birth. That stress arises originally from the generational stress brought on by racism and oppression over the centuries but has been compounded by poverty, racial injustice, lack of access to adequate nutrition, lower education levels, environmental factors, and other determinants of health.
“The bottom line, as Dr. Brown said, is that we need to decrease the stress level of Black mothers giving birth,” Dr. Mitchell said. “How can I, as a provider, decrease the stress level of my patients? Well, No. 1, I can identify and eliminate implicit bias that I may harbor.”
Slavery husbandry laid the groundwork for today
The most surprising aspect of Dr. Brown’s lecture for Dr. Mitchell was the fact that enslaved women received a measure of protection that other enslaved people did not to “ensure that they were healthy and that they were able to reproduce in the future,” Dr. Mitchell said. “It was for the wrong reasons – to keep slavery going – but in a sense they were prioritizing Black women to take advantage of their reproductive capacity, compared to nowadays where Black women are facing severe disparities.”
To safeguard enslaved women’s fecundity, plantation owners attempted to reduce stressors in the women’s lives, such as allowing them to cohabitate with a husband and nuclear family, though sexual assault and abuse still occurred. The owners also tracked the enslaved girls’ menstrual cycles after menarche to maximize their “breeding” potential, especially between the ages of 15 and 24. Slave owners delegated older enslaved women as maternity caregivers and midwives, leading to the passing down of midwifery skills through generations of Black American women.
“Pregnant women received the best medical care on the plantation because of the premium placed on reproduction,” Dr. Brown said. Wealthier planters called in doctors for complicated deliveries, which provided J. Marian Sims the ability conduct surgical experiments on Betsey, Lucy, and Anarcha to treat vesicovaginal fistula since fistula “limited her ability to do the maximum work she could in the house or on the plantation,” Dr. Brown said.
After slavery ended, health care access did not improve for Black people. In 1920, there was approximately 1 Black physician for every 3,000 Black people, compared with 1 in 500 for the White population, and grannie midwives continued to be the primary birthing attendants for Black women. Over the next several decades, however, both maternal and infant mortality across all races began steeply dropping. Reasons for the drop included the incorporation of the American Board of Obstetrics and Gynecology in 1930, a shift from home births to hospital births, and the legalization of abortion, which led to an 89% decline in deaths from septic illegal abortions from 1950 to 1973.
Still, Black maternal and infant mortality remained higher than White, and the poverty gap further exacerbated outcomes.
“Substandard maternity care really is the origin of many of the Black maternal and infant morbidity and mortality” complications, such as low birth weight, small for gestational age, growth restriction, and intrauterine starvation, “which we now believe are the origin of things like hypertension, diabetes, and obesity,” Dr. Brown said.
Today, inequities persist because of the systemic racism throughout this history.
“As we talk about health disparities, prematurity, growth restriction, and maternal morbidity, the fetal origins for adult disease in diabetes and hypertension and obesity have generational implications over the last 400 years,” Dr. Brown said. “Generational stress and stresses in lack women from slavery to present times are some of the origins of the things that we see today, including segregation, economic inequities, eugenic sterilizations, the quality of education, and of course, systemic racism on health care access and quality.”
It is this long arc of history that Dr. Mitchell hopes attendees will begin to grasp.
“If you don’t understand all that and have that depth, there’s no way for you to truly understand the problems that are going on and how to solve them,” Dr. Mitchell said. She hopes that especially those who have been more “resistant to accepting these truths” can start to see the big picture. “Hopefully, they can look at it as a systemic problem and then focus on how they can change the system.”
Dr Brown is a contributor to UpToDate and the Merck Manual and serves on the advisory boards of Merck for Mothers Global Women’s Health and BabyScripts. Dr. Mitchell has no disclosures.
The health disparities seen in today’s high rates of Black infant and maternal morbidity and mortality are rooted in health inequities and generational stress dating back centuries in the United States, but today’s obstetricians can make changes in their own practices to address this inequity, according to Haywood L. Brown, MD, professor of ob.gyn. and associate dean of diversity at the Morsani College of Medicine and vice president of institutional equity at the University of South Florida, Tampa.
Dr. Brown delivered his remarks during the Benson and Pamela Harer Seminar on History at the annual meeting of the American College of Obstetricians and Gynecologists on May 2. His talk focused on the origins of perinatal and maternal health inequities and how those original factors play out today in increased maternal and neonatal morbidity and mortality among Black women and their babies.
“Racial and ethnic disparities and inequity in maternal and child health are prevalent and persistent. We have to move beyond the documentation,” Dr. Brown told attendees. “We have to adopt uniform care standards, recognizing our own biases and understanding that the contribution of social determinants of health are important in the care and outcome of women. And we have to work on decreasing the stress of women who give birth.”
Evelyn Nicole Mitchell, MD, faculty chair of the ob.gyn. diversity and inclusion committee at the University of Southern California, found Dr. Brown’s talk compelling and hopes it opens the eyes of others who attended.
“You really have to understand the why behind the problems we have, and it really goes back to slavery and this historical distrust that’s been here from the beginning,” Dr. Mitchell said in an interview. “I hope this allows people to open their eyes and think about this situation from their patients’ shoes, to really put their guard down and explore, ‘how can I contribute to fixing this system that has been here from the beginning?’ I think a lot of people get defensive and think: ‘Oh, I’m not a racist. I just don’t want to talk about this,’ but it’s about a system being racist.” The question then, Dr. Mitchell said, is: “So how do I contribute to that system?”
Dr. Brown frequently returned to the theme of high stress levels in Black mothers contributing to poorer outcomes, such as preterm birth. That stress arises originally from the generational stress brought on by racism and oppression over the centuries but has been compounded by poverty, racial injustice, lack of access to adequate nutrition, lower education levels, environmental factors, and other determinants of health.
“The bottom line, as Dr. Brown said, is that we need to decrease the stress level of Black mothers giving birth,” Dr. Mitchell said. “How can I, as a provider, decrease the stress level of my patients? Well, No. 1, I can identify and eliminate implicit bias that I may harbor.”
Slavery husbandry laid the groundwork for today
The most surprising aspect of Dr. Brown’s lecture for Dr. Mitchell was the fact that enslaved women received a measure of protection that other enslaved people did not to “ensure that they were healthy and that they were able to reproduce in the future,” Dr. Mitchell said. “It was for the wrong reasons – to keep slavery going – but in a sense they were prioritizing Black women to take advantage of their reproductive capacity, compared to nowadays where Black women are facing severe disparities.”
To safeguard enslaved women’s fecundity, plantation owners attempted to reduce stressors in the women’s lives, such as allowing them to cohabitate with a husband and nuclear family, though sexual assault and abuse still occurred. The owners also tracked the enslaved girls’ menstrual cycles after menarche to maximize their “breeding” potential, especially between the ages of 15 and 24. Slave owners delegated older enslaved women as maternity caregivers and midwives, leading to the passing down of midwifery skills through generations of Black American women.
“Pregnant women received the best medical care on the plantation because of the premium placed on reproduction,” Dr. Brown said. Wealthier planters called in doctors for complicated deliveries, which provided J. Marian Sims the ability conduct surgical experiments on Betsey, Lucy, and Anarcha to treat vesicovaginal fistula since fistula “limited her ability to do the maximum work she could in the house or on the plantation,” Dr. Brown said.
After slavery ended, health care access did not improve for Black people. In 1920, there was approximately 1 Black physician for every 3,000 Black people, compared with 1 in 500 for the White population, and grannie midwives continued to be the primary birthing attendants for Black women. Over the next several decades, however, both maternal and infant mortality across all races began steeply dropping. Reasons for the drop included the incorporation of the American Board of Obstetrics and Gynecology in 1930, a shift from home births to hospital births, and the legalization of abortion, which led to an 89% decline in deaths from septic illegal abortions from 1950 to 1973.
Still, Black maternal and infant mortality remained higher than White, and the poverty gap further exacerbated outcomes.
“Substandard maternity care really is the origin of many of the Black maternal and infant morbidity and mortality” complications, such as low birth weight, small for gestational age, growth restriction, and intrauterine starvation, “which we now believe are the origin of things like hypertension, diabetes, and obesity,” Dr. Brown said.
Today, inequities persist because of the systemic racism throughout this history.
“As we talk about health disparities, prematurity, growth restriction, and maternal morbidity, the fetal origins for adult disease in diabetes and hypertension and obesity have generational implications over the last 400 years,” Dr. Brown said. “Generational stress and stresses in lack women from slavery to present times are some of the origins of the things that we see today, including segregation, economic inequities, eugenic sterilizations, the quality of education, and of course, systemic racism on health care access and quality.”
It is this long arc of history that Dr. Mitchell hopes attendees will begin to grasp.
“If you don’t understand all that and have that depth, there’s no way for you to truly understand the problems that are going on and how to solve them,” Dr. Mitchell said. She hopes that especially those who have been more “resistant to accepting these truths” can start to see the big picture. “Hopefully, they can look at it as a systemic problem and then focus on how they can change the system.”
Dr Brown is a contributor to UpToDate and the Merck Manual and serves on the advisory boards of Merck for Mothers Global Women’s Health and BabyScripts. Dr. Mitchell has no disclosures.
The health disparities seen in today’s high rates of Black infant and maternal morbidity and mortality are rooted in health inequities and generational stress dating back centuries in the United States, but today’s obstetricians can make changes in their own practices to address this inequity, according to Haywood L. Brown, MD, professor of ob.gyn. and associate dean of diversity at the Morsani College of Medicine and vice president of institutional equity at the University of South Florida, Tampa.
Dr. Brown delivered his remarks during the Benson and Pamela Harer Seminar on History at the annual meeting of the American College of Obstetricians and Gynecologists on May 2. His talk focused on the origins of perinatal and maternal health inequities and how those original factors play out today in increased maternal and neonatal morbidity and mortality among Black women and their babies.
“Racial and ethnic disparities and inequity in maternal and child health are prevalent and persistent. We have to move beyond the documentation,” Dr. Brown told attendees. “We have to adopt uniform care standards, recognizing our own biases and understanding that the contribution of social determinants of health are important in the care and outcome of women. And we have to work on decreasing the stress of women who give birth.”
Evelyn Nicole Mitchell, MD, faculty chair of the ob.gyn. diversity and inclusion committee at the University of Southern California, found Dr. Brown’s talk compelling and hopes it opens the eyes of others who attended.
“You really have to understand the why behind the problems we have, and it really goes back to slavery and this historical distrust that’s been here from the beginning,” Dr. Mitchell said in an interview. “I hope this allows people to open their eyes and think about this situation from their patients’ shoes, to really put their guard down and explore, ‘how can I contribute to fixing this system that has been here from the beginning?’ I think a lot of people get defensive and think: ‘Oh, I’m not a racist. I just don’t want to talk about this,’ but it’s about a system being racist.” The question then, Dr. Mitchell said, is: “So how do I contribute to that system?”
Dr. Brown frequently returned to the theme of high stress levels in Black mothers contributing to poorer outcomes, such as preterm birth. That stress arises originally from the generational stress brought on by racism and oppression over the centuries but has been compounded by poverty, racial injustice, lack of access to adequate nutrition, lower education levels, environmental factors, and other determinants of health.
“The bottom line, as Dr. Brown said, is that we need to decrease the stress level of Black mothers giving birth,” Dr. Mitchell said. “How can I, as a provider, decrease the stress level of my patients? Well, No. 1, I can identify and eliminate implicit bias that I may harbor.”
Slavery husbandry laid the groundwork for today
The most surprising aspect of Dr. Brown’s lecture for Dr. Mitchell was the fact that enslaved women received a measure of protection that other enslaved people did not to “ensure that they were healthy and that they were able to reproduce in the future,” Dr. Mitchell said. “It was for the wrong reasons – to keep slavery going – but in a sense they were prioritizing Black women to take advantage of their reproductive capacity, compared to nowadays where Black women are facing severe disparities.”
To safeguard enslaved women’s fecundity, plantation owners attempted to reduce stressors in the women’s lives, such as allowing them to cohabitate with a husband and nuclear family, though sexual assault and abuse still occurred. The owners also tracked the enslaved girls’ menstrual cycles after menarche to maximize their “breeding” potential, especially between the ages of 15 and 24. Slave owners delegated older enslaved women as maternity caregivers and midwives, leading to the passing down of midwifery skills through generations of Black American women.
“Pregnant women received the best medical care on the plantation because of the premium placed on reproduction,” Dr. Brown said. Wealthier planters called in doctors for complicated deliveries, which provided J. Marian Sims the ability conduct surgical experiments on Betsey, Lucy, and Anarcha to treat vesicovaginal fistula since fistula “limited her ability to do the maximum work she could in the house or on the plantation,” Dr. Brown said.
After slavery ended, health care access did not improve for Black people. In 1920, there was approximately 1 Black physician for every 3,000 Black people, compared with 1 in 500 for the White population, and grannie midwives continued to be the primary birthing attendants for Black women. Over the next several decades, however, both maternal and infant mortality across all races began steeply dropping. Reasons for the drop included the incorporation of the American Board of Obstetrics and Gynecology in 1930, a shift from home births to hospital births, and the legalization of abortion, which led to an 89% decline in deaths from septic illegal abortions from 1950 to 1973.
Still, Black maternal and infant mortality remained higher than White, and the poverty gap further exacerbated outcomes.
“Substandard maternity care really is the origin of many of the Black maternal and infant morbidity and mortality” complications, such as low birth weight, small for gestational age, growth restriction, and intrauterine starvation, “which we now believe are the origin of things like hypertension, diabetes, and obesity,” Dr. Brown said.
Today, inequities persist because of the systemic racism throughout this history.
“As we talk about health disparities, prematurity, growth restriction, and maternal morbidity, the fetal origins for adult disease in diabetes and hypertension and obesity have generational implications over the last 400 years,” Dr. Brown said. “Generational stress and stresses in lack women from slavery to present times are some of the origins of the things that we see today, including segregation, economic inequities, eugenic sterilizations, the quality of education, and of course, systemic racism on health care access and quality.”
It is this long arc of history that Dr. Mitchell hopes attendees will begin to grasp.
“If you don’t understand all that and have that depth, there’s no way for you to truly understand the problems that are going on and how to solve them,” Dr. Mitchell said. She hopes that especially those who have been more “resistant to accepting these truths” can start to see the big picture. “Hopefully, they can look at it as a systemic problem and then focus on how they can change the system.”
Dr Brown is a contributor to UpToDate and the Merck Manual and serves on the advisory boards of Merck for Mothers Global Women’s Health and BabyScripts. Dr. Mitchell has no disclosures.
FROM ACOG 2021
Lesions in pelvis may be ‘tip of the iceberg’ in endometriosis
Recognizing the systemic effects of endometriosis may help doctors better understand the experiences of patients with the disease and guide the approach to diagnosis and treatment, according to the president of the American Society for Reproductive Medicine (ASRM).
, Hugh S. Taylor, MD, said at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Its systemic manifestations may explain why women with endometriosis tend to have a lower body mass index, compared with women without the disease, Dr. Taylor said.
“Stem cells, microRNAs, and generalized inflammation are some of the mechanisms that mediate these long-range effects on distant organ systems,” he said.
Studies have indicated that lesions in the pelvis do not fully explain the disease, and investigators continue to elucidate how “endometriosis that we see in the pelvis is really just the tip of the iceberg,” said Dr. Taylor, chair of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.
Pain, including dysmenorrhea, pelvic pain, and dyspareunia, “can be just as bad with ... stage 1 disease as it can be with stage 4 disease,” he said.
Some patients may not have pain, but have infertility. Other women are asymptomatic, and doctors find endometriosis incidentally.
One common definition of endometriosis – ectopic endometrial glands and stroma predominantly caused by retrograde menstruation – “probably overly simplifies this complex disease,” said Dr. Taylor, who reviewed the current understanding of endometriosis in an article in The Lancet. “The lesions in the pelvis are important. We see them. We treat them. But endometriosis has ... effects throughout the body.”
Dr. Taylor’s research group has shown that stem cells are a potential source of endometriosis. “There are cells from the endometriosis that can be found traveling in the circulation,” but their effects are unclear, he said.
Levels of several microRNAs may be increased or decreased in women with endometriosis, and these altered levels may induce the production of inflammatory cytokines. They also may serve as the basis of a blood test for endometriosis that could be ready for clinical use soon, Dr. Taylor said.
In a mouse model of endometriosis, the disease changes the electrophysiology of the brain and behavior. “We see changes in anxiety induced by endometriosis. We see changes in pain sensitivity induced by endometriosis. And we also see an increase in depression induced by endometriosis in this animal model,” Dr. Taylor said.
Although surgical therapy treats local disease, medical therapy may be needed to treat the systemic manifestations.
During a question-and-answer period after the presentation, Marcelle I. Cedars, MD, asked whether analgesic and hormonal management may be sufficient when a woman has suspected or laparoscopically diagnosed endometriosis and pain is the primary complaint.
“Given the understanding of endometriosis, how would you suggest approaching treatment?” asked Dr. Cedars, president elect of the ASRM and director of the division of reproductive endocrinology and infertility at the University of California, San Francisco.
Analgesic and hormonal therapies remain “the best treatments we have,” Dr. Taylor said. He starts treatment with an oral contraceptive and a nonsteroidal anti-inflammatory medication – “not only for pain relief but to tamp some of the inflammation associated with endometriosis,” he said. If an oral contraceptive does not work, a gonadotropin-releasing hormone antagonist typically is the next step.
Dr. Taylor has disclosed ties to Dot Lab and AbbVie. Dr. Cedars had no disclosures.
Recognizing the systemic effects of endometriosis may help doctors better understand the experiences of patients with the disease and guide the approach to diagnosis and treatment, according to the president of the American Society for Reproductive Medicine (ASRM).
, Hugh S. Taylor, MD, said at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Its systemic manifestations may explain why women with endometriosis tend to have a lower body mass index, compared with women without the disease, Dr. Taylor said.
“Stem cells, microRNAs, and generalized inflammation are some of the mechanisms that mediate these long-range effects on distant organ systems,” he said.
Studies have indicated that lesions in the pelvis do not fully explain the disease, and investigators continue to elucidate how “endometriosis that we see in the pelvis is really just the tip of the iceberg,” said Dr. Taylor, chair of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.
Pain, including dysmenorrhea, pelvic pain, and dyspareunia, “can be just as bad with ... stage 1 disease as it can be with stage 4 disease,” he said.
Some patients may not have pain, but have infertility. Other women are asymptomatic, and doctors find endometriosis incidentally.
One common definition of endometriosis – ectopic endometrial glands and stroma predominantly caused by retrograde menstruation – “probably overly simplifies this complex disease,” said Dr. Taylor, who reviewed the current understanding of endometriosis in an article in The Lancet. “The lesions in the pelvis are important. We see them. We treat them. But endometriosis has ... effects throughout the body.”
Dr. Taylor’s research group has shown that stem cells are a potential source of endometriosis. “There are cells from the endometriosis that can be found traveling in the circulation,” but their effects are unclear, he said.
Levels of several microRNAs may be increased or decreased in women with endometriosis, and these altered levels may induce the production of inflammatory cytokines. They also may serve as the basis of a blood test for endometriosis that could be ready for clinical use soon, Dr. Taylor said.
In a mouse model of endometriosis, the disease changes the electrophysiology of the brain and behavior. “We see changes in anxiety induced by endometriosis. We see changes in pain sensitivity induced by endometriosis. And we also see an increase in depression induced by endometriosis in this animal model,” Dr. Taylor said.
Although surgical therapy treats local disease, medical therapy may be needed to treat the systemic manifestations.
During a question-and-answer period after the presentation, Marcelle I. Cedars, MD, asked whether analgesic and hormonal management may be sufficient when a woman has suspected or laparoscopically diagnosed endometriosis and pain is the primary complaint.
“Given the understanding of endometriosis, how would you suggest approaching treatment?” asked Dr. Cedars, president elect of the ASRM and director of the division of reproductive endocrinology and infertility at the University of California, San Francisco.
Analgesic and hormonal therapies remain “the best treatments we have,” Dr. Taylor said. He starts treatment with an oral contraceptive and a nonsteroidal anti-inflammatory medication – “not only for pain relief but to tamp some of the inflammation associated with endometriosis,” he said. If an oral contraceptive does not work, a gonadotropin-releasing hormone antagonist typically is the next step.
Dr. Taylor has disclosed ties to Dot Lab and AbbVie. Dr. Cedars had no disclosures.
Recognizing the systemic effects of endometriosis may help doctors better understand the experiences of patients with the disease and guide the approach to diagnosis and treatment, according to the president of the American Society for Reproductive Medicine (ASRM).
, Hugh S. Taylor, MD, said at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Its systemic manifestations may explain why women with endometriosis tend to have a lower body mass index, compared with women without the disease, Dr. Taylor said.
“Stem cells, microRNAs, and generalized inflammation are some of the mechanisms that mediate these long-range effects on distant organ systems,” he said.
Studies have indicated that lesions in the pelvis do not fully explain the disease, and investigators continue to elucidate how “endometriosis that we see in the pelvis is really just the tip of the iceberg,” said Dr. Taylor, chair of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.
Pain, including dysmenorrhea, pelvic pain, and dyspareunia, “can be just as bad with ... stage 1 disease as it can be with stage 4 disease,” he said.
Some patients may not have pain, but have infertility. Other women are asymptomatic, and doctors find endometriosis incidentally.
One common definition of endometriosis – ectopic endometrial glands and stroma predominantly caused by retrograde menstruation – “probably overly simplifies this complex disease,” said Dr. Taylor, who reviewed the current understanding of endometriosis in an article in The Lancet. “The lesions in the pelvis are important. We see them. We treat them. But endometriosis has ... effects throughout the body.”
Dr. Taylor’s research group has shown that stem cells are a potential source of endometriosis. “There are cells from the endometriosis that can be found traveling in the circulation,” but their effects are unclear, he said.
Levels of several microRNAs may be increased or decreased in women with endometriosis, and these altered levels may induce the production of inflammatory cytokines. They also may serve as the basis of a blood test for endometriosis that could be ready for clinical use soon, Dr. Taylor said.
In a mouse model of endometriosis, the disease changes the electrophysiology of the brain and behavior. “We see changes in anxiety induced by endometriosis. We see changes in pain sensitivity induced by endometriosis. And we also see an increase in depression induced by endometriosis in this animal model,” Dr. Taylor said.
Although surgical therapy treats local disease, medical therapy may be needed to treat the systemic manifestations.
During a question-and-answer period after the presentation, Marcelle I. Cedars, MD, asked whether analgesic and hormonal management may be sufficient when a woman has suspected or laparoscopically diagnosed endometriosis and pain is the primary complaint.
“Given the understanding of endometriosis, how would you suggest approaching treatment?” asked Dr. Cedars, president elect of the ASRM and director of the division of reproductive endocrinology and infertility at the University of California, San Francisco.
Analgesic and hormonal therapies remain “the best treatments we have,” Dr. Taylor said. He starts treatment with an oral contraceptive and a nonsteroidal anti-inflammatory medication – “not only for pain relief but to tamp some of the inflammation associated with endometriosis,” he said. If an oral contraceptive does not work, a gonadotropin-releasing hormone antagonist typically is the next step.
Dr. Taylor has disclosed ties to Dot Lab and AbbVie. Dr. Cedars had no disclosures.
FROM ACOG 2021
Primary ovarian insufficiency requires long-term management of sequelae
Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.
Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.
“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.
Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.
Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.
Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
Etiology of POI and associated conditions
A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.
Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.
Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.
Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.
“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.
To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:
- Menstrual irregularity for at least 3-4 months
- Test FSH and estradiol
- Test hCG, TSH, and prolactin
- If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.
However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
Long-term consequences of POI
Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.
“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
No interventions have been shown to increase ovarian activity
Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.
“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.
For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.
Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.
“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.
Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
Treatment of POI
Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.
The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.
Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.
Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”
Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.
Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.
Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.
“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.
Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.
Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.
Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
Etiology of POI and associated conditions
A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.
Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.
Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.
Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.
“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.
To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:
- Menstrual irregularity for at least 3-4 months
- Test FSH and estradiol
- Test hCG, TSH, and prolactin
- If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.
However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
Long-term consequences of POI
Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.
“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
No interventions have been shown to increase ovarian activity
Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.
“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.
For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.
Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.
“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.
Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
Treatment of POI
Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.
The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.
Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.
Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”
Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.
Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.
Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.
“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.
Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.
Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.
Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
Etiology of POI and associated conditions
A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.
Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.
Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.
Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.
“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.
To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:
- Menstrual irregularity for at least 3-4 months
- Test FSH and estradiol
- Test hCG, TSH, and prolactin
- If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.
However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
Long-term consequences of POI
Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.
“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
No interventions have been shown to increase ovarian activity
Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.
“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.
For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.
Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.
“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.
Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
Treatment of POI
Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.
The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.
Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.
Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”
Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.
FROM ACOG 2021
Heavy cannabis use in pregnancy correlates with risks to infant
Cannabis use that interferes with a woman’s ability to function during pregnancy is a risk factor for severe health problems in the child, new research indicates.
Pregnant women with cannabis use disorder are more likely to have children with low birth weights and children who die within 1 year of birth, compared with matched controls, according to a study published online in Addiction.
The death rate among infants exposed to prenatal cannabis use disorder was 0.98%, compared with 0.75% among infants whose mothers did not have this diagnosis.
Cannabis use disorder during pregnancy “has increased dramatically in the past two decades,” but few studies have examined the health impacts on offspring, study author Yuyan Shi, PhD, said in an interview. “It is particularly concerning in states with cannabis legalization where cannabis is increasingly available.”
Dr. Shi, a researcher at the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, and colleagues analyzed data from more than 4.8 million mothers who delivered a live singleton birth in California between 2001 and 2012 and their infants. They focused on 20,237 mothers who had a diagnosis of cannabis use disorder at delivery. The disorder is defined by continued use of the drug despite impairments in physical, psychological, and social functioning.
The researchers matched mothers with cannabis use disorder 1:2 to mothers who did not have this diagnosis. They aimed to balance factors such as maternal age, educational attainment, health insurance, physical and mental health conditions, prenatal care, and alcohol and opioid use disorder.
An increasingly common diagnosis
Over the study period, the rate of cannabis use disorder increased from 2.8 cases per 1,000 deliveries in 2001 to 6.9 cases per 1,000 deliveries in 2012.
Cannabis use disorder was associated with increased odds of preterm birth (odds ratio, 1.06), small for gestational age (OR, 1.13), low birth weight (OR, 1.13), and death within 1 year of birth (OR, 1.35), according to the researchers’ estimates. Cannabis use disorder was associated with lower odds of hospitalization within 1 year of birth, however (OR, 0.91).
“The most notable observation is that exposed infants were 35% more likely to die within 1 year of birth than unexposed infants,” Dr. Shi and colleagues wrote. More research is needed to understand the causes of death at different stages of infancy, they said.
The results “imply that cannabis use disorder screening as well as appropriate education, counseling, or referral to substance abuse treatment services should be encouraged among pregnant women,” Dr. Shi said.
The study does not establish that cannabis use disorder causes adverse effects, and it is not clear how the results might apply to mothers who use cannabis but do not meet diagnostic criteria for the disorder, the authors noted.
“Presumably the health consequences of mothers who use cannabis but do not meet the criteria ... are less severe than mothers with cannabis use disorder,” Dr. Shi said. “Unfortunately, no research has been conducted to test this hypothesis.”
Enough data to recommend abstaining
Many clinicians may not feel equipped to make a diagnosis of cannabis use disorder, said Jamie Lo, MD, assistant professor of obstetrics and gynecology at Oregon Health and Science University in Portland.
Although many clinicians ask patients about substance use in general, specifically screening for cannabis use is not necessarily routine practice. “I think people are starting to adopt that, but it probably will take a little bit of time,” Dr. Lo said.
Dr. Lo, who was not involved in the study, researches the effects of marijuana during pregnancy.
Confounding factors such as frequent co-use of tobacco have so far made it “difficult to suss out” whether observed effects are directly from cannabis use, other substances or exposures, or a combination, said Dr. Lo. The possibility that stigma may lead to inaccurate self-reporting poses another challenge. And the range of cannabis delivery devices further complicates matters.
“It is hard to compare smoking a bowl versus a joint versus using the oils or CBD or edibles,” Dr. Lo said. The data regarding cigarettes and alcohol are cleaner and more precise, in comparison.
Still, federal agencies and professional societies agree that “what we do know is enough to recommend that pregnant women abstain from using cannabis during pregnancy,” Dr. Lo said.
The National Institute on Drug Abuse, which funded the study, said the results add to the evidence that prenatal exposure to cannabis may be associated with poor birth outcomes and infant health.
“While we cannot establish that cannabis use caused negative outcomes in this study, these data reinforce the case for caution around using cannabis during pregnancy,” Nora D. Volkow, MD, the director of the agency, said in a news release.
“Careful analysis of data like these is one way we can responsibly study how cannabis use affects the developing child, all while a natural experiment is playing out across our country in places where cannabis is becoming widely available to pregnant consumers.”
The study authors and Dr. Lo had no disclosures.
Cannabis use that interferes with a woman’s ability to function during pregnancy is a risk factor for severe health problems in the child, new research indicates.
Pregnant women with cannabis use disorder are more likely to have children with low birth weights and children who die within 1 year of birth, compared with matched controls, according to a study published online in Addiction.
The death rate among infants exposed to prenatal cannabis use disorder was 0.98%, compared with 0.75% among infants whose mothers did not have this diagnosis.
Cannabis use disorder during pregnancy “has increased dramatically in the past two decades,” but few studies have examined the health impacts on offspring, study author Yuyan Shi, PhD, said in an interview. “It is particularly concerning in states with cannabis legalization where cannabis is increasingly available.”
Dr. Shi, a researcher at the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, and colleagues analyzed data from more than 4.8 million mothers who delivered a live singleton birth in California between 2001 and 2012 and their infants. They focused on 20,237 mothers who had a diagnosis of cannabis use disorder at delivery. The disorder is defined by continued use of the drug despite impairments in physical, psychological, and social functioning.
The researchers matched mothers with cannabis use disorder 1:2 to mothers who did not have this diagnosis. They aimed to balance factors such as maternal age, educational attainment, health insurance, physical and mental health conditions, prenatal care, and alcohol and opioid use disorder.
An increasingly common diagnosis
Over the study period, the rate of cannabis use disorder increased from 2.8 cases per 1,000 deliveries in 2001 to 6.9 cases per 1,000 deliveries in 2012.
Cannabis use disorder was associated with increased odds of preterm birth (odds ratio, 1.06), small for gestational age (OR, 1.13), low birth weight (OR, 1.13), and death within 1 year of birth (OR, 1.35), according to the researchers’ estimates. Cannabis use disorder was associated with lower odds of hospitalization within 1 year of birth, however (OR, 0.91).
“The most notable observation is that exposed infants were 35% more likely to die within 1 year of birth than unexposed infants,” Dr. Shi and colleagues wrote. More research is needed to understand the causes of death at different stages of infancy, they said.
The results “imply that cannabis use disorder screening as well as appropriate education, counseling, or referral to substance abuse treatment services should be encouraged among pregnant women,” Dr. Shi said.
The study does not establish that cannabis use disorder causes adverse effects, and it is not clear how the results might apply to mothers who use cannabis but do not meet diagnostic criteria for the disorder, the authors noted.
“Presumably the health consequences of mothers who use cannabis but do not meet the criteria ... are less severe than mothers with cannabis use disorder,” Dr. Shi said. “Unfortunately, no research has been conducted to test this hypothesis.”
Enough data to recommend abstaining
Many clinicians may not feel equipped to make a diagnosis of cannabis use disorder, said Jamie Lo, MD, assistant professor of obstetrics and gynecology at Oregon Health and Science University in Portland.
Although many clinicians ask patients about substance use in general, specifically screening for cannabis use is not necessarily routine practice. “I think people are starting to adopt that, but it probably will take a little bit of time,” Dr. Lo said.
Dr. Lo, who was not involved in the study, researches the effects of marijuana during pregnancy.
Confounding factors such as frequent co-use of tobacco have so far made it “difficult to suss out” whether observed effects are directly from cannabis use, other substances or exposures, or a combination, said Dr. Lo. The possibility that stigma may lead to inaccurate self-reporting poses another challenge. And the range of cannabis delivery devices further complicates matters.
“It is hard to compare smoking a bowl versus a joint versus using the oils or CBD or edibles,” Dr. Lo said. The data regarding cigarettes and alcohol are cleaner and more precise, in comparison.
Still, federal agencies and professional societies agree that “what we do know is enough to recommend that pregnant women abstain from using cannabis during pregnancy,” Dr. Lo said.
The National Institute on Drug Abuse, which funded the study, said the results add to the evidence that prenatal exposure to cannabis may be associated with poor birth outcomes and infant health.
“While we cannot establish that cannabis use caused negative outcomes in this study, these data reinforce the case for caution around using cannabis during pregnancy,” Nora D. Volkow, MD, the director of the agency, said in a news release.
“Careful analysis of data like these is one way we can responsibly study how cannabis use affects the developing child, all while a natural experiment is playing out across our country in places where cannabis is becoming widely available to pregnant consumers.”
The study authors and Dr. Lo had no disclosures.
Cannabis use that interferes with a woman’s ability to function during pregnancy is a risk factor for severe health problems in the child, new research indicates.
Pregnant women with cannabis use disorder are more likely to have children with low birth weights and children who die within 1 year of birth, compared with matched controls, according to a study published online in Addiction.
The death rate among infants exposed to prenatal cannabis use disorder was 0.98%, compared with 0.75% among infants whose mothers did not have this diagnosis.
Cannabis use disorder during pregnancy “has increased dramatically in the past two decades,” but few studies have examined the health impacts on offspring, study author Yuyan Shi, PhD, said in an interview. “It is particularly concerning in states with cannabis legalization where cannabis is increasingly available.”
Dr. Shi, a researcher at the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, and colleagues analyzed data from more than 4.8 million mothers who delivered a live singleton birth in California between 2001 and 2012 and their infants. They focused on 20,237 mothers who had a diagnosis of cannabis use disorder at delivery. The disorder is defined by continued use of the drug despite impairments in physical, psychological, and social functioning.
The researchers matched mothers with cannabis use disorder 1:2 to mothers who did not have this diagnosis. They aimed to balance factors such as maternal age, educational attainment, health insurance, physical and mental health conditions, prenatal care, and alcohol and opioid use disorder.
An increasingly common diagnosis
Over the study period, the rate of cannabis use disorder increased from 2.8 cases per 1,000 deliveries in 2001 to 6.9 cases per 1,000 deliveries in 2012.
Cannabis use disorder was associated with increased odds of preterm birth (odds ratio, 1.06), small for gestational age (OR, 1.13), low birth weight (OR, 1.13), and death within 1 year of birth (OR, 1.35), according to the researchers’ estimates. Cannabis use disorder was associated with lower odds of hospitalization within 1 year of birth, however (OR, 0.91).
“The most notable observation is that exposed infants were 35% more likely to die within 1 year of birth than unexposed infants,” Dr. Shi and colleagues wrote. More research is needed to understand the causes of death at different stages of infancy, they said.
The results “imply that cannabis use disorder screening as well as appropriate education, counseling, or referral to substance abuse treatment services should be encouraged among pregnant women,” Dr. Shi said.
The study does not establish that cannabis use disorder causes adverse effects, and it is not clear how the results might apply to mothers who use cannabis but do not meet diagnostic criteria for the disorder, the authors noted.
“Presumably the health consequences of mothers who use cannabis but do not meet the criteria ... are less severe than mothers with cannabis use disorder,” Dr. Shi said. “Unfortunately, no research has been conducted to test this hypothesis.”
Enough data to recommend abstaining
Many clinicians may not feel equipped to make a diagnosis of cannabis use disorder, said Jamie Lo, MD, assistant professor of obstetrics and gynecology at Oregon Health and Science University in Portland.
Although many clinicians ask patients about substance use in general, specifically screening for cannabis use is not necessarily routine practice. “I think people are starting to adopt that, but it probably will take a little bit of time,” Dr. Lo said.
Dr. Lo, who was not involved in the study, researches the effects of marijuana during pregnancy.
Confounding factors such as frequent co-use of tobacco have so far made it “difficult to suss out” whether observed effects are directly from cannabis use, other substances or exposures, or a combination, said Dr. Lo. The possibility that stigma may lead to inaccurate self-reporting poses another challenge. And the range of cannabis delivery devices further complicates matters.
“It is hard to compare smoking a bowl versus a joint versus using the oils or CBD or edibles,” Dr. Lo said. The data regarding cigarettes and alcohol are cleaner and more precise, in comparison.
Still, federal agencies and professional societies agree that “what we do know is enough to recommend that pregnant women abstain from using cannabis during pregnancy,” Dr. Lo said.
The National Institute on Drug Abuse, which funded the study, said the results add to the evidence that prenatal exposure to cannabis may be associated with poor birth outcomes and infant health.
“While we cannot establish that cannabis use caused negative outcomes in this study, these data reinforce the case for caution around using cannabis during pregnancy,” Nora D. Volkow, MD, the director of the agency, said in a news release.
“Careful analysis of data like these is one way we can responsibly study how cannabis use affects the developing child, all while a natural experiment is playing out across our country in places where cannabis is becoming widely available to pregnant consumers.”
The study authors and Dr. Lo had no disclosures.
55 new chemicals found in pregnant women, their newborns
Fifty-five chemicals never before reported in humans were found in pregnant women, according to a study from the University of California, San Francisco. The chemicals likely come from consumer products or industrial sources, researchers say.
Findings were published online in Environmental Science and Technology.
Co-first authors Aolin Wang, PhD, and Dimitri Panagopoulos Abrahamsson, PhD, postdoctoral fellows in UCSF’s obstetrics and gynecology department, and colleagues found 109 chemicals in the blood of pregnant women, including 42 “mystery chemicals” whose sources and uses are not known.
The chemicals were also found in their newborns, tests from umbilical cord blood show, suggesting the chemicals cross through the placenta.
Among the chemicals, 40 are used as plasticizers, 28 are used in cosmetics, another 25 are used in consumer products, 29 as pharmaceuticals, 23 as pesticides, three as flame retardants, and seven are PFAS [per- and polyfluoroalkyl substances] compounds used in multiple applications including carpeting and upholstery, the authors report.
Senior author Tracey Woodruff, PhD, MPH, characterized their discoveries as “disturbing.”
She told this news organization that it’s not only frustrating to know the chemicals are present but to know so little about them.
“We know it’s a chemical registered to be manufactured, and it’s used in commerce, but we don’t know where,” she explained. “That’s very disturbing, that we can’t trace them, and that shows a failure in public policy and government.”
“Exposures are occurring without our consent,” said Ms. Woodruff, a former U.S. Environmental Protection Agency scientist, who directs the Program on Reproductive Health and the Environment (PRHE) and the Environmental Research and Translation for Health (EaRTH) Center, both at UCSF.
She said researchers know from previous studies that when the U.S. government acts to remove harmful chemicals from the marketplace, the levels of those chemicals measured in people drop.
“Examples include lead, certain PFAS, flame retardant chemicals, and certain phthalates,” she said. “So public policies can be effective in preventing exposures that can be harmful.”
Technological advances led to the discoveries
The team used high-resolution mass spectrometry (HRMS) to identify human-made chemicals in people.
Dr. Abrahamsson said in an interview that the technology is relatively new in research and had not previously been used to scan for chemicals in pregnant women and their infants.
Because scientists often study what other scientists have studied, he said, the same chemicals tend to get attention. The wider scope made possible by the new technology helps illumine where to focus future research, he said.
A benefit of the technology is that now researchers don’t have to know which chemicals they are looking for when they scan blood samples, but they can observe whatever appears, he said.
Ms. Woodruff said, “We hope this is further data and evidence that support government policies that require industries to tell us where they are using their chemicals and how we might be exposed to them.”
She said this research will also help identify which chemicals to prioritize for monitoring in the environment.
Average age of the women in the study was 32 years. Nearly half were Hispanic; 37% were non-Hispanic Whites; and 17% were non-Hispanic Asians, Pacific Islanders, and African Americans. Half of the participants were born outside the United States and had lived in the U.S. for an average 22 years.
Sean Palfrey, MD, a professor of clinical pediatrics and public health at Boston University, said more chemical discoveries like these will come as technology continues to evolve.
Dr. Palfrey, who was not involved in the study, agrees with the authors that there is a lack of oversight as to what substances are used in products.
“Our industrial regulations are very poor and therefore our industries get away with using new and untested substances in their products,” he told this news organization.
“This lack of regulation is really important when it results in us not recognizing that known and serious toxins are being put into foods or other products, or when a new class of toxin has been invented which is a serious poison. Most of the toxins, though, are discovered in products in very low levels,” he said.
Dr. Palfrey said, however, that focus should stay on the known and serious toxins that seep into the environment from common products.
“It has taken us decades to ban certain flame retardants from home products,” he said. “TOSCA [the Toxic Substances Control Act passed by Congress in 1976] was too limited when it was passed decades ago and is now fearfully out of date. Unless we discover a COVID among the toxins discovered in studies like this, we should focus on the big stuff.”
The authors and Dr. Palfrey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Fifty-five chemicals never before reported in humans were found in pregnant women, according to a study from the University of California, San Francisco. The chemicals likely come from consumer products or industrial sources, researchers say.
Findings were published online in Environmental Science and Technology.
Co-first authors Aolin Wang, PhD, and Dimitri Panagopoulos Abrahamsson, PhD, postdoctoral fellows in UCSF’s obstetrics and gynecology department, and colleagues found 109 chemicals in the blood of pregnant women, including 42 “mystery chemicals” whose sources and uses are not known.
The chemicals were also found in their newborns, tests from umbilical cord blood show, suggesting the chemicals cross through the placenta.
Among the chemicals, 40 are used as plasticizers, 28 are used in cosmetics, another 25 are used in consumer products, 29 as pharmaceuticals, 23 as pesticides, three as flame retardants, and seven are PFAS [per- and polyfluoroalkyl substances] compounds used in multiple applications including carpeting and upholstery, the authors report.
Senior author Tracey Woodruff, PhD, MPH, characterized their discoveries as “disturbing.”
She told this news organization that it’s not only frustrating to know the chemicals are present but to know so little about them.
“We know it’s a chemical registered to be manufactured, and it’s used in commerce, but we don’t know where,” she explained. “That’s very disturbing, that we can’t trace them, and that shows a failure in public policy and government.”
“Exposures are occurring without our consent,” said Ms. Woodruff, a former U.S. Environmental Protection Agency scientist, who directs the Program on Reproductive Health and the Environment (PRHE) and the Environmental Research and Translation for Health (EaRTH) Center, both at UCSF.
She said researchers know from previous studies that when the U.S. government acts to remove harmful chemicals from the marketplace, the levels of those chemicals measured in people drop.
“Examples include lead, certain PFAS, flame retardant chemicals, and certain phthalates,” she said. “So public policies can be effective in preventing exposures that can be harmful.”
Technological advances led to the discoveries
The team used high-resolution mass spectrometry (HRMS) to identify human-made chemicals in people.
Dr. Abrahamsson said in an interview that the technology is relatively new in research and had not previously been used to scan for chemicals in pregnant women and their infants.
Because scientists often study what other scientists have studied, he said, the same chemicals tend to get attention. The wider scope made possible by the new technology helps illumine where to focus future research, he said.
A benefit of the technology is that now researchers don’t have to know which chemicals they are looking for when they scan blood samples, but they can observe whatever appears, he said.
Ms. Woodruff said, “We hope this is further data and evidence that support government policies that require industries to tell us where they are using their chemicals and how we might be exposed to them.”
She said this research will also help identify which chemicals to prioritize for monitoring in the environment.
Average age of the women in the study was 32 years. Nearly half were Hispanic; 37% were non-Hispanic Whites; and 17% were non-Hispanic Asians, Pacific Islanders, and African Americans. Half of the participants were born outside the United States and had lived in the U.S. for an average 22 years.
Sean Palfrey, MD, a professor of clinical pediatrics and public health at Boston University, said more chemical discoveries like these will come as technology continues to evolve.
Dr. Palfrey, who was not involved in the study, agrees with the authors that there is a lack of oversight as to what substances are used in products.
“Our industrial regulations are very poor and therefore our industries get away with using new and untested substances in their products,” he told this news organization.
“This lack of regulation is really important when it results in us not recognizing that known and serious toxins are being put into foods or other products, or when a new class of toxin has been invented which is a serious poison. Most of the toxins, though, are discovered in products in very low levels,” he said.
Dr. Palfrey said, however, that focus should stay on the known and serious toxins that seep into the environment from common products.
“It has taken us decades to ban certain flame retardants from home products,” he said. “TOSCA [the Toxic Substances Control Act passed by Congress in 1976] was too limited when it was passed decades ago and is now fearfully out of date. Unless we discover a COVID among the toxins discovered in studies like this, we should focus on the big stuff.”
The authors and Dr. Palfrey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Fifty-five chemicals never before reported in humans were found in pregnant women, according to a study from the University of California, San Francisco. The chemicals likely come from consumer products or industrial sources, researchers say.
Findings were published online in Environmental Science and Technology.
Co-first authors Aolin Wang, PhD, and Dimitri Panagopoulos Abrahamsson, PhD, postdoctoral fellows in UCSF’s obstetrics and gynecology department, and colleagues found 109 chemicals in the blood of pregnant women, including 42 “mystery chemicals” whose sources and uses are not known.
The chemicals were also found in their newborns, tests from umbilical cord blood show, suggesting the chemicals cross through the placenta.
Among the chemicals, 40 are used as plasticizers, 28 are used in cosmetics, another 25 are used in consumer products, 29 as pharmaceuticals, 23 as pesticides, three as flame retardants, and seven are PFAS [per- and polyfluoroalkyl substances] compounds used in multiple applications including carpeting and upholstery, the authors report.
Senior author Tracey Woodruff, PhD, MPH, characterized their discoveries as “disturbing.”
She told this news organization that it’s not only frustrating to know the chemicals are present but to know so little about them.
“We know it’s a chemical registered to be manufactured, and it’s used in commerce, but we don’t know where,” she explained. “That’s very disturbing, that we can’t trace them, and that shows a failure in public policy and government.”
“Exposures are occurring without our consent,” said Ms. Woodruff, a former U.S. Environmental Protection Agency scientist, who directs the Program on Reproductive Health and the Environment (PRHE) and the Environmental Research and Translation for Health (EaRTH) Center, both at UCSF.
She said researchers know from previous studies that when the U.S. government acts to remove harmful chemicals from the marketplace, the levels of those chemicals measured in people drop.
“Examples include lead, certain PFAS, flame retardant chemicals, and certain phthalates,” she said. “So public policies can be effective in preventing exposures that can be harmful.”
Technological advances led to the discoveries
The team used high-resolution mass spectrometry (HRMS) to identify human-made chemicals in people.
Dr. Abrahamsson said in an interview that the technology is relatively new in research and had not previously been used to scan for chemicals in pregnant women and their infants.
Because scientists often study what other scientists have studied, he said, the same chemicals tend to get attention. The wider scope made possible by the new technology helps illumine where to focus future research, he said.
A benefit of the technology is that now researchers don’t have to know which chemicals they are looking for when they scan blood samples, but they can observe whatever appears, he said.
Ms. Woodruff said, “We hope this is further data and evidence that support government policies that require industries to tell us where they are using their chemicals and how we might be exposed to them.”
She said this research will also help identify which chemicals to prioritize for monitoring in the environment.
Average age of the women in the study was 32 years. Nearly half were Hispanic; 37% were non-Hispanic Whites; and 17% were non-Hispanic Asians, Pacific Islanders, and African Americans. Half of the participants were born outside the United States and had lived in the U.S. for an average 22 years.
Sean Palfrey, MD, a professor of clinical pediatrics and public health at Boston University, said more chemical discoveries like these will come as technology continues to evolve.
Dr. Palfrey, who was not involved in the study, agrees with the authors that there is a lack of oversight as to what substances are used in products.
“Our industrial regulations are very poor and therefore our industries get away with using new and untested substances in their products,” he told this news organization.
“This lack of regulation is really important when it results in us not recognizing that known and serious toxins are being put into foods or other products, or when a new class of toxin has been invented which is a serious poison. Most of the toxins, though, are discovered in products in very low levels,” he said.
Dr. Palfrey said, however, that focus should stay on the known and serious toxins that seep into the environment from common products.
“It has taken us decades to ban certain flame retardants from home products,” he said. “TOSCA [the Toxic Substances Control Act passed by Congress in 1976] was too limited when it was passed decades ago and is now fearfully out of date. Unless we discover a COVID among the toxins discovered in studies like this, we should focus on the big stuff.”
The authors and Dr. Palfrey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Self-harm is a leading cause of death for new moms
Death by self-harm through suicide or overdose is a leading cause of death for women in the first year post partum, data indicate. Many of these deaths may be preventable, said Adrienne Griffen, MPP, executive director of the Maternal Mental Health Leadership Alliance.
Ms. Griffen discussed these findings and ways clinicians may be able to help at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Women “visit a health care provider an average of 25 times during a healthy pregnancy and first year of baby’s life,” she said. “Obstetric and primary care providers who serve pregnant and postpartum women are uniquely positioned to intervene effectively to screen and assess women for mental health disorders.”
To that end, clinicians should discuss mental health “early and often,” Ms. Griffen said.
“Asking about mental health issues and suicide will not cause women to think these thoughts,” she said. “We cannot wait for women to raise their hand and ask for help because by the time they do that, they needed help many weeks ago.”
For example, a doctor might tell a patient: “Your mental health is just as important as your physical health, and anxiety and depression are the most common complications of pregnancy and childbirth,” Ms. Griffen suggested. “Every time I see you, I’m going to ask you how you are doing, and we’ll do a formal screening assessment periodically over the course of the pregnancy. … Your job is to answer us honestly so that we can connect you with resources as soon as possible to minimize the impact on you and your baby.”
Although the obstetric provider should introduce this topic, a nurse, lactation consultant, or social worker may conduct screenings and help patients who are experiencing distress, she said.
During the past decade, several medical associations have issued new guidance around screening new mothers for anxiety and depression. One recent ACOG committee opinion recommends screening for depression at least once during pregnancy and once post partum, and encourages doctors to initiate medical therapy if possible and provide resources and referrals.
Another committee opinion suggests that doctors should have contact with a patient between 2 and 3 weeks post partum, primarily to assess for mental health.
Limited data
In discussing maternal suicide statistics, Ms. Griffen focused on data from Maternal Mortality Review Committees (MMRCs).
Two other sources of data about maternal mortality – the National Vital Statistics System and the Pregnancy Mortality Surveillance System – do not include information about suicide, which may be a reason this cause of death is not discussed more often, Ms. Griffen noted.
MMRCs, on the other hand, include information about suicide and self-harm. About half of the states in the United States have these multidisciplinary committees. Committee members review deaths of all women during pregnancy or within 1 year of pregnancy. Members consider a range of clinical and nonclinical data, including reports from social services and police, to try to understand the circumstances of each death.
A report that examined pregnancy-related deaths using data from 14 U.S. MMRCs between 2008 and 2017 showed that mental health conditions were the leading cause of death for non-Hispanic White women. In all, 34% of pregnancy-related suicide deaths had a documented prior suicide attempt, and the majority of suicides happened in the late postpartum time frame (43-365 days post partum).
Some physicians cite a lack of education, time, reimbursement, or referral resources as barriers to maternal mental health screening and treatment, but there may be useful options available, Ms. Griffen said. Postpartum Support International provides resources for physicians, as well as mothers. The National Curriculum in Reproductive Psychiatry and the Seleni Institute also have educational resources.
Some states have psychiatry access programs, where psychiatrists educate obstetricians, family physicians, and pediatricians about how to assess for and treat maternal mental health issues, Ms. Griffen noted.
Self care, social support, and talk therapy may help patients. “Sometimes medication is needed, but a combination of all of these things … can help women recover from maternal mental health conditions,” Ms. Griffen said.
Need to intervene
Although medical societies have emphasized the importance of maternal mental health screening and treatment in recent years, the risk of self-harm has been a concern for obstetricians and gynecologists long before then, said Marc Alan Landsberg, MD, a member of the meeting’s scientific committee who moderated the session.
“We have been talking about this at ACOG for a long time,” Dr. Landsberg said in an interview.
The presentation highlighted why obstetricians, gynecologists, and other doctors who deliver babies and care for women post partum “have got to screen these people,” he said. The finding that 34% of pregnancy-related suicide deaths had a prior suicide attempt indicates that clinicians may be able to identify these patients, Dr. Landsberg said. Suicide and overdose are leading causes of death in the first year post partum and “probably 100% of these are preventable,” he said.
As a first step, screening may be relatively simple. The Edinburgh Postnatal Depression Scale, highlighted during the talk, is an easy and quick tool to use, Dr. Landsberg said. It contains 10 items and assesses for anxiety and depression. It also specifically asks about suicide.
Ms. Griffen and Dr. Landsberg had no conflicts of interest.
Death by self-harm through suicide or overdose is a leading cause of death for women in the first year post partum, data indicate. Many of these deaths may be preventable, said Adrienne Griffen, MPP, executive director of the Maternal Mental Health Leadership Alliance.
Ms. Griffen discussed these findings and ways clinicians may be able to help at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Women “visit a health care provider an average of 25 times during a healthy pregnancy and first year of baby’s life,” she said. “Obstetric and primary care providers who serve pregnant and postpartum women are uniquely positioned to intervene effectively to screen and assess women for mental health disorders.”
To that end, clinicians should discuss mental health “early and often,” Ms. Griffen said.
“Asking about mental health issues and suicide will not cause women to think these thoughts,” she said. “We cannot wait for women to raise their hand and ask for help because by the time they do that, they needed help many weeks ago.”
For example, a doctor might tell a patient: “Your mental health is just as important as your physical health, and anxiety and depression are the most common complications of pregnancy and childbirth,” Ms. Griffen suggested. “Every time I see you, I’m going to ask you how you are doing, and we’ll do a formal screening assessment periodically over the course of the pregnancy. … Your job is to answer us honestly so that we can connect you with resources as soon as possible to minimize the impact on you and your baby.”
Although the obstetric provider should introduce this topic, a nurse, lactation consultant, or social worker may conduct screenings and help patients who are experiencing distress, she said.
During the past decade, several medical associations have issued new guidance around screening new mothers for anxiety and depression. One recent ACOG committee opinion recommends screening for depression at least once during pregnancy and once post partum, and encourages doctors to initiate medical therapy if possible and provide resources and referrals.
Another committee opinion suggests that doctors should have contact with a patient between 2 and 3 weeks post partum, primarily to assess for mental health.
Limited data
In discussing maternal suicide statistics, Ms. Griffen focused on data from Maternal Mortality Review Committees (MMRCs).
Two other sources of data about maternal mortality – the National Vital Statistics System and the Pregnancy Mortality Surveillance System – do not include information about suicide, which may be a reason this cause of death is not discussed more often, Ms. Griffen noted.
MMRCs, on the other hand, include information about suicide and self-harm. About half of the states in the United States have these multidisciplinary committees. Committee members review deaths of all women during pregnancy or within 1 year of pregnancy. Members consider a range of clinical and nonclinical data, including reports from social services and police, to try to understand the circumstances of each death.
A report that examined pregnancy-related deaths using data from 14 U.S. MMRCs between 2008 and 2017 showed that mental health conditions were the leading cause of death for non-Hispanic White women. In all, 34% of pregnancy-related suicide deaths had a documented prior suicide attempt, and the majority of suicides happened in the late postpartum time frame (43-365 days post partum).
Some physicians cite a lack of education, time, reimbursement, or referral resources as barriers to maternal mental health screening and treatment, but there may be useful options available, Ms. Griffen said. Postpartum Support International provides resources for physicians, as well as mothers. The National Curriculum in Reproductive Psychiatry and the Seleni Institute also have educational resources.
Some states have psychiatry access programs, where psychiatrists educate obstetricians, family physicians, and pediatricians about how to assess for and treat maternal mental health issues, Ms. Griffen noted.
Self care, social support, and talk therapy may help patients. “Sometimes medication is needed, but a combination of all of these things … can help women recover from maternal mental health conditions,” Ms. Griffen said.
Need to intervene
Although medical societies have emphasized the importance of maternal mental health screening and treatment in recent years, the risk of self-harm has been a concern for obstetricians and gynecologists long before then, said Marc Alan Landsberg, MD, a member of the meeting’s scientific committee who moderated the session.
“We have been talking about this at ACOG for a long time,” Dr. Landsberg said in an interview.
The presentation highlighted why obstetricians, gynecologists, and other doctors who deliver babies and care for women post partum “have got to screen these people,” he said. The finding that 34% of pregnancy-related suicide deaths had a prior suicide attempt indicates that clinicians may be able to identify these patients, Dr. Landsberg said. Suicide and overdose are leading causes of death in the first year post partum and “probably 100% of these are preventable,” he said.
As a first step, screening may be relatively simple. The Edinburgh Postnatal Depression Scale, highlighted during the talk, is an easy and quick tool to use, Dr. Landsberg said. It contains 10 items and assesses for anxiety and depression. It also specifically asks about suicide.
Ms. Griffen and Dr. Landsberg had no conflicts of interest.
Death by self-harm through suicide or overdose is a leading cause of death for women in the first year post partum, data indicate. Many of these deaths may be preventable, said Adrienne Griffen, MPP, executive director of the Maternal Mental Health Leadership Alliance.
Ms. Griffen discussed these findings and ways clinicians may be able to help at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Women “visit a health care provider an average of 25 times during a healthy pregnancy and first year of baby’s life,” she said. “Obstetric and primary care providers who serve pregnant and postpartum women are uniquely positioned to intervene effectively to screen and assess women for mental health disorders.”
To that end, clinicians should discuss mental health “early and often,” Ms. Griffen said.
“Asking about mental health issues and suicide will not cause women to think these thoughts,” she said. “We cannot wait for women to raise their hand and ask for help because by the time they do that, they needed help many weeks ago.”
For example, a doctor might tell a patient: “Your mental health is just as important as your physical health, and anxiety and depression are the most common complications of pregnancy and childbirth,” Ms. Griffen suggested. “Every time I see you, I’m going to ask you how you are doing, and we’ll do a formal screening assessment periodically over the course of the pregnancy. … Your job is to answer us honestly so that we can connect you with resources as soon as possible to minimize the impact on you and your baby.”
Although the obstetric provider should introduce this topic, a nurse, lactation consultant, or social worker may conduct screenings and help patients who are experiencing distress, she said.
During the past decade, several medical associations have issued new guidance around screening new mothers for anxiety and depression. One recent ACOG committee opinion recommends screening for depression at least once during pregnancy and once post partum, and encourages doctors to initiate medical therapy if possible and provide resources and referrals.
Another committee opinion suggests that doctors should have contact with a patient between 2 and 3 weeks post partum, primarily to assess for mental health.
Limited data
In discussing maternal suicide statistics, Ms. Griffen focused on data from Maternal Mortality Review Committees (MMRCs).
Two other sources of data about maternal mortality – the National Vital Statistics System and the Pregnancy Mortality Surveillance System – do not include information about suicide, which may be a reason this cause of death is not discussed more often, Ms. Griffen noted.
MMRCs, on the other hand, include information about suicide and self-harm. About half of the states in the United States have these multidisciplinary committees. Committee members review deaths of all women during pregnancy or within 1 year of pregnancy. Members consider a range of clinical and nonclinical data, including reports from social services and police, to try to understand the circumstances of each death.
A report that examined pregnancy-related deaths using data from 14 U.S. MMRCs between 2008 and 2017 showed that mental health conditions were the leading cause of death for non-Hispanic White women. In all, 34% of pregnancy-related suicide deaths had a documented prior suicide attempt, and the majority of suicides happened in the late postpartum time frame (43-365 days post partum).
Some physicians cite a lack of education, time, reimbursement, or referral resources as barriers to maternal mental health screening and treatment, but there may be useful options available, Ms. Griffen said. Postpartum Support International provides resources for physicians, as well as mothers. The National Curriculum in Reproductive Psychiatry and the Seleni Institute also have educational resources.
Some states have psychiatry access programs, where psychiatrists educate obstetricians, family physicians, and pediatricians about how to assess for and treat maternal mental health issues, Ms. Griffen noted.
Self care, social support, and talk therapy may help patients. “Sometimes medication is needed, but a combination of all of these things … can help women recover from maternal mental health conditions,” Ms. Griffen said.
Need to intervene
Although medical societies have emphasized the importance of maternal mental health screening and treatment in recent years, the risk of self-harm has been a concern for obstetricians and gynecologists long before then, said Marc Alan Landsberg, MD, a member of the meeting’s scientific committee who moderated the session.
“We have been talking about this at ACOG for a long time,” Dr. Landsberg said in an interview.
The presentation highlighted why obstetricians, gynecologists, and other doctors who deliver babies and care for women post partum “have got to screen these people,” he said. The finding that 34% of pregnancy-related suicide deaths had a prior suicide attempt indicates that clinicians may be able to identify these patients, Dr. Landsberg said. Suicide and overdose are leading causes of death in the first year post partum and “probably 100% of these are preventable,” he said.
As a first step, screening may be relatively simple. The Edinburgh Postnatal Depression Scale, highlighted during the talk, is an easy and quick tool to use, Dr. Landsberg said. It contains 10 items and assesses for anxiety and depression. It also specifically asks about suicide.
Ms. Griffen and Dr. Landsberg had no conflicts of interest.
FROM ACOG 2021
BERENICE: Further evidence of heart safety of dual HER2 blockade
Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.
After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).
Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.
Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.
BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.
“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.
Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”
Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.
That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.
“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.
The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
BERENICE study design
BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.
Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.
Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.
Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.
The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.
The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
Discussion points
Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.
“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”
Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.
“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”
The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.
Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.
After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).
Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.
Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.
BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.
“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.
Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”
Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.
That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.
“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.
The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
BERENICE study design
BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.
Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.
Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.
Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.
The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.
The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
Discussion points
Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.
“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”
Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.
“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”
The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.
Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.
After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).
Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.
Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.
BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.
“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.
Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”
Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.
That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.
“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.
The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
BERENICE study design
BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.
Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.
Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.
Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.
The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.
The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
Discussion points
Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.
“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”
Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.
“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”
The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.
FROM ESMO BREAST CANCER 2021