Women's Health

Disease-modifying antirheumatic drugs (DMARDs) such as biologics may carry an increased risk for preterm birth or cesarean delivery for pregnant women with psoriatic arthritis (PsA), according to a recent study published in Arthritis & Rheumatology.

zoranm/Getty Images

The risk was particularly high for women with PsA who received biologic disease-modifying antirheumatic drugs (bDMARDs), according to Katarina Remaeus, PhD, of the Karolinska Institute in Stockholm and colleagues.

“The results may indicate that a more severe or active PsA disease that requires antirheumatic treatment during pregnancy, especially bDMARDs, is associated with increased risks of adverse pregnancy outcomes compared to non-PsA pregnancies,” Dr. Remaeus and colleagues write in their study. “The risk of preterm birth in PsA pregnancies is further influenced by parity with the most increased risks observed in first pregnancies.”

In a nationwide, register-based cohort study, the researchers evaluated 921 pregnancies of women with PsA between 2007 and 2017, comparing them to the pregnancies of 9,210 women without PsA over the same time frame. The pregnancies for women with PsA were further categorized based on whether the women had not received antirheumatic treatment in the year prior to and/or during pregnancy (495 pregnancies) or had received antirheumatic treatment at any point in the year before and/or during pregnancy (426 pregnancies).

Of the women in the PsA group who were treated in the year prior to pregnancy (170 women), 39.4% received monotherapy with a conventional synthetic DMARD (csDMARD) such as an antimalarial, methotrexate, or sulfasalazine; 24.1% received oral corticosteroids, and 15.9% received a tumor necrosis factor inhibitor (TNFi), whereas about 20% of women received two or more antirheumatic drugs.

In the group of women treated during pregnancy (256 women), 153 did not receive bDMARDs; of these, 41.8% had monotherapy with either a csDMARD or corticosteroids, whereas the group treated with bDMARDs received TNFi monotherapy (43.7%) or TNFi with corticosteroids (35.9%), TNFi with csDMARD (9.7%), or TNFi with csDMARD plus corticosteroids (9.7%).

A majority of women in both groups (70.1%) were between ages 30 and 34 years (37.1%) or older than age 35 years (33%) and had delivered more than one child (63.2%). Women in the PsA group were more likely to be born in a Nordic country (91.8% vs. 82.8%), to have a body mass index between 30.0 and 60.0 kg/m² (19.9% vs. 12.6%), to be a smoker (9.2% vs. 5.3%), to have hypertension (1.4% vs. 0.8%) or diabetes (1.3% vs. 0.5%) prior to pregnancy, and to have a higher level of education (>12 years; 50.1% vs. 43.3%), compared with women in the non-PsA group.

The results showed women in the PsA group were more likely to experience preterm birth (adjusted odds ratio, 1.69; 95% confidence interval, 1.27-2.24) and undergo an elective (aOR, 1.77; 95% CI, 1.43-2.20) or emergency C-section (aOR, 1.42; 95% CI, 1.10-1.84). The group at highest risk for preterm birth with regard to parity was women with PsA having their first child (aOR, 3.95; 95% CI, 1.43-10.95).

Women who received antirheumatic treatment were at greater risk for experiencing preterm birth (aOR, 2.30; 95% CI, 1.49-3.56), and this risk was even higher for treatment with bDMARDs, compared with women without PsA (aOR, 4.49; 95% CI, 2.60-7.79). Use of bDMARDs also was associated with higher risks for spontaneous preterm birth (aOR, 4.73; 95% CI, 2.53-8.87), preterm birth between 32 and 36 weeks’ gestation (aOR, 5.06; 95% CI, 2.91-8.79), elective C-section (aOR, 2.72; 95% CI, 1.61-4.59), emergency C-section (aOR, 2.06; 95% CI, 1.04-4.07), and preeclampsia (aOR, 2.88, 95% CI, 1.35-6.17).

The researchers note that women with PsA should be evaluated for preterm birth particularly if they are having their first child, and “from a clinical point of view, all women with PsA, regardless of antirheumatic treatment, should be counseled about pregnancy outcomes and receive individualized monitoring during pregnancy.”

Are adverse outcomes linked to disease activity or treatment?

Patients in the study had a higher risk of adverse outcomes when they had a PsA diagnosis, and when they received antirheumatic treatment – but were the adverse outcomes associated with a patient’s high disease activity or need for antirheumatic treatment?

“Our interpretation is that a PsA disease that requires continued antirheumatic treatment during pregnancy is more severe than PsA that does not require treatment,” Dr. Remaeus and colleagues write. “Thus, the increased risk of adverse outcomes in pregnancies with maternal antirheumatic treatment is probably attributed to disease severity rather than an effect of the medication itself.”

Anja Strangfeld, MD, PhD, of the German Rheumatism Research Centre in Berlin, told this news organization that the results of the study are important because it is one of the first to report differences in risk in pregnancy outcomes for women with and without PsA.

“The information is relevant to guide rheumatologists in advising patients with PsA when planning the first or subsequent pregnancies,” she said. “The results are reassuring in reporting that the elevated risk for PsA patients for adverse pregnancy outcomes is low in patients not in need of antirheumatic medication, presumably in low-disease activity.”

However, the study is still unclear on whether the association with adverse pregnancy outcomes in patients is the result of higher disease activity or the need for antirheumatic treatment, she explained.

“It was only hypothesized that those patients under bDMARD treatment are/were in high disease activity. There [is] no information on disease activity in the data sources, which limits the results,” she said. “The investigation still does not solve the important question – if adverse pregnancy outcomes are rather related to high disease activity or the medication to treat this situation.”

There was no specific funding for this study. The study authors and Dr. Strangfeld have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Disease-modifying antirheumatic drugs (DMARDs) such as biologics may carry an increased risk for preterm birth or cesarean delivery for pregnant women with psoriatic arthritis (PsA), according to a recent study published in Arthritis & Rheumatology.

zoranm/Getty Images

The risk was particularly high for women with PsA who received biologic disease-modifying antirheumatic drugs (bDMARDs), according to Katarina Remaeus, PhD, of the Karolinska Institute in Stockholm and colleagues.

“The results may indicate that a more severe or active PsA disease that requires antirheumatic treatment during pregnancy, especially bDMARDs, is associated with increased risks of adverse pregnancy outcomes compared to non-PsA pregnancies,” Dr. Remaeus and colleagues write in their study. “The risk of preterm birth in PsA pregnancies is further influenced by parity with the most increased risks observed in first pregnancies.”

In a nationwide, register-based cohort study, the researchers evaluated 921 pregnancies of women with PsA between 2007 and 2017, comparing them to the pregnancies of 9,210 women without PsA over the same time frame. The pregnancies for women with PsA were further categorized based on whether the women had not received antirheumatic treatment in the year prior to and/or during pregnancy (495 pregnancies) or had received antirheumatic treatment at any point in the year before and/or during pregnancy (426 pregnancies).

Of the women in the PsA group who were treated in the year prior to pregnancy (170 women), 39.4% received monotherapy with a conventional synthetic DMARD (csDMARD) such as an antimalarial, methotrexate, or sulfasalazine; 24.1% received oral corticosteroids, and 15.9% received a tumor necrosis factor inhibitor (TNFi), whereas about 20% of women received two or more antirheumatic drugs.

In the group of women treated during pregnancy (256 women), 153 did not receive bDMARDs; of these, 41.8% had monotherapy with either a csDMARD or corticosteroids, whereas the group treated with bDMARDs received TNFi monotherapy (43.7%) or TNFi with corticosteroids (35.9%), TNFi with csDMARD (9.7%), or TNFi with csDMARD plus corticosteroids (9.7%).

A majority of women in both groups (70.1%) were between ages 30 and 34 years (37.1%) or older than age 35 years (33%) and had delivered more than one child (63.2%). Women in the PsA group were more likely to be born in a Nordic country (91.8% vs. 82.8%), to have a body mass index between 30.0 and 60.0 kg/m² (19.9% vs. 12.6%), to be a smoker (9.2% vs. 5.3%), to have hypertension (1.4% vs. 0.8%) or diabetes (1.3% vs. 0.5%) prior to pregnancy, and to have a higher level of education (>12 years; 50.1% vs. 43.3%), compared with women in the non-PsA group.

The results showed women in the PsA group were more likely to experience preterm birth (adjusted odds ratio, 1.69; 95% confidence interval, 1.27-2.24) and undergo an elective (aOR, 1.77; 95% CI, 1.43-2.20) or emergency C-section (aOR, 1.42; 95% CI, 1.10-1.84). The group at highest risk for preterm birth with regard to parity was women with PsA having their first child (aOR, 3.95; 95% CI, 1.43-10.95).

Women who received antirheumatic treatment were at greater risk for experiencing preterm birth (aOR, 2.30; 95% CI, 1.49-3.56), and this risk was even higher for treatment with bDMARDs, compared with women without PsA (aOR, 4.49; 95% CI, 2.60-7.79). Use of bDMARDs also was associated with higher risks for spontaneous preterm birth (aOR, 4.73; 95% CI, 2.53-8.87), preterm birth between 32 and 36 weeks’ gestation (aOR, 5.06; 95% CI, 2.91-8.79), elective C-section (aOR, 2.72; 95% CI, 1.61-4.59), emergency C-section (aOR, 2.06; 95% CI, 1.04-4.07), and preeclampsia (aOR, 2.88, 95% CI, 1.35-6.17).

The researchers note that women with PsA should be evaluated for preterm birth particularly if they are having their first child, and “from a clinical point of view, all women with PsA, regardless of antirheumatic treatment, should be counseled about pregnancy outcomes and receive individualized monitoring during pregnancy.”

Are adverse outcomes linked to disease activity or treatment?

Patients in the study had a higher risk of adverse outcomes when they had a PsA diagnosis, and when they received antirheumatic treatment – but were the adverse outcomes associated with a patient’s high disease activity or need for antirheumatic treatment?

“Our interpretation is that a PsA disease that requires continued antirheumatic treatment during pregnancy is more severe than PsA that does not require treatment,” Dr. Remaeus and colleagues write. “Thus, the increased risk of adverse outcomes in pregnancies with maternal antirheumatic treatment is probably attributed to disease severity rather than an effect of the medication itself.”

Anja Strangfeld, MD, PhD, of the German Rheumatism Research Centre in Berlin, told this news organization that the results of the study are important because it is one of the first to report differences in risk in pregnancy outcomes for women with and without PsA.

“The information is relevant to guide rheumatologists in advising patients with PsA when planning the first or subsequent pregnancies,” she said. “The results are reassuring in reporting that the elevated risk for PsA patients for adverse pregnancy outcomes is low in patients not in need of antirheumatic medication, presumably in low-disease activity.”

However, the study is still unclear on whether the association with adverse pregnancy outcomes in patients is the result of higher disease activity or the need for antirheumatic treatment, she explained.

“It was only hypothesized that those patients under bDMARD treatment are/were in high disease activity. There [is] no information on disease activity in the data sources, which limits the results,” she said. “The investigation still does not solve the important question – if adverse pregnancy outcomes are rather related to high disease activity or the medication to treat this situation.”

There was no specific funding for this study. The study authors and Dr. Strangfeld have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Disease-modifying antirheumatic drugs (DMARDs) such as biologics may carry an increased risk for preterm birth or cesarean delivery for pregnant women with psoriatic arthritis (PsA), according to a recent study published in Arthritis & Rheumatology.

zoranm/Getty Images

The risk was particularly high for women with PsA who received biologic disease-modifying antirheumatic drugs (bDMARDs), according to Katarina Remaeus, PhD, of the Karolinska Institute in Stockholm and colleagues.

“The results may indicate that a more severe or active PsA disease that requires antirheumatic treatment during pregnancy, especially bDMARDs, is associated with increased risks of adverse pregnancy outcomes compared to non-PsA pregnancies,” Dr. Remaeus and colleagues write in their study. “The risk of preterm birth in PsA pregnancies is further influenced by parity with the most increased risks observed in first pregnancies.”

In a nationwide, register-based cohort study, the researchers evaluated 921 pregnancies of women with PsA between 2007 and 2017, comparing them to the pregnancies of 9,210 women without PsA over the same time frame. The pregnancies for women with PsA were further categorized based on whether the women had not received antirheumatic treatment in the year prior to and/or during pregnancy (495 pregnancies) or had received antirheumatic treatment at any point in the year before and/or during pregnancy (426 pregnancies).

Of the women in the PsA group who were treated in the year prior to pregnancy (170 women), 39.4% received monotherapy with a conventional synthetic DMARD (csDMARD) such as an antimalarial, methotrexate, or sulfasalazine; 24.1% received oral corticosteroids, and 15.9% received a tumor necrosis factor inhibitor (TNFi), whereas about 20% of women received two or more antirheumatic drugs.

In the group of women treated during pregnancy (256 women), 153 did not receive bDMARDs; of these, 41.8% had monotherapy with either a csDMARD or corticosteroids, whereas the group treated with bDMARDs received TNFi monotherapy (43.7%) or TNFi with corticosteroids (35.9%), TNFi with csDMARD (9.7%), or TNFi with csDMARD plus corticosteroids (9.7%).

A majority of women in both groups (70.1%) were between ages 30 and 34 years (37.1%) or older than age 35 years (33%) and had delivered more than one child (63.2%). Women in the PsA group were more likely to be born in a Nordic country (91.8% vs. 82.8%), to have a body mass index between 30.0 and 60.0 kg/m² (19.9% vs. 12.6%), to be a smoker (9.2% vs. 5.3%), to have hypertension (1.4% vs. 0.8%) or diabetes (1.3% vs. 0.5%) prior to pregnancy, and to have a higher level of education (>12 years; 50.1% vs. 43.3%), compared with women in the non-PsA group.

The results showed women in the PsA group were more likely to experience preterm birth (adjusted odds ratio, 1.69; 95% confidence interval, 1.27-2.24) and undergo an elective (aOR, 1.77; 95% CI, 1.43-2.20) or emergency C-section (aOR, 1.42; 95% CI, 1.10-1.84). The group at highest risk for preterm birth with regard to parity was women with PsA having their first child (aOR, 3.95; 95% CI, 1.43-10.95).

Women who received antirheumatic treatment were at greater risk for experiencing preterm birth (aOR, 2.30; 95% CI, 1.49-3.56), and this risk was even higher for treatment with bDMARDs, compared with women without PsA (aOR, 4.49; 95% CI, 2.60-7.79). Use of bDMARDs also was associated with higher risks for spontaneous preterm birth (aOR, 4.73; 95% CI, 2.53-8.87), preterm birth between 32 and 36 weeks’ gestation (aOR, 5.06; 95% CI, 2.91-8.79), elective C-section (aOR, 2.72; 95% CI, 1.61-4.59), emergency C-section (aOR, 2.06; 95% CI, 1.04-4.07), and preeclampsia (aOR, 2.88, 95% CI, 1.35-6.17).

The researchers note that women with PsA should be evaluated for preterm birth particularly if they are having their first child, and “from a clinical point of view, all women with PsA, regardless of antirheumatic treatment, should be counseled about pregnancy outcomes and receive individualized monitoring during pregnancy.”

Are adverse outcomes linked to disease activity or treatment?

Patients in the study had a higher risk of adverse outcomes when they had a PsA diagnosis, and when they received antirheumatic treatment – but were the adverse outcomes associated with a patient’s high disease activity or need for antirheumatic treatment?

“Our interpretation is that a PsA disease that requires continued antirheumatic treatment during pregnancy is more severe than PsA that does not require treatment,” Dr. Remaeus and colleagues write. “Thus, the increased risk of adverse outcomes in pregnancies with maternal antirheumatic treatment is probably attributed to disease severity rather than an effect of the medication itself.”

Anja Strangfeld, MD, PhD, of the German Rheumatism Research Centre in Berlin, told this news organization that the results of the study are important because it is one of the first to report differences in risk in pregnancy outcomes for women with and without PsA.

“The information is relevant to guide rheumatologists in advising patients with PsA when planning the first or subsequent pregnancies,” she said. “The results are reassuring in reporting that the elevated risk for PsA patients for adverse pregnancy outcomes is low in patients not in need of antirheumatic medication, presumably in low-disease activity.”

However, the study is still unclear on whether the association with adverse pregnancy outcomes in patients is the result of higher disease activity or the need for antirheumatic treatment, she explained.

“It was only hypothesized that those patients under bDMARD treatment are/were in high disease activity. There [is] no information on disease activity in the data sources, which limits the results,” she said. “The investigation still does not solve the important question – if adverse pregnancy outcomes are rather related to high disease activity or the medication to treat this situation.”

There was no specific funding for this study. The study authors and Dr. Strangfeld have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at [email protected].
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at [email protected].
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at [email protected].
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.

New evidence points to the importance of helping mothers with their mental health during pregnancy.

Researchers from the National Institutes of Health in Bethesda, Md., have found that feelings of stress or depression while pregnant are linked to changes in the placenta where the child is growing. The findings, published in Epigenomics, show these changes could alter gene activity.

Stress and depression are not uncommon among expectant women, with depression affecting an estimated 1 in 10 pregnancies, according to the American College of Obstetricians and Gynecologists.

And current evidence already suggests that depression during pregnancy can negatively affect a child later in life. For instance, one study found that depression during pregnancy was linked to behavioral and emotional disorders during childhood, and another found that it raised the risk of depression at age 18.

To investigate stress and depression during pregnancy, the NIH investigators evaluated 301 pregnant women from 12 clinics in the United States who had taken part in an earlier clinical study. The group was ethnically diverse, with 34% identifying as Hispanic, 26% as non-Hispanic White, 24% as non-Hispanic Black, and 17% as Asian or Pacific Islander.

At the start of the study, the women were asked to complete questionnaires routinely used to screen for stress and depression. They completed the questionnaire five more times during their pregnancies. Shortly after each woman gave birth, researchers took tissue samples from the placenta and analyzed the genetics.

The purpose of studying the placenta, according to lead researcher Markos Tesfaye, MD, a postdoctoral fellow at the NIH, is that chemical changes can regulate whether a nearby gene can be activated.

There is evidence that chemical modifications in the placenta can lead to changes in fetal tissues, such as the brain, he said. And the placenta is known for making neurotransmitters, which are needed for fetal brain development.

The team found 16 areas where changes to the exterior of placental DNA were linked to depression in the second or third trimester. They also found two areas where these changes were associated with stress in the third trimester.

“Maternal depression leaves signals in the placenta at genes critical for fetal brain programming,” said study author Fasil Tekola-Ayele, PhD, from the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Two of the chemical changes linked to depression were near genes that are known to be involved with fetal brain development and neurologic and psychiatric illnesses.

“The findings illustrate that the developing fetus is sensitive to the mother›s condition during pregnancy, including maternal symptoms of low mood and perceived stress,” said Thalia K. Robakis, MD, from the women’s mental health program at Icahn School of Medicine at Mount Sinai, New York, who was not involved in the study.

But Dr. Robakis cautioned that no clinical outcomes were measured among the babies born, meaning that the study could not document any effects of maternal depression and stress on fetal development. Rather, the work contributes to figuring out what mechanisms are involved.

“Pregnant women should continue to focus on optimizing their own physical and mental health,” Dr. Robakis said. “And they should know that a happy, healthy mother is the most important factor supporting the development of a happy, healthy baby.”

A version of this article first appeared on WebMD.com.

New evidence points to the importance of helping mothers with their mental health during pregnancy.

Researchers from the National Institutes of Health in Bethesda, Md., have found that feelings of stress or depression while pregnant are linked to changes in the placenta where the child is growing. The findings, published in Epigenomics, show these changes could alter gene activity.

Stress and depression are not uncommon among expectant women, with depression affecting an estimated 1 in 10 pregnancies, according to the American College of Obstetricians and Gynecologists.

And current evidence already suggests that depression during pregnancy can negatively affect a child later in life. For instance, one study found that depression during pregnancy was linked to behavioral and emotional disorders during childhood, and another found that it raised the risk of depression at age 18.

To investigate stress and depression during pregnancy, the NIH investigators evaluated 301 pregnant women from 12 clinics in the United States who had taken part in an earlier clinical study. The group was ethnically diverse, with 34% identifying as Hispanic, 26% as non-Hispanic White, 24% as non-Hispanic Black, and 17% as Asian or Pacific Islander.

At the start of the study, the women were asked to complete questionnaires routinely used to screen for stress and depression. They completed the questionnaire five more times during their pregnancies. Shortly after each woman gave birth, researchers took tissue samples from the placenta and analyzed the genetics.

The purpose of studying the placenta, according to lead researcher Markos Tesfaye, MD, a postdoctoral fellow at the NIH, is that chemical changes can regulate whether a nearby gene can be activated.

There is evidence that chemical modifications in the placenta can lead to changes in fetal tissues, such as the brain, he said. And the placenta is known for making neurotransmitters, which are needed for fetal brain development.

The team found 16 areas where changes to the exterior of placental DNA were linked to depression in the second or third trimester. They also found two areas where these changes were associated with stress in the third trimester.

“Maternal depression leaves signals in the placenta at genes critical for fetal brain programming,” said study author Fasil Tekola-Ayele, PhD, from the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Two of the chemical changes linked to depression were near genes that are known to be involved with fetal brain development and neurologic and psychiatric illnesses.

“The findings illustrate that the developing fetus is sensitive to the mother›s condition during pregnancy, including maternal symptoms of low mood and perceived stress,” said Thalia K. Robakis, MD, from the women’s mental health program at Icahn School of Medicine at Mount Sinai, New York, who was not involved in the study.

But Dr. Robakis cautioned that no clinical outcomes were measured among the babies born, meaning that the study could not document any effects of maternal depression and stress on fetal development. Rather, the work contributes to figuring out what mechanisms are involved.

“Pregnant women should continue to focus on optimizing their own physical and mental health,” Dr. Robakis said. “And they should know that a happy, healthy mother is the most important factor supporting the development of a happy, healthy baby.”

A version of this article first appeared on WebMD.com.

New evidence points to the importance of helping mothers with their mental health during pregnancy.

Researchers from the National Institutes of Health in Bethesda, Md., have found that feelings of stress or depression while pregnant are linked to changes in the placenta where the child is growing. The findings, published in Epigenomics, show these changes could alter gene activity.

Stress and depression are not uncommon among expectant women, with depression affecting an estimated 1 in 10 pregnancies, according to the American College of Obstetricians and Gynecologists.

And current evidence already suggests that depression during pregnancy can negatively affect a child later in life. For instance, one study found that depression during pregnancy was linked to behavioral and emotional disorders during childhood, and another found that it raised the risk of depression at age 18.

To investigate stress and depression during pregnancy, the NIH investigators evaluated 301 pregnant women from 12 clinics in the United States who had taken part in an earlier clinical study. The group was ethnically diverse, with 34% identifying as Hispanic, 26% as non-Hispanic White, 24% as non-Hispanic Black, and 17% as Asian or Pacific Islander.

At the start of the study, the women were asked to complete questionnaires routinely used to screen for stress and depression. They completed the questionnaire five more times during their pregnancies. Shortly after each woman gave birth, researchers took tissue samples from the placenta and analyzed the genetics.

The purpose of studying the placenta, according to lead researcher Markos Tesfaye, MD, a postdoctoral fellow at the NIH, is that chemical changes can regulate whether a nearby gene can be activated.

There is evidence that chemical modifications in the placenta can lead to changes in fetal tissues, such as the brain, he said. And the placenta is known for making neurotransmitters, which are needed for fetal brain development.

The team found 16 areas where changes to the exterior of placental DNA were linked to depression in the second or third trimester. They also found two areas where these changes were associated with stress in the third trimester.

“Maternal depression leaves signals in the placenta at genes critical for fetal brain programming,” said study author Fasil Tekola-Ayele, PhD, from the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Two of the chemical changes linked to depression were near genes that are known to be involved with fetal brain development and neurologic and psychiatric illnesses.

“The findings illustrate that the developing fetus is sensitive to the mother›s condition during pregnancy, including maternal symptoms of low mood and perceived stress,” said Thalia K. Robakis, MD, from the women’s mental health program at Icahn School of Medicine at Mount Sinai, New York, who was not involved in the study.

But Dr. Robakis cautioned that no clinical outcomes were measured among the babies born, meaning that the study could not document any effects of maternal depression and stress on fetal development. Rather, the work contributes to figuring out what mechanisms are involved.

“Pregnant women should continue to focus on optimizing their own physical and mental health,” Dr. Robakis said. “And they should know that a happy, healthy mother is the most important factor supporting the development of a happy, healthy baby.”

A version of this article first appeared on WebMD.com.

Approximately 12,000 new cases of cervical cancer are diagnosed in women in the United States each year, based on data from the Centers for Disease Control and Prevention, said B.J. Rimel, MD, of Cedars-Sinai Medical Center, Los Angeles, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.

Despite increased cervical cancer prevention and screening efforts, the incidence of, and mortality from, cervical cancer has remained stable for the past 2 decades, said Dr. Rimel.

Cervical cancer is the only cancer that can be prevented by vaccination, Dr. Rimel noted. It is essential to identify the women who are dying from cervical cancer, as well as who gets screened, who gets vaccinated, and who ends up in clinical trials, she said.

Novel agents for treating cervical cancer suggest that improvement in stagnant mortality rates is possible, said Dr. Rimel. She noted recent studies of cemiplimab, tisotumab vedotin, and a combination therapy involving pembrolizumab and platinum/paclitaxel, with and without bevacizumab.

Dr. Rimel suggested several opportunities to improve the identification and treatment of cervical cancer: Treat it like a rare disease; address structural racism through clinical trials; create opportunities for low–socioeconomic status patients to be involved in research; and develop solutions according to location (urban vs. rural), she said.

Compared with other cancers, cervical cancer is relatively rare in the United States, Dr. Rimel said. However, “It is important that those with cervical cancer can get treated and get healed from the disease,” she said. To better identify the women with cervical cancer who need treatment and to get them into clinical trials, she suggested using strategies employed by rare disease groups, such as seeking out patient support groups and registries.

Significant racial and ethnic disparities persist in cervical cancer, Dr. Rimel emphasized. Data from the CDC show that Black and Hispanic women in the United States are diagnosed with cervical cancer more frequently than women of other races and ethnicities and are less likely to survive.

“Reimagine cervical cancer as a disease of patients who are historically underrepresented due to race, language, poverty, and location,” she said.

Improving equity in cervical cancer care involves structural and trial-specific issues, said Dr. Rimel. Structural issues start with addressing how women enter into the health care system, she said. Consider where women receive care, and whether women have the opportunity to be vaccinated, and later screened, she said. Consider barriers to cervical cancer trials in centers with larger underserved populations, not only cost or insurance, but also issues of language and trust between patients and health care providers, she noted.

To improve the equity of cervical cancer clinical trials, consider potential barriers to enrollment, she added.

“Low English fluency is a barrier to trial enrollment,” said Dr. Rimel. In-person translation is essential for consent to participate in a trial, and “clinical trial budgets must reflect this requirement,” she added. Patient-reported outcomes need to be in the patient’s preferred language, “this includes online content,” Dr. Rimel said.

Dr. Rimel presented other strategies for clinical trial designs to improve equity.

“Compensate patients for their travel, or provide them with tech to allow for off-site monitoring,” she proposed. Patients of lower socioeconomic status in rural and urban areas have different barriers to enrollment, but virtual visits might be an option for those able to access the Internet when given a device. For others, smaller trial sites closer to home, combined with compensation for travel or missed work, might create more opportunities to participate, Dr. Rimel said. Finally, researchers should consider potential roles for smaller or broader studies that involve less travel and testing that would be feasible for more patients who might not otherwise participate in a clinical trial, she concluded.

Dr. Rimel had no financial conflicts to disclose.

Approximately 12,000 new cases of cervical cancer are diagnosed in women in the United States each year, based on data from the Centers for Disease Control and Prevention, said B.J. Rimel, MD, of Cedars-Sinai Medical Center, Los Angeles, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.

Despite increased cervical cancer prevention and screening efforts, the incidence of, and mortality from, cervical cancer has remained stable for the past 2 decades, said Dr. Rimel.

Cervical cancer is the only cancer that can be prevented by vaccination, Dr. Rimel noted. It is essential to identify the women who are dying from cervical cancer, as well as who gets screened, who gets vaccinated, and who ends up in clinical trials, she said.

Novel agents for treating cervical cancer suggest that improvement in stagnant mortality rates is possible, said Dr. Rimel. She noted recent studies of cemiplimab, tisotumab vedotin, and a combination therapy involving pembrolizumab and platinum/paclitaxel, with and without bevacizumab.

Dr. Rimel suggested several opportunities to improve the identification and treatment of cervical cancer: Treat it like a rare disease; address structural racism through clinical trials; create opportunities for low–socioeconomic status patients to be involved in research; and develop solutions according to location (urban vs. rural), she said.

Compared with other cancers, cervical cancer is relatively rare in the United States, Dr. Rimel said. However, “It is important that those with cervical cancer can get treated and get healed from the disease,” she said. To better identify the women with cervical cancer who need treatment and to get them into clinical trials, she suggested using strategies employed by rare disease groups, such as seeking out patient support groups and registries.

Significant racial and ethnic disparities persist in cervical cancer, Dr. Rimel emphasized. Data from the CDC show that Black and Hispanic women in the United States are diagnosed with cervical cancer more frequently than women of other races and ethnicities and are less likely to survive.

“Reimagine cervical cancer as a disease of patients who are historically underrepresented due to race, language, poverty, and location,” she said.

Improving equity in cervical cancer care involves structural and trial-specific issues, said Dr. Rimel. Structural issues start with addressing how women enter into the health care system, she said. Consider where women receive care, and whether women have the opportunity to be vaccinated, and later screened, she said. Consider barriers to cervical cancer trials in centers with larger underserved populations, not only cost or insurance, but also issues of language and trust between patients and health care providers, she noted.

To improve the equity of cervical cancer clinical trials, consider potential barriers to enrollment, she added.

“Low English fluency is a barrier to trial enrollment,” said Dr. Rimel. In-person translation is essential for consent to participate in a trial, and “clinical trial budgets must reflect this requirement,” she added. Patient-reported outcomes need to be in the patient’s preferred language, “this includes online content,” Dr. Rimel said.

Dr. Rimel presented other strategies for clinical trial designs to improve equity.

“Compensate patients for their travel, or provide them with tech to allow for off-site monitoring,” she proposed. Patients of lower socioeconomic status in rural and urban areas have different barriers to enrollment, but virtual visits might be an option for those able to access the Internet when given a device. For others, smaller trial sites closer to home, combined with compensation for travel or missed work, might create more opportunities to participate, Dr. Rimel said. Finally, researchers should consider potential roles for smaller or broader studies that involve less travel and testing that would be feasible for more patients who might not otherwise participate in a clinical trial, she concluded.

Dr. Rimel had no financial conflicts to disclose.

Approximately 12,000 new cases of cervical cancer are diagnosed in women in the United States each year, based on data from the Centers for Disease Control and Prevention, said B.J. Rimel, MD, of Cedars-Sinai Medical Center, Los Angeles, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.

Despite increased cervical cancer prevention and screening efforts, the incidence of, and mortality from, cervical cancer has remained stable for the past 2 decades, said Dr. Rimel.

Cervical cancer is the only cancer that can be prevented by vaccination, Dr. Rimel noted. It is essential to identify the women who are dying from cervical cancer, as well as who gets screened, who gets vaccinated, and who ends up in clinical trials, she said.

Novel agents for treating cervical cancer suggest that improvement in stagnant mortality rates is possible, said Dr. Rimel. She noted recent studies of cemiplimab, tisotumab vedotin, and a combination therapy involving pembrolizumab and platinum/paclitaxel, with and without bevacizumab.

Dr. Rimel suggested several opportunities to improve the identification and treatment of cervical cancer: Treat it like a rare disease; address structural racism through clinical trials; create opportunities for low–socioeconomic status patients to be involved in research; and develop solutions according to location (urban vs. rural), she said.

Compared with other cancers, cervical cancer is relatively rare in the United States, Dr. Rimel said. However, “It is important that those with cervical cancer can get treated and get healed from the disease,” she said. To better identify the women with cervical cancer who need treatment and to get them into clinical trials, she suggested using strategies employed by rare disease groups, such as seeking out patient support groups and registries.

Significant racial and ethnic disparities persist in cervical cancer, Dr. Rimel emphasized. Data from the CDC show that Black and Hispanic women in the United States are diagnosed with cervical cancer more frequently than women of other races and ethnicities and are less likely to survive.

“Reimagine cervical cancer as a disease of patients who are historically underrepresented due to race, language, poverty, and location,” she said.

Improving equity in cervical cancer care involves structural and trial-specific issues, said Dr. Rimel. Structural issues start with addressing how women enter into the health care system, she said. Consider where women receive care, and whether women have the opportunity to be vaccinated, and later screened, she said. Consider barriers to cervical cancer trials in centers with larger underserved populations, not only cost or insurance, but also issues of language and trust between patients and health care providers, she noted.

To improve the equity of cervical cancer clinical trials, consider potential barriers to enrollment, she added.

“Low English fluency is a barrier to trial enrollment,” said Dr. Rimel. In-person translation is essential for consent to participate in a trial, and “clinical trial budgets must reflect this requirement,” she added. Patient-reported outcomes need to be in the patient’s preferred language, “this includes online content,” Dr. Rimel said.

Dr. Rimel presented other strategies for clinical trial designs to improve equity.

“Compensate patients for their travel, or provide them with tech to allow for off-site monitoring,” she proposed. Patients of lower socioeconomic status in rural and urban areas have different barriers to enrollment, but virtual visits might be an option for those able to access the Internet when given a device. For others, smaller trial sites closer to home, combined with compensation for travel or missed work, might create more opportunities to participate, Dr. Rimel said. Finally, researchers should consider potential roles for smaller or broader studies that involve less travel and testing that would be feasible for more patients who might not otherwise participate in a clinical trial, she concluded.

Dr. Rimel had no financial conflicts to disclose.

An increasing number of people who are unvaccinated and pregnant are being hospitalized for COVID-19, report investigators who saw hospital admissions double in a single year.

“With the surge, we had expected to begin treating patients who developed severe or critical illness again in pregnancy,” says Emily Adhikari, MD, from the University of Texas Southwestern Medical Center in Dallas. “But we did not expect the level of respiratory illness that we began to see in our patients. That was a surprise and an alarming finding that we felt was really important to get out there.”

The researchers followed more than 1,500 pregnant women diagnosed with COVID-19 who received care from Parkland Health and Hospital System in Dallas County, one of the nation’s busiest for deliveries. After the emergence of the Delta variant, the number of pregnant women hospitalized with COVID-19 more than doubled over the previous year.

And 82 pregnant women went on to develop severe or critical COVID, they report in their study, published online in the American Journal of Obstetrics and Gynecology. All but 1 of these patients were unvaccinated, 10 needed a ventilator, and two died.

The proportion of cases that were critical was about 5% in 2020. However, in April 2021, even though the number of total cases remained low, the number of severe illnesses started to rise. After the Delta variant became dominant, both the number and severity of cases increased, and after August 2021, more than 25% of pregnant people diagnosed with COVID-19 required hospitalization.
 

Hospitalizations Double

“We need to focus and really act urgently to recommend vaccination in pregnancy because that is the primary prevention tool that we have,” says Dr. Adhikari. “We do not have a proven cure for this illness, and that is important to know.”

These findings, which focus on a vulnerable population, are especially important given the elevated prevalence of COVID-19 in pregnant people of lower economic status, said Lissette Tanner, MD, MPH, from Emory University in Atlanta, who was not involved with the study.

“There are higher rates of hospitalization and death among Black, Hispanic, and Native American communities,” she reported. “It is essential to know how the virus is affecting those most affected and often most disadvantaged to deal with the pandemic.”

Vaccination rates are low in this population; just 19.2% of pregnant women receive at least one dose during pregnancy, according to the CDC. But pregnancy confers a higher risk for severe COVID-19 illness and for adverse outcomes, such as preterm birth and stillbirth.

Of the 665 people in the study cohort who were pregnant or had given birth when the vaccines were available, only 21.4% received at least one dose of a COVID-19 vaccine.

Given the increased risk for COVID-19 during pregnancy, the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC recommend vaccination for people who are pregnant, breastfeeding, or trying to get pregnant.

According to ACOG, pregnant women who are fully vaccinated can follow the same guidelines as everyone else who is fully vaccinated; however, to prevent breakthrough infections, they might want to continue wearing a mask. ACOG also recommends that those not fully vaccinated follow physical-distancing guidelines and limit contact with people as much as possible to avoid infection.

A version of this article first appeared on WebMD.com.

An increasing number of people who are unvaccinated and pregnant are being hospitalized for COVID-19, report investigators who saw hospital admissions double in a single year.

“With the surge, we had expected to begin treating patients who developed severe or critical illness again in pregnancy,” says Emily Adhikari, MD, from the University of Texas Southwestern Medical Center in Dallas. “But we did not expect the level of respiratory illness that we began to see in our patients. That was a surprise and an alarming finding that we felt was really important to get out there.”

The researchers followed more than 1,500 pregnant women diagnosed with COVID-19 who received care from Parkland Health and Hospital System in Dallas County, one of the nation’s busiest for deliveries. After the emergence of the Delta variant, the number of pregnant women hospitalized with COVID-19 more than doubled over the previous year.

And 82 pregnant women went on to develop severe or critical COVID, they report in their study, published online in the American Journal of Obstetrics and Gynecology. All but 1 of these patients were unvaccinated, 10 needed a ventilator, and two died.

The proportion of cases that were critical was about 5% in 2020. However, in April 2021, even though the number of total cases remained low, the number of severe illnesses started to rise. After the Delta variant became dominant, both the number and severity of cases increased, and after August 2021, more than 25% of pregnant people diagnosed with COVID-19 required hospitalization.
 

Hospitalizations Double

“We need to focus and really act urgently to recommend vaccination in pregnancy because that is the primary prevention tool that we have,” says Dr. Adhikari. “We do not have a proven cure for this illness, and that is important to know.”

These findings, which focus on a vulnerable population, are especially important given the elevated prevalence of COVID-19 in pregnant people of lower economic status, said Lissette Tanner, MD, MPH, from Emory University in Atlanta, who was not involved with the study.

“There are higher rates of hospitalization and death among Black, Hispanic, and Native American communities,” she reported. “It is essential to know how the virus is affecting those most affected and often most disadvantaged to deal with the pandemic.”

Vaccination rates are low in this population; just 19.2% of pregnant women receive at least one dose during pregnancy, according to the CDC. But pregnancy confers a higher risk for severe COVID-19 illness and for adverse outcomes, such as preterm birth and stillbirth.

Of the 665 people in the study cohort who were pregnant or had given birth when the vaccines were available, only 21.4% received at least one dose of a COVID-19 vaccine.

Given the increased risk for COVID-19 during pregnancy, the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC recommend vaccination for people who are pregnant, breastfeeding, or trying to get pregnant.

According to ACOG, pregnant women who are fully vaccinated can follow the same guidelines as everyone else who is fully vaccinated; however, to prevent breakthrough infections, they might want to continue wearing a mask. ACOG also recommends that those not fully vaccinated follow physical-distancing guidelines and limit contact with people as much as possible to avoid infection.

A version of this article first appeared on WebMD.com.

An increasing number of people who are unvaccinated and pregnant are being hospitalized for COVID-19, report investigators who saw hospital admissions double in a single year.

“With the surge, we had expected to begin treating patients who developed severe or critical illness again in pregnancy,” says Emily Adhikari, MD, from the University of Texas Southwestern Medical Center in Dallas. “But we did not expect the level of respiratory illness that we began to see in our patients. That was a surprise and an alarming finding that we felt was really important to get out there.”

The researchers followed more than 1,500 pregnant women diagnosed with COVID-19 who received care from Parkland Health and Hospital System in Dallas County, one of the nation’s busiest for deliveries. After the emergence of the Delta variant, the number of pregnant women hospitalized with COVID-19 more than doubled over the previous year.

And 82 pregnant women went on to develop severe or critical COVID, they report in their study, published online in the American Journal of Obstetrics and Gynecology. All but 1 of these patients were unvaccinated, 10 needed a ventilator, and two died.

The proportion of cases that were critical was about 5% in 2020. However, in April 2021, even though the number of total cases remained low, the number of severe illnesses started to rise. After the Delta variant became dominant, both the number and severity of cases increased, and after August 2021, more than 25% of pregnant people diagnosed with COVID-19 required hospitalization.
 

Hospitalizations Double

“We need to focus and really act urgently to recommend vaccination in pregnancy because that is the primary prevention tool that we have,” says Dr. Adhikari. “We do not have a proven cure for this illness, and that is important to know.”

These findings, which focus on a vulnerable population, are especially important given the elevated prevalence of COVID-19 in pregnant people of lower economic status, said Lissette Tanner, MD, MPH, from Emory University in Atlanta, who was not involved with the study.

“There are higher rates of hospitalization and death among Black, Hispanic, and Native American communities,” she reported. “It is essential to know how the virus is affecting those most affected and often most disadvantaged to deal with the pandemic.”

Vaccination rates are low in this population; just 19.2% of pregnant women receive at least one dose during pregnancy, according to the CDC. But pregnancy confers a higher risk for severe COVID-19 illness and for adverse outcomes, such as preterm birth and stillbirth.

Of the 665 people in the study cohort who were pregnant or had given birth when the vaccines were available, only 21.4% received at least one dose of a COVID-19 vaccine.

Given the increased risk for COVID-19 during pregnancy, the American College of Obstetricians and Gynecologists, the Society for Maternal-Fetal Medicine, and the CDC recommend vaccination for people who are pregnant, breastfeeding, or trying to get pregnant.

According to ACOG, pregnant women who are fully vaccinated can follow the same guidelines as everyone else who is fully vaccinated; however, to prevent breakthrough infections, they might want to continue wearing a mask. ACOG also recommends that those not fully vaccinated follow physical-distancing guidelines and limit contact with people as much as possible to avoid infection.

A version of this article first appeared on WebMD.com.

Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.

The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.

“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”

The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.

One year post implementation, the following outcomes emerged, compared with preimplementation:

• Overall projected saving of $181,000 a year in the maternity unit
• Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
• A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
• No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
• Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
• No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)

“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”

Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
 

The study

Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.

Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.

Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.

Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.

The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.

Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”

The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”

The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.

Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.

The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.

“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”

The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.

One year post implementation, the following outcomes emerged, compared with preimplementation:

• Overall projected saving of $181,000 a year in the maternity unit
• Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
• A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
• No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
• Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
• No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)

“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”

Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
 

The study

Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.

Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.

Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.

Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.

The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.

Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”

The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”

The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.

Implementing a selective type-and-screen blood testing policy in the labor and delivery unit was associated with projected annual savings of close to $200,000, a large single-center study found. Furthermore, there was no evidence of increased maternal morbidity in the university-based facility performing more than 4,400 deliveries per year, according to Ashley E. Benson, MD, MA, of the department of obstetrics and gynecology at the University of Utah, Salt Lake City, and colleagues.

The study, published in Obstetrics & Gynecology, evaluated patient safety, resource utilization, and transfusion-related costs after a policy change from universal type and screen to selective, risk-based type and screen on admission to labor and delivery.

“There had been some national interest in moving toward decreased resource utilization, and findings that universal screening was not cost effective,” Dr. Benson, who has since relocated to Oregon Health & Science University, Portland, said in an interview. An earlier cost-effective modeling study at her center had suggested that universal test and screen was not cost effective and likely not safer either. “So based on that data we felt an implementation study was warranted.”

The switch to a selective policy was made in 2018, after which her group compared outcomes from October 2017 to September 2019, looking those both 1 year preimplementation and 1 year post implementation.

One year post implementation, the following outcomes emerged, compared with preimplementation:

• Overall projected saving of $181,000 a year in the maternity unit
• Lower mean monthly type- and screen-related costs, such as those for ABO typing, antibody screen, and antibody workup. cross-matches, hold clots, and transfused products: $9,753 vs. $20,676 in the preimplementation year (P < .001)
• A lower mean monthly cost of total transfusion preparedness: $25,090 vs. $39,211 (P < .001)
• No differences in emergency-release transfusion events (four vs. three, P = .99),the study’s primary safety outcome
• Fewer emergency-release red blood cell units transfused (9 vs. 24, P = .002) and O-negative RBC units transfused (8 vs. 18, P = .016)
• No differences in hysterectomies (0.05% vs. 0.1%, P = .44) and ICU admissions (0.45% vs. 0.51%, P = .43)

“In a year of selective type and screen, we saw a 51% reduction in costs related to type and screen, and a 38% reduction in overall transfusion-related costs,” the authors wrote. “This study supports other literature suggesting that more judicious use of type and screen may be safe and cost effective.”

Dr. Benson said the results were positively received when presented a meeting 2 years ago but the published version has yet to prompt feedback.
 

The study

Antepartum patients underwent transfusion preparedness tests according to the center’s standard antenatal admission order sets and were risk stratified in alignment with California Maternal Quality Care Collaborative recommendations. The mean maternal age of patients in both time periods was similar at just over 29 years and the mean gestational age at delivery was just under 38 weeks.

Under the new policy, a “hold clot” is obtained for women stratified as low or medium risk on admission. In this instance, a tube of patient blood is held in the blood bank but processed only if needed, as in the event of active hemorrhage or an order for transfusion. A blood cross-match is obtained on all women stratified as high risk or having a prior positive antibody screen.

Relevant costs were the direct costs of transfusion-related testing in the labor and delivery unit from a health system perspective.

Obstetric hemorrhage is the leading cause of maternal death worldwide, the authors pointed out. While transfusion in obstetric patients occurs in only 1% or 2% of all deliveries it is nevertheless difficult to predict which patients will need transfusion, with only 2%-8% of those stratified as high risk ultimately requiring transfusion. Although obstetric hemorrhage safety bundles recommend risk stratification on admission to labor and delivery with selective type and screen for higher-risk individuals, for safety and simplicity’s sake, many labor and delivery units perform universal type and screen.

The authors cautioned that these results occurred in an academic tertiary care center with systems fine-tuned to deal with active hemorrhage and deliver timely transfusable blood. “At the moment we don’t have enough data to say whether the selective approach would be safe in hospitals with more limited blood bank capacity and access and fewer transfusion specialists in a setting optimized to respond to emergent needs, Dr. Benson said.

Katayoun F. M. Fomani, MD, a transfusion medicine specialist and medical director of blood bank and transfusion services at Long Island Jewish Medical Center, New York, agreed. “This approach only works in a controlled environment such as in this study where eligible women were assessed antenatally at the same center, but it would not work at every institution,” she said in an interview. “In addition, all patients were assessed according to the California Collaborative guideline, which itself increases the safety level but is not followed everywhere.”

The obstetric division at her hospital in New York adheres to the universal type and screen. “We have patients coming in from outside whose antenatal testing was not done at our hospital,” she said. “For this selective approach to work you need a controlled population and the electronic resources and personnel to follow each patient carefully.”

The authors indicated no specific funding for this study and disclosed no potential conflicts of interest. Dr. Fomani had no potential competing interests to declare.

Maternal mortality is a public health crisis for all women, said Elizabeth A. Howell, MD, of the University of Pennsylvania, Philadelphia, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.

The maternal mortality rate in the United States in 2018 was 17.4 maternal deaths per 100,000 live births, according to data from the Centers for Disease Control and Prevention, Dr. Howell said. Maternal mortality is defined as death during pregnancy or within 42 days of delivery; pregnancy-related mortality includes death during pregnancy or within 1 year of pregnancy, from pregnancy or as a result of any cause related to, or aggravated by, pregnancy, according to the CDC.

However, “Black women are two to three times more likely than White women to die from a pregnancy-related cause,” Dr. Howell said. These disparities are even more marked in some cities; data show that Black women in New York City are eight times more likely than White women to die from a pregnancy-related cause, she noted.

Pregnancy-related mortality persists regardless of education level, and remains significantly higher in Black women, compared with White women with at least a college degree, Dr. Howell added.

In her presentation, Dr. Howell reviewed some top causes of maternal mortality overall, and potential factors driving disparities. Data from the CDC show cardiomyopathy, cardiovascular conditions, and preeclampsia/eclampsia as the top three underlying causes of pregnancy-related deaths among non-Hispanic Black women, compared with mental health conditions, cardiovascular conditions, and hemorrhage in non-Hispanic White women, Dr. Howell said.

To help prevent maternal mortality across all populations, “It is important for us to think about the timing of deaths so we can better understand the causes,” said Dr. Howell.

CDC Vital Signs data show that approximately one-third of pregnancy-related deaths occur during pregnancy, but approximately 20% occur between 43 and 365 days postpartum, she said.

Although cardiovascular conditions top the list of clinical causes of pregnancy-related maternal mortality, maternal self-harm should not be discounted, and is likely underreported, Dr. Howell said. Data show that the peak incidence of maternal suicide occurs between 9 and 12 months’ postpartum, and risk factors include major depression, substance use disorder, and intimate partner violence, she noted.

Dr. Howell then shared the results of studies she conducted in 2020 and 2016 on racial disparities, hospital quality, and maternal mortality. One of her key findings in the 2020 study, presented at this year’s virtual meeting of the American College of Obstetricians and Gynecologists, showed that women delivering in the lowest-ranked hospitals had six times the rate of severe maternal morbidity, and an accompanying simulation/thought exercise showed that the hospital of delivery accounted for approximately half of the disparity in severe maternal morbidity between Black and White women. An earlier study she published in 2016 of between-hospital differences in New York City showed that Black and Latina women were significantly more likely than White women to deliver in hospitals with higher rates of severe maternal mortality.

These findings illustrate that “racial segregation in neighborhoods is also part of the story,” of maternal mortality, Dr. Howell said.

Dr. Howell outlined ways the health care community can reduce severe maternal morbidity and mortality for all women, including promoting contraception and preconception health, improving postpartum management, eliminating bias, and using patient navigators as needed to enhance communication among the care team,

“Think about ways to engage the community,” in support of women’s pregnancy health, Dr. Howell said. She also emphasized the need to enroll more pregnant women in clinical trials.
 

Don’t exclude pregnant women from trials

In a follow-up session, Cynthia Gyamfi-Bannerman, MD, of the University of California, San Diego, expanded on opportunities to include pregnant women in clinical research.

Clinical trials for pregnant people fall into two categories, she noted; those studying interventions to improve pregnancy outcomes and those studying interventions for common medical conditions that coexist with pregnancy. These trials are either initiated by the investigators, conducted under contract, or federally funded, Dr. Gyamfi-Bannerman said. Currently, the only obstetric clinical trials research network is the Maternal-Fetal Medicine Units Network, established in 1986 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The MFMU has conducted significant and life-saving research, but “we need more networks to focus on researching pregnancy complications,” Dr. Gyamfi-Bannerman said. Once the infrastructure exists in multiple settings, the ability to conduct trials will improve, she said.

Dr. Gyamfi-Bannerman stressed the need to engage and involve community-based physicians in clinical trials; using those relationships to enroll a more diverse population for whom working with their local physician would be more feasible than traveling to a larger clinical trial center.

She also commented on the need to include pregnant women in nonobstetric clinical trials. The exclusion of pregnant women from COVID-19 vaccine trials left clinicians with no information for guiding pregnant patients, she said. “It is important to think about why we are excluding pregnant women,” she said.

Finally, Dr. Gyamfi-Bannerman recommended a national effort to coordinate and leverage EHR data, which could have an effect on reducing maternal morbidity by facilitating the study of nonobstetric interventions in pregnancy, such as behavior interventions and mental health care.

Dr. Howell and Dr. Gyamfi-Bannerman had no financial conflicts to disclose.
 

Maternal mortality is a public health crisis for all women, said Elizabeth A. Howell, MD, of the University of Pennsylvania, Philadelphia, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.

The maternal mortality rate in the United States in 2018 was 17.4 maternal deaths per 100,000 live births, according to data from the Centers for Disease Control and Prevention, Dr. Howell said. Maternal mortality is defined as death during pregnancy or within 42 days of delivery; pregnancy-related mortality includes death during pregnancy or within 1 year of pregnancy, from pregnancy or as a result of any cause related to, or aggravated by, pregnancy, according to the CDC.

However, “Black women are two to three times more likely than White women to die from a pregnancy-related cause,” Dr. Howell said. These disparities are even more marked in some cities; data show that Black women in New York City are eight times more likely than White women to die from a pregnancy-related cause, she noted.

Pregnancy-related mortality persists regardless of education level, and remains significantly higher in Black women, compared with White women with at least a college degree, Dr. Howell added.

In her presentation, Dr. Howell reviewed some top causes of maternal mortality overall, and potential factors driving disparities. Data from the CDC show cardiomyopathy, cardiovascular conditions, and preeclampsia/eclampsia as the top three underlying causes of pregnancy-related deaths among non-Hispanic Black women, compared with mental health conditions, cardiovascular conditions, and hemorrhage in non-Hispanic White women, Dr. Howell said.

To help prevent maternal mortality across all populations, “It is important for us to think about the timing of deaths so we can better understand the causes,” said Dr. Howell.

CDC Vital Signs data show that approximately one-third of pregnancy-related deaths occur during pregnancy, but approximately 20% occur between 43 and 365 days postpartum, she said.

Although cardiovascular conditions top the list of clinical causes of pregnancy-related maternal mortality, maternal self-harm should not be discounted, and is likely underreported, Dr. Howell said. Data show that the peak incidence of maternal suicide occurs between 9 and 12 months’ postpartum, and risk factors include major depression, substance use disorder, and intimate partner violence, she noted.

Dr. Howell then shared the results of studies she conducted in 2020 and 2016 on racial disparities, hospital quality, and maternal mortality. One of her key findings in the 2020 study, presented at this year’s virtual meeting of the American College of Obstetricians and Gynecologists, showed that women delivering in the lowest-ranked hospitals had six times the rate of severe maternal morbidity, and an accompanying simulation/thought exercise showed that the hospital of delivery accounted for approximately half of the disparity in severe maternal morbidity between Black and White women. An earlier study she published in 2016 of between-hospital differences in New York City showed that Black and Latina women were significantly more likely than White women to deliver in hospitals with higher rates of severe maternal mortality.

These findings illustrate that “racial segregation in neighborhoods is also part of the story,” of maternal mortality, Dr. Howell said.

Dr. Howell outlined ways the health care community can reduce severe maternal morbidity and mortality for all women, including promoting contraception and preconception health, improving postpartum management, eliminating bias, and using patient navigators as needed to enhance communication among the care team,

“Think about ways to engage the community,” in support of women’s pregnancy health, Dr. Howell said. She also emphasized the need to enroll more pregnant women in clinical trials.
 

Don’t exclude pregnant women from trials

In a follow-up session, Cynthia Gyamfi-Bannerman, MD, of the University of California, San Diego, expanded on opportunities to include pregnant women in clinical research.

Clinical trials for pregnant people fall into two categories, she noted; those studying interventions to improve pregnancy outcomes and those studying interventions for common medical conditions that coexist with pregnancy. These trials are either initiated by the investigators, conducted under contract, or federally funded, Dr. Gyamfi-Bannerman said. Currently, the only obstetric clinical trials research network is the Maternal-Fetal Medicine Units Network, established in 1986 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The MFMU has conducted significant and life-saving research, but “we need more networks to focus on researching pregnancy complications,” Dr. Gyamfi-Bannerman said. Once the infrastructure exists in multiple settings, the ability to conduct trials will improve, she said.

Dr. Gyamfi-Bannerman stressed the need to engage and involve community-based physicians in clinical trials; using those relationships to enroll a more diverse population for whom working with their local physician would be more feasible than traveling to a larger clinical trial center.

She also commented on the need to include pregnant women in nonobstetric clinical trials. The exclusion of pregnant women from COVID-19 vaccine trials left clinicians with no information for guiding pregnant patients, she said. “It is important to think about why we are excluding pregnant women,” she said.

Finally, Dr. Gyamfi-Bannerman recommended a national effort to coordinate and leverage EHR data, which could have an effect on reducing maternal morbidity by facilitating the study of nonobstetric interventions in pregnancy, such as behavior interventions and mental health care.

Dr. Howell and Dr. Gyamfi-Bannerman had no financial conflicts to disclose.
 

Maternal mortality is a public health crisis for all women, said Elizabeth A. Howell, MD, of the University of Pennsylvania, Philadelphia, in a presentation at the virtual Advancing NIH Research on the Health of Women conference sponsored by the National Institutes of Health.

The maternal mortality rate in the United States in 2018 was 17.4 maternal deaths per 100,000 live births, according to data from the Centers for Disease Control and Prevention, Dr. Howell said. Maternal mortality is defined as death during pregnancy or within 42 days of delivery; pregnancy-related mortality includes death during pregnancy or within 1 year of pregnancy, from pregnancy or as a result of any cause related to, or aggravated by, pregnancy, according to the CDC.

However, “Black women are two to three times more likely than White women to die from a pregnancy-related cause,” Dr. Howell said. These disparities are even more marked in some cities; data show that Black women in New York City are eight times more likely than White women to die from a pregnancy-related cause, she noted.

Pregnancy-related mortality persists regardless of education level, and remains significantly higher in Black women, compared with White women with at least a college degree, Dr. Howell added.

In her presentation, Dr. Howell reviewed some top causes of maternal mortality overall, and potential factors driving disparities. Data from the CDC show cardiomyopathy, cardiovascular conditions, and preeclampsia/eclampsia as the top three underlying causes of pregnancy-related deaths among non-Hispanic Black women, compared with mental health conditions, cardiovascular conditions, and hemorrhage in non-Hispanic White women, Dr. Howell said.

To help prevent maternal mortality across all populations, “It is important for us to think about the timing of deaths so we can better understand the causes,” said Dr. Howell.

CDC Vital Signs data show that approximately one-third of pregnancy-related deaths occur during pregnancy, but approximately 20% occur between 43 and 365 days postpartum, she said.

Although cardiovascular conditions top the list of clinical causes of pregnancy-related maternal mortality, maternal self-harm should not be discounted, and is likely underreported, Dr. Howell said. Data show that the peak incidence of maternal suicide occurs between 9 and 12 months’ postpartum, and risk factors include major depression, substance use disorder, and intimate partner violence, she noted.

Dr. Howell then shared the results of studies she conducted in 2020 and 2016 on racial disparities, hospital quality, and maternal mortality. One of her key findings in the 2020 study, presented at this year’s virtual meeting of the American College of Obstetricians and Gynecologists, showed that women delivering in the lowest-ranked hospitals had six times the rate of severe maternal morbidity, and an accompanying simulation/thought exercise showed that the hospital of delivery accounted for approximately half of the disparity in severe maternal morbidity between Black and White women. An earlier study she published in 2016 of between-hospital differences in New York City showed that Black and Latina women were significantly more likely than White women to deliver in hospitals with higher rates of severe maternal mortality.

These findings illustrate that “racial segregation in neighborhoods is also part of the story,” of maternal mortality, Dr. Howell said.

Dr. Howell outlined ways the health care community can reduce severe maternal morbidity and mortality for all women, including promoting contraception and preconception health, improving postpartum management, eliminating bias, and using patient navigators as needed to enhance communication among the care team,

“Think about ways to engage the community,” in support of women’s pregnancy health, Dr. Howell said. She also emphasized the need to enroll more pregnant women in clinical trials.
 

Don’t exclude pregnant women from trials

In a follow-up session, Cynthia Gyamfi-Bannerman, MD, of the University of California, San Diego, expanded on opportunities to include pregnant women in clinical research.

Clinical trials for pregnant people fall into two categories, she noted; those studying interventions to improve pregnancy outcomes and those studying interventions for common medical conditions that coexist with pregnancy. These trials are either initiated by the investigators, conducted under contract, or federally funded, Dr. Gyamfi-Bannerman said. Currently, the only obstetric clinical trials research network is the Maternal-Fetal Medicine Units Network, established in 1986 by the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The MFMU has conducted significant and life-saving research, but “we need more networks to focus on researching pregnancy complications,” Dr. Gyamfi-Bannerman said. Once the infrastructure exists in multiple settings, the ability to conduct trials will improve, she said.

Dr. Gyamfi-Bannerman stressed the need to engage and involve community-based physicians in clinical trials; using those relationships to enroll a more diverse population for whom working with their local physician would be more feasible than traveling to a larger clinical trial center.

She also commented on the need to include pregnant women in nonobstetric clinical trials. The exclusion of pregnant women from COVID-19 vaccine trials left clinicians with no information for guiding pregnant patients, she said. “It is important to think about why we are excluding pregnant women,” she said.

Finally, Dr. Gyamfi-Bannerman recommended a national effort to coordinate and leverage EHR data, which could have an effect on reducing maternal morbidity by facilitating the study of nonobstetric interventions in pregnancy, such as behavior interventions and mental health care.

Dr. Howell and Dr. Gyamfi-Bannerman had no financial conflicts to disclose.
 

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

Nearly 9 in 10 U.S. women take a medication at some point in their pregnancy, with approximately 50% of women taking at least one prescription medication.¹ These medications may be prescribed without the benefit of knowledge gained through clinical trials. Knowledge is gained after market, often after multiple years, and potentially following widespread use. The situation is similar for vaccines, as was recently seen with the SARS-CoV2 pandemic. Early in the pandemic, evidence emerged that pregnancy increased the risk for severe illness from COVID-19, yet pregnant people and their providers were forced to make a difficult decision of risk/benefit with little data to guide them.

The FDA product label provides a summary and narrative of animal and human safety studies relating to pregnancy. But what if that label contains little to no information, or reports studies with conflicting results? Perhaps the product is new on the market or is infrequently used during pregnancy. Regardless, health care providers and pregnant patients still need to make decisions about medication use. The following list outlines information that can be found, and strategies to support providers and patients in making informed choices for a treatment plan.


Taking stock of the available information:

• If possible, connect with the specialist who prescribed the patient’s medication in question. They may have already assembled information regarding use of that medication in pregnancy.
• The sponsor may have published useful information from the phase 3 trials, including the outcomes of enrolled patients who inadvertently became pregnant.
• Review the animal data in the product label. Regulators require the careful selection of animal models, and this data can present a source of adjunct information regarding the medication’s effects on pregnancy, reproduction, and development. Negative results can be as revealing as positive results.
• Pharmacologic data in the label can also be informative. Although most labels have pharmacologic data based on trials in healthy nonpregnant individuals, understanding pregnancy physiology and the patient’s preexisting or pregnancy-specific condition(s) can provide insights.² Close patient monitoring and follow-up are of key importance.
• Consider viable alternatives that may address the patient’s needs. There may be effective alternatives that have been better studied and shown to have low reproductive toxicity.
• Consider the risks to the patient as well as the developing fetus if the preexisting or pregnancy-specific condition is uncontrolled.
• Consult a teratogen specialist who can provide information to both patients and health care providers on the reproductive hazards or safety of many exposures, even those with limited data regarding use in pregnancy. For example, MotherToBaby provides a network of teratogen specialists.

Understanding perceptions of risk, decision-making, and strategies to support informed choices:

• Perceptions of risk: Each person perceives risk and benefit differently. The few studies that have attempted to investigate perception of teratogenic risk have found that many pregnant people overestimate the magnitude of teratogenic risk associated with a particular exposure.³ Alternatively, a medication’s benefit in controlling the maternal condition is often not considered sufficiently. Health care providers may have their own distorted perceptions of risk, even in the presence of evidence.
• Decision-making: Most teratogen data inherently involve uncertainty; it is rare to have completely nonconflicting data with which to make a decision. This makes decisions about whether or not to utilize a particular medication or other agent in pregnancy very difficult. For example, a patient would prefer to be told a black and white answer such as vaccines are either 100% safe or 100% harmful. However, no medical treatment is held to that standard of certainty. Even though it may be more comfortable to avoid an action and “just let things happen,” the lack of a decision is still a decision. The decision to not take medication may have risks inherent in not treating a condition and may result in adverse outcomes in the developing fetus. Lastly, presenting teratogen information often involves challenges in portraying and interpreting numerical risk. For example, when considering data presented in fraction format, patients and some health care providers may focus on the numerator or count of adverse events, while ignoring the magnitude of the denominator.
• Strategies: Health literacy “best practice” strategies are useful whether there is a lot of data or very little. These include the of use plain language and messages delivered in a clear and respectful voice, the use of visual aids, and the use effective teaching methods such as asking open-ended questions to assess understanding. Other strategies include using caution in framing information: for example, discussing a 1% increase in risk for a baby to have a medication-associated birth defect should also be presented as a 99% chance the medication will not cause a birth defect. Numeracy challenges can also be addressed by using natural numbers rather than fractions or percentages: for example, if there were 100 women in this room, one would have a baby with a birth defect after taking this medication in pregnancy, but 99 of these women would not.

In today’s medical world, shared decision-making is the preferred approach to choices. Communicating and appropriately utilizing information to make choices about medication safety in pregnancy are vital undertakings. An important provider responsibility is helping patients understand that science is built on evidence that amasses and changes over time and that it represents rich shades of gray rather than “black and white” options.

Dr. Hardy is executive director, head of pharmacoepidemiology, Biohaven Pharmaceuticals. She serves as a member of Council for the Society for Birth Defects Research and Prevention (BDRP), represents the BDRP on the Coalition to Advance Maternal Therapeutics, and is a member of the North American Board for Amandla Development, South Africa. Dr. Conover is the director of Nebraska MotherToBaby. She is assistant professor at the Munroe Meyer Institute, University of Nebraska Medical Center.

References

1. Mitchell AA et al. Am J Obstet Gynecol. 2011;205(1):51:e1-e8.

2. Feghali M et al. Semin Perinatol 2015;39:512-9.

3. Conover EA, Polifka JE. Am J Med Genet Part C Semin Med Genet 2011;157:227-33.

As a pediatric kidney doctor, Elaine S. Kamil, MD, is used to long hours helping children and teens with a variety of issues, some very serious, and also makes time to give back to her specialty.

In late 2013, she was in Washington, D.C., planning a meeting of the American Society of Nephrology. When the organizers decided at the last minute that another session was needed, she stayed late, putting it together. Then she hopped on a plane and returned home to Los Angeles on a Saturday night.

Right after midnight, Dr. Kamil knew something was wrong.

“I had really severe chest pain,” she says. “I have reflux, and I know what that feels like. This was much more intense. It really hurt.” She debated: “Should I wake up my husband?”

Soon, the pain got so bad, she had to.

At the hospital, an electrocardiogram was slightly abnormal, as was a blood test that measures damage to the heart. Next, she got an angiogram, an imaging technique to visualize the heart. Once doctors looked at the image on the screen during the angiogram, they knew the diagnosis: Broken heart syndrome, known medically as takotsubo cardiomyopathy or stress-induced cardiomyopathy. As the name suggests, it’s triggered by extreme stress or loss.

The common symptoms are chest pain that can seem to come from a heart attack, shortness of breath, and fainting. The telltale clue to the diagnosis is the appearance of the walls of the heart’s left ventricle, its main pumping chamber. When the condition is present, the left ventricle changes shape, developing a narrow neck and a round bottom, resembling an octopus pot called takotsubo used by fishermen in Japan, where the condition was first recognized in 1990.

Like most who are affected, Dr. Kamil, now 74, is fine now. She is still actively working, as a researcher and professor emerita at Cedars-Sinai Medical Center and a health sciences clinical professor of pediatrics at UCLA. But she focuses more now on stress reduction.
 

Study: condition on the rise

New research from Cedars-Sinai suggests that broken heart syndrome, while still not common, is not as rare as once thought. And it’s on the rise, especially among middle-age and older women.

This ‘’middle” group – women ages 50 to 74 – had the greatest rate of increase over the years studied, 2006-2017, says Susan Cheng, MD, lead author of the study, published in the Journal of the American Heart Association. She is the director of the Institute for Research on Healthy Aging at the Smidt Heart Institute at Cedars-Sinai Medical Center.

Dr. Cheng and her team used national hospital inpatient data collected from more than 135,000 men and women diagnosed with the condition during the 12 years of the study. More than 88% of all cases were women, especially in those age 50 or older. When the researchers looked more closely, they found the diagnosis has been increasing at least 6 to 10 times more rapidly for women in the 50-to-74 age group than in any other group.

For every case of the condition in younger women, or in men of all age groups, the researchers found an additional 10 cases for middle-aged women and six additional cases for older women. For example, while the syndrome occurred in 15 younger women per million per year, it occurred in 128 middle aged women per year.

The age groups found most at risk was surprising, says Dr. Cheng, who expected the risk would be highest in the oldest age group of women, those over 75.

While doctors are more aware of the condition now, “it’s not just the increased recognition,” she says. “There is something going on” driving the continual increase. It probably has something to do with environmental changes, she says.

Hormones and hormonal differences between men and women aren’t the whole story either, she says. Her team will study it further, hoping eventually to find who might be more likely to get the condition by talking to those who have had it and collecting clues. “There probably is some underlying genetic predisposition,” she says.

“The neural hormones that drive the flight-or-fight response (such as adrenaline) are definitely elevated,” she says. “The brain and the heart are talking to each other.”

Experts say these surging stress hormones essentially “stun” the heart, affecting how it functions. The question is, what makes women particularly more susceptible to being excessively triggered when exposed to stress? That is unclear, Dr. Cheng says.

While the condition is a frightening experience, ‘’the overall prognosis is much better than having a garden-variety heart attack,” she says.

But researchers are still figuring out long-term outcomes, and she can’t tell patients if they are likely to have another episode.
 

Research findings reflected in practice

Other cardiologists say they are not surprised by the new findings.

“I think it’s very consistent with what I am seeing clinically,” says Tracy Stevens, MD, a cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, MO. In the last 5 years, she has diagnosed at least 100 cases, she says. The increase is partly but not entirely due to increased awareness by doctors of the condition, she agrees.

If a postmenopausal woman comes to the hospital with chest pain, the condition is more likely now than in the past to be suspected, says Dr. Stevens, who’s also the medical director of the Muriel I. Kauffman Women’s Heart Center at Saint Luke’s. The octopus pot-like image is hard to miss.

“What we see at the base of the left ventricle is, it is squeezing like crazy, it is ballooning.”

“We probably see at least five to ten a month,” says Kevin Bybee, MD, an associate professor of medicine at the University of Missouri-Kansas City School of Medicine.

The increase in numbers found by the Los Angeles researchers may not even capture the true picture of how many people have gotten this condition, he says. He suspects some women whose deaths are blamed on sudden cardiac death might actually have had broken heart syndrome.

“I have always wondered how many don’t make it to the hospital.”

Dr. Bybee, who’s also medical director of cardiovascular services at St. Luke’s South in Overland Park, KS, became interested in the syndrome during his fellowship at Mayo Clinic when he diagnosed three patients in just 2 months. He and his team published the case histories of seven patients in 2004. Since then, many more reports have been published.

Researchers from Texas used the same national database as the Cedars researchers to look at cases from 2005 to 2014, and also found an increase. But study co-author Abhijeet Dhoble, MD, a cardiologist and associate professor of medicine at UT Health Science Center and Memorial Hermann-Texas Medical Center in Houston, believes more recognition explains most of the increase.

And the pandemic is now playing a role in driving up cases, he says.

“In the last 2 years, we have been noticing increasing numbers of cases, probably due to the pandemic,” he says.
 

Profiles of cases

Over the years, Dr. Bybee has collected information on what is happening before the heart begins to go haywire.

“Fifteen to twenty percent of the time, there is no obvious trigger,” he says.

Other times, a stressful emotional event, such as the death of a spouse or a severe car accident, can trigger it.

One patient with an extreme fear of public speaking had to give a talk in front of a large group when she was new to a job. Another woman lost money at a casino before it happened, Dr. Bybee says. Yet another patient took her dog out for a walk in the woods, and the dog got caught in a raccoon trap.

Fierce arguments as well as surprise parties have triggered the condition, Dr. Bybee says. Physical problems such as asthma or sepsis, a life-threatening complication of an infection, can also trigger broken heart.

“It’s challenging because this is unpredictable,” he says.
 

Treatments and recovery

The condition is rarely fatal, say experts from Harvard and Mayo Clinic, but some can have complications such as heart failure.

There are no standard guidelines for treatment, Dr. Dhoble, of Memorial Hermann, says. “We give medications to keep blood pressures in the optimal range.” Doctors may also prescribe lipid-lowering medicines and blood thinner medications. “Most patients recover within 3 to 7 days.”

“Usually within a month, their [heart] function returns to normal,” Dr. Stevens says.

Getting one’s full energy back can take longer, as Dr. Kamil found. “It was about 6 months before I was up to speed.”
 

Survivors talk

Looking back, Dr. Kamil realizes now how much stress she was under before her episode.

“I took care of chronically ill kids,” she says, and worried about them. “I’m kind of a mother hen.”

Besides patient care and her cross-county meeting planning, she was flying back and forth to Florida to tend to her mother, who had chronic health problems. She was also managing that year’s annual media prize at a San Diego university that she and her husband established after the death of their adult son several years before.

“I was busy with that, and it is a bittersweet experience,” she says.

She is trying to take her cardiologist’s advice to slow down.

“I used to be notorious for saying, ‘I need to get one more thing done,’” she says.

Joanie Simpson says she, too, has slowed down. She was diagnosed with broken heart in 2016, after a cascade of stressful events. Her son was facing back surgery, her son-in-law had lost his job, and her tiny Yorkshire terrier Meha died. And she and her husband, Benny, had issues with their rental property.

Now 66 and retired in Camp Wood, Texas, she has learned to enjoy life and worry a little less. Music is one way.

“We’re Parrotheads,” she says, referencing the nickname given to fans of singer Jimmy Buffett. “We listen to Buffett and to ’60s, ’70s, ’80s music. We dance around the house. We aren’t big tavern goers, so we dance around the living room and hope we don’t fall over the coffee table. So far, so good.”

They have plans to buy a small pontoon boat and go fishing. Benny especially loves that idea, she says, laughing, as he finds it’s the only time she stops talking.
 

Reducing the what-ifs

Patients have a common question and worry: What if it happens again?

“I definitely worried more about it in the beginning,” Dr. Kamil says. “Could I have permanent heart damage? Will I be a cardiac cripple?” Her worry has eased.

If you suspect the condition, ‘’get yourself to a provider who knows about it,” she says.

Cardiologists are very likely to suspect the condition, Dr. Bybee says, as are doctors working in a large-volume emergency department.

Dr. Stevens, of St. Luke’s, is straightforward, telling her patients what is known and what is not about the condition. She recommends her patients go to cardiac rehab.

“It gives them that confidence to know what they can do,” she says.

She also gives lifestyle advice, suggesting patients get a home blood pressure cuff and use it. She suggests paying attention to good nutrition and exercise and not lifting anything so heavy that grunting is necessary.

Focus on protecting heart health, Dr. Cheng tells patients. She encourages them to find the stress reduction plan that works for them. Most important, she tells patients to understand that it is not their fault.

A version of this article first appeared on WebMD.com.

As a pediatric kidney doctor, Elaine S. Kamil, MD, is used to long hours helping children and teens with a variety of issues, some very serious, and also makes time to give back to her specialty.

In late 2013, she was in Washington, D.C., planning a meeting of the American Society of Nephrology. When the organizers decided at the last minute that another session was needed, she stayed late, putting it together. Then she hopped on a plane and returned home to Los Angeles on a Saturday night.

Right after midnight, Dr. Kamil knew something was wrong.

“I had really severe chest pain,” she says. “I have reflux, and I know what that feels like. This was much more intense. It really hurt.” She debated: “Should I wake up my husband?”

Soon, the pain got so bad, she had to.

At the hospital, an electrocardiogram was slightly abnormal, as was a blood test that measures damage to the heart. Next, she got an angiogram, an imaging technique to visualize the heart. Once doctors looked at the image on the screen during the angiogram, they knew the diagnosis: Broken heart syndrome, known medically as takotsubo cardiomyopathy or stress-induced cardiomyopathy. As the name suggests, it’s triggered by extreme stress or loss.

The common symptoms are chest pain that can seem to come from a heart attack, shortness of breath, and fainting. The telltale clue to the diagnosis is the appearance of the walls of the heart’s left ventricle, its main pumping chamber. When the condition is present, the left ventricle changes shape, developing a narrow neck and a round bottom, resembling an octopus pot called takotsubo used by fishermen in Japan, where the condition was first recognized in 1990.

Like most who are affected, Dr. Kamil, now 74, is fine now. She is still actively working, as a researcher and professor emerita at Cedars-Sinai Medical Center and a health sciences clinical professor of pediatrics at UCLA. But she focuses more now on stress reduction.
 

Study: condition on the rise

New research from Cedars-Sinai suggests that broken heart syndrome, while still not common, is not as rare as once thought. And it’s on the rise, especially among middle-age and older women.

This ‘’middle” group – women ages 50 to 74 – had the greatest rate of increase over the years studied, 2006-2017, says Susan Cheng, MD, lead author of the study, published in the Journal of the American Heart Association. She is the director of the Institute for Research on Healthy Aging at the Smidt Heart Institute at Cedars-Sinai Medical Center.

Dr. Cheng and her team used national hospital inpatient data collected from more than 135,000 men and women diagnosed with the condition during the 12 years of the study. More than 88% of all cases were women, especially in those age 50 or older. When the researchers looked more closely, they found the diagnosis has been increasing at least 6 to 10 times more rapidly for women in the 50-to-74 age group than in any other group.

For every case of the condition in younger women, or in men of all age groups, the researchers found an additional 10 cases for middle-aged women and six additional cases for older women. For example, while the syndrome occurred in 15 younger women per million per year, it occurred in 128 middle aged women per year.

The age groups found most at risk was surprising, says Dr. Cheng, who expected the risk would be highest in the oldest age group of women, those over 75.

While doctors are more aware of the condition now, “it’s not just the increased recognition,” she says. “There is something going on” driving the continual increase. It probably has something to do with environmental changes, she says.

Hormones and hormonal differences between men and women aren’t the whole story either, she says. Her team will study it further, hoping eventually to find who might be more likely to get the condition by talking to those who have had it and collecting clues. “There probably is some underlying genetic predisposition,” she says.

“The neural hormones that drive the flight-or-fight response (such as adrenaline) are definitely elevated,” she says. “The brain and the heart are talking to each other.”

Experts say these surging stress hormones essentially “stun” the heart, affecting how it functions. The question is, what makes women particularly more susceptible to being excessively triggered when exposed to stress? That is unclear, Dr. Cheng says.

While the condition is a frightening experience, ‘’the overall prognosis is much better than having a garden-variety heart attack,” she says.

But researchers are still figuring out long-term outcomes, and she can’t tell patients if they are likely to have another episode.
 

Research findings reflected in practice

Other cardiologists say they are not surprised by the new findings.

“I think it’s very consistent with what I am seeing clinically,” says Tracy Stevens, MD, a cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, MO. In the last 5 years, she has diagnosed at least 100 cases, she says. The increase is partly but not entirely due to increased awareness by doctors of the condition, she agrees.

If a postmenopausal woman comes to the hospital with chest pain, the condition is more likely now than in the past to be suspected, says Dr. Stevens, who’s also the medical director of the Muriel I. Kauffman Women’s Heart Center at Saint Luke’s. The octopus pot-like image is hard to miss.

“What we see at the base of the left ventricle is, it is squeezing like crazy, it is ballooning.”

“We probably see at least five to ten a month,” says Kevin Bybee, MD, an associate professor of medicine at the University of Missouri-Kansas City School of Medicine.

The increase in numbers found by the Los Angeles researchers may not even capture the true picture of how many people have gotten this condition, he says. He suspects some women whose deaths are blamed on sudden cardiac death might actually have had broken heart syndrome.

“I have always wondered how many don’t make it to the hospital.”

Dr. Bybee, who’s also medical director of cardiovascular services at St. Luke’s South in Overland Park, KS, became interested in the syndrome during his fellowship at Mayo Clinic when he diagnosed three patients in just 2 months. He and his team published the case histories of seven patients in 2004. Since then, many more reports have been published.

Researchers from Texas used the same national database as the Cedars researchers to look at cases from 2005 to 2014, and also found an increase. But study co-author Abhijeet Dhoble, MD, a cardiologist and associate professor of medicine at UT Health Science Center and Memorial Hermann-Texas Medical Center in Houston, believes more recognition explains most of the increase.

And the pandemic is now playing a role in driving up cases, he says.

“In the last 2 years, we have been noticing increasing numbers of cases, probably due to the pandemic,” he says.
 

Profiles of cases

Over the years, Dr. Bybee has collected information on what is happening before the heart begins to go haywire.

“Fifteen to twenty percent of the time, there is no obvious trigger,” he says.

Other times, a stressful emotional event, such as the death of a spouse or a severe car accident, can trigger it.

One patient with an extreme fear of public speaking had to give a talk in front of a large group when she was new to a job. Another woman lost money at a casino before it happened, Dr. Bybee says. Yet another patient took her dog out for a walk in the woods, and the dog got caught in a raccoon trap.

Fierce arguments as well as surprise parties have triggered the condition, Dr. Bybee says. Physical problems such as asthma or sepsis, a life-threatening complication of an infection, can also trigger broken heart.

“It’s challenging because this is unpredictable,” he says.
 

Treatments and recovery

The condition is rarely fatal, say experts from Harvard and Mayo Clinic, but some can have complications such as heart failure.

There are no standard guidelines for treatment, Dr. Dhoble, of Memorial Hermann, says. “We give medications to keep blood pressures in the optimal range.” Doctors may also prescribe lipid-lowering medicines and blood thinner medications. “Most patients recover within 3 to 7 days.”

“Usually within a month, their [heart] function returns to normal,” Dr. Stevens says.

Getting one’s full energy back can take longer, as Dr. Kamil found. “It was about 6 months before I was up to speed.”
 

Survivors talk

Looking back, Dr. Kamil realizes now how much stress she was under before her episode.

“I took care of chronically ill kids,” she says, and worried about them. “I’m kind of a mother hen.”

Besides patient care and her cross-county meeting planning, she was flying back and forth to Florida to tend to her mother, who had chronic health problems. She was also managing that year’s annual media prize at a San Diego university that she and her husband established after the death of their adult son several years before.

“I was busy with that, and it is a bittersweet experience,” she says.

She is trying to take her cardiologist’s advice to slow down.

“I used to be notorious for saying, ‘I need to get one more thing done,’” she says.

Joanie Simpson says she, too, has slowed down. She was diagnosed with broken heart in 2016, after a cascade of stressful events. Her son was facing back surgery, her son-in-law had lost his job, and her tiny Yorkshire terrier Meha died. And she and her husband, Benny, had issues with their rental property.

Now 66 and retired in Camp Wood, Texas, she has learned to enjoy life and worry a little less. Music is one way.

“We’re Parrotheads,” she says, referencing the nickname given to fans of singer Jimmy Buffett. “We listen to Buffett and to ’60s, ’70s, ’80s music. We dance around the house. We aren’t big tavern goers, so we dance around the living room and hope we don’t fall over the coffee table. So far, so good.”

They have plans to buy a small pontoon boat and go fishing. Benny especially loves that idea, she says, laughing, as he finds it’s the only time she stops talking.
 

Reducing the what-ifs

Patients have a common question and worry: What if it happens again?

“I definitely worried more about it in the beginning,” Dr. Kamil says. “Could I have permanent heart damage? Will I be a cardiac cripple?” Her worry has eased.

If you suspect the condition, ‘’get yourself to a provider who knows about it,” she says.

Cardiologists are very likely to suspect the condition, Dr. Bybee says, as are doctors working in a large-volume emergency department.

Dr. Stevens, of St. Luke’s, is straightforward, telling her patients what is known and what is not about the condition. She recommends her patients go to cardiac rehab.

“It gives them that confidence to know what they can do,” she says.

She also gives lifestyle advice, suggesting patients get a home blood pressure cuff and use it. She suggests paying attention to good nutrition and exercise and not lifting anything so heavy that grunting is necessary.

Focus on protecting heart health, Dr. Cheng tells patients. She encourages them to find the stress reduction plan that works for them. Most important, she tells patients to understand that it is not their fault.

A version of this article first appeared on WebMD.com.

As a pediatric kidney doctor, Elaine S. Kamil, MD, is used to long hours helping children and teens with a variety of issues, some very serious, and also makes time to give back to her specialty.

In late 2013, she was in Washington, D.C., planning a meeting of the American Society of Nephrology. When the organizers decided at the last minute that another session was needed, she stayed late, putting it together. Then she hopped on a plane and returned home to Los Angeles on a Saturday night.

Right after midnight, Dr. Kamil knew something was wrong.

“I had really severe chest pain,” she says. “I have reflux, and I know what that feels like. This was much more intense. It really hurt.” She debated: “Should I wake up my husband?”

Soon, the pain got so bad, she had to.

At the hospital, an electrocardiogram was slightly abnormal, as was a blood test that measures damage to the heart. Next, she got an angiogram, an imaging technique to visualize the heart. Once doctors looked at the image on the screen during the angiogram, they knew the diagnosis: Broken heart syndrome, known medically as takotsubo cardiomyopathy or stress-induced cardiomyopathy. As the name suggests, it’s triggered by extreme stress or loss.

The common symptoms are chest pain that can seem to come from a heart attack, shortness of breath, and fainting. The telltale clue to the diagnosis is the appearance of the walls of the heart’s left ventricle, its main pumping chamber. When the condition is present, the left ventricle changes shape, developing a narrow neck and a round bottom, resembling an octopus pot called takotsubo used by fishermen in Japan, where the condition was first recognized in 1990.

Like most who are affected, Dr. Kamil, now 74, is fine now. She is still actively working, as a researcher and professor emerita at Cedars-Sinai Medical Center and a health sciences clinical professor of pediatrics at UCLA. But she focuses more now on stress reduction.
 

Study: condition on the rise

New research from Cedars-Sinai suggests that broken heart syndrome, while still not common, is not as rare as once thought. And it’s on the rise, especially among middle-age and older women.

This ‘’middle” group – women ages 50 to 74 – had the greatest rate of increase over the years studied, 2006-2017, says Susan Cheng, MD, lead author of the study, published in the Journal of the American Heart Association. She is the director of the Institute for Research on Healthy Aging at the Smidt Heart Institute at Cedars-Sinai Medical Center.

Dr. Cheng and her team used national hospital inpatient data collected from more than 135,000 men and women diagnosed with the condition during the 12 years of the study. More than 88% of all cases were women, especially in those age 50 or older. When the researchers looked more closely, they found the diagnosis has been increasing at least 6 to 10 times more rapidly for women in the 50-to-74 age group than in any other group.

For every case of the condition in younger women, or in men of all age groups, the researchers found an additional 10 cases for middle-aged women and six additional cases for older women. For example, while the syndrome occurred in 15 younger women per million per year, it occurred in 128 middle aged women per year.

The age groups found most at risk was surprising, says Dr. Cheng, who expected the risk would be highest in the oldest age group of women, those over 75.

While doctors are more aware of the condition now, “it’s not just the increased recognition,” she says. “There is something going on” driving the continual increase. It probably has something to do with environmental changes, she says.

Hormones and hormonal differences between men and women aren’t the whole story either, she says. Her team will study it further, hoping eventually to find who might be more likely to get the condition by talking to those who have had it and collecting clues. “There probably is some underlying genetic predisposition,” she says.

“The neural hormones that drive the flight-or-fight response (such as adrenaline) are definitely elevated,” she says. “The brain and the heart are talking to each other.”

Experts say these surging stress hormones essentially “stun” the heart, affecting how it functions. The question is, what makes women particularly more susceptible to being excessively triggered when exposed to stress? That is unclear, Dr. Cheng says.

While the condition is a frightening experience, ‘’the overall prognosis is much better than having a garden-variety heart attack,” she says.

But researchers are still figuring out long-term outcomes, and she can’t tell patients if they are likely to have another episode.
 

Research findings reflected in practice

Other cardiologists say they are not surprised by the new findings.

“I think it’s very consistent with what I am seeing clinically,” says Tracy Stevens, MD, a cardiologist at Saint Luke’s Mid America Heart Institute in Kansas City, MO. In the last 5 years, she has diagnosed at least 100 cases, she says. The increase is partly but not entirely due to increased awareness by doctors of the condition, she agrees.

If a postmenopausal woman comes to the hospital with chest pain, the condition is more likely now than in the past to be suspected, says Dr. Stevens, who’s also the medical director of the Muriel I. Kauffman Women’s Heart Center at Saint Luke’s. The octopus pot-like image is hard to miss.

“What we see at the base of the left ventricle is, it is squeezing like crazy, it is ballooning.”

“We probably see at least five to ten a month,” says Kevin Bybee, MD, an associate professor of medicine at the University of Missouri-Kansas City School of Medicine.

The increase in numbers found by the Los Angeles researchers may not even capture the true picture of how many people have gotten this condition, he says. He suspects some women whose deaths are blamed on sudden cardiac death might actually have had broken heart syndrome.

“I have always wondered how many don’t make it to the hospital.”

Dr. Bybee, who’s also medical director of cardiovascular services at St. Luke’s South in Overland Park, KS, became interested in the syndrome during his fellowship at Mayo Clinic when he diagnosed three patients in just 2 months. He and his team published the case histories of seven patients in 2004. Since then, many more reports have been published.

Researchers from Texas used the same national database as the Cedars researchers to look at cases from 2005 to 2014, and also found an increase. But study co-author Abhijeet Dhoble, MD, a cardiologist and associate professor of medicine at UT Health Science Center and Memorial Hermann-Texas Medical Center in Houston, believes more recognition explains most of the increase.

And the pandemic is now playing a role in driving up cases, he says.

“In the last 2 years, we have been noticing increasing numbers of cases, probably due to the pandemic,” he says.
 

Profiles of cases

Over the years, Dr. Bybee has collected information on what is happening before the heart begins to go haywire.

“Fifteen to twenty percent of the time, there is no obvious trigger,” he says.

Other times, a stressful emotional event, such as the death of a spouse or a severe car accident, can trigger it.

One patient with an extreme fear of public speaking had to give a talk in front of a large group when she was new to a job. Another woman lost money at a casino before it happened, Dr. Bybee says. Yet another patient took her dog out for a walk in the woods, and the dog got caught in a raccoon trap.

Fierce arguments as well as surprise parties have triggered the condition, Dr. Bybee says. Physical problems such as asthma or sepsis, a life-threatening complication of an infection, can also trigger broken heart.

“It’s challenging because this is unpredictable,” he says.
 

Treatments and recovery

The condition is rarely fatal, say experts from Harvard and Mayo Clinic, but some can have complications such as heart failure.

There are no standard guidelines for treatment, Dr. Dhoble, of Memorial Hermann, says. “We give medications to keep blood pressures in the optimal range.” Doctors may also prescribe lipid-lowering medicines and blood thinner medications. “Most patients recover within 3 to 7 days.”

“Usually within a month, their [heart] function returns to normal,” Dr. Stevens says.

Getting one’s full energy back can take longer, as Dr. Kamil found. “It was about 6 months before I was up to speed.”
 

Survivors talk

Looking back, Dr. Kamil realizes now how much stress she was under before her episode.

“I took care of chronically ill kids,” she says, and worried about them. “I’m kind of a mother hen.”

Besides patient care and her cross-county meeting planning, she was flying back and forth to Florida to tend to her mother, who had chronic health problems. She was also managing that year’s annual media prize at a San Diego university that she and her husband established after the death of their adult son several years before.

“I was busy with that, and it is a bittersweet experience,” she says.

She is trying to take her cardiologist’s advice to slow down.

“I used to be notorious for saying, ‘I need to get one more thing done,’” she says.

Joanie Simpson says she, too, has slowed down. She was diagnosed with broken heart in 2016, after a cascade of stressful events. Her son was facing back surgery, her son-in-law had lost his job, and her tiny Yorkshire terrier Meha died. And she and her husband, Benny, had issues with their rental property.

Now 66 and retired in Camp Wood, Texas, she has learned to enjoy life and worry a little less. Music is one way.

“We’re Parrotheads,” she says, referencing the nickname given to fans of singer Jimmy Buffett. “We listen to Buffett and to ’60s, ’70s, ’80s music. We dance around the house. We aren’t big tavern goers, so we dance around the living room and hope we don’t fall over the coffee table. So far, so good.”

They have plans to buy a small pontoon boat and go fishing. Benny especially loves that idea, she says, laughing, as he finds it’s the only time she stops talking.
 

Reducing the what-ifs

Patients have a common question and worry: What if it happens again?

“I definitely worried more about it in the beginning,” Dr. Kamil says. “Could I have permanent heart damage? Will I be a cardiac cripple?” Her worry has eased.

If you suspect the condition, ‘’get yourself to a provider who knows about it,” she says.

Cardiologists are very likely to suspect the condition, Dr. Bybee says, as are doctors working in a large-volume emergency department.

Dr. Stevens, of St. Luke’s, is straightforward, telling her patients what is known and what is not about the condition. She recommends her patients go to cardiac rehab.

“It gives them that confidence to know what they can do,” she says.

She also gives lifestyle advice, suggesting patients get a home blood pressure cuff and use it. She suggests paying attention to good nutrition and exercise and not lifting anything so heavy that grunting is necessary.

Focus on protecting heart health, Dr. Cheng tells patients. She encourages them to find the stress reduction plan that works for them. Most important, she tells patients to understand that it is not their fault.

A version of this article first appeared on WebMD.com.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.

A survey of more than 12,000 women of reproductive age found that one in three had experienced changes to their menstrual cycles and symptoms during the COVID-19 pandemic. Noticeably higher stress levels than prepandemic benchmarks could be affecting menstruation.

This has implications for women trying to conceive or struggling with infertility, said Shannon M. Malloy, a research and data associate with Ovia Health, a women’s and family health technology company in Boston. Ms. Malloy presented this study at the American Society of Reproductive Medicine’s 2021 meeting.

COVID-19 has introduced new psychosocial, interpersonal, and environmental stressors. The pandemic is “one of the most stressful, collectively experienced disasters modern society has ever seen,” said Ms. Malloy. Once imagined as an explicit event in time, COVID-19 has ingrained itself into daily life for the foreseeable future.

Research has shown that chronic, long-term stress produces high cortisol levels, which can alter endocrinology and regulation of menstrual cycles. This can make family building even more challenging, said Ms. Malloy. Physicians and other providers have always taken stress into account when managing patients, but never at this level of chronic, episodic stress, she said.
 

Survey examines impact on ART

Ovia Health decided to investigate the relationship between perceived stress and menstrual cycle and symptom changes during the COVID-19 pandemic, to see how it might affect assisted reproductive technology (ART).

From March 2020 to April 2021, users of Ovia Health’s Fertility mobile application in the United States took part in a survey. Items captured changes in menstruation pattern and symptomatology and included the Perceived Stress Scale 4-item version (PSS-4). A paired t-test evaluated differences between groups (menstrual changes versus no menstrual changes). The survey asked participants what changes they noticed in their menstrual cycle and why they thought cycle patterns or symptoms changed.
 

One-third report changes in cycle, symptoms

Among 12,302 respondents, 1 in 3 (36%) reported changes in cycle or symptoms. Eighty-seven percent said that their cycle started early or late. Twenty-nine percent reported stronger symptoms during menstruation such as low back pain, cramping, or discharge changes, and 27% said bleeding was heavier during periods.

These results are similar to other studies investigating the affect of episodic stress on menstruation, said Ms. Malloy.

Those who reported menstrual cycle or symptom changes scored higher on average on the PSS-4 compared with those who didn’t report any changes (8.5 v. 8.3, respectively, P < .05). PSS-4 scores across the board were notably higher in all respondents, regardless of cycle/symptom irregularity, compared with prepandemic benchmarking in similar populations.

Slightly more than half (55%) thought stress contributed to their menstrual cycle pattern and/or symptom changes, whereas 33% pointed to changes in mental health, such as depression or anxiety. “Interestingly, many users believed the COVID-19 vaccine impacted their menstrual cycle symptom changes,” said Ms. Malloy.
 

No definitive link between vaccine, menstruation

While known side effects of the vaccine include sore arm, fever, fatigue, and myalgia, some women have reported changes in their menstrual cycle, Mark P. Trolice, MD, professor of obstetrics and gynecology at the University of Central Florida and director of the IVF Center in Orlando, said in an interview.

“Vaccination reaction from the immune response rather than the vaccine may be the implicating factor,” said Dr. Trolice, who was not involved in the study.

Currently, there’s no direct link between the vaccine and subsequent effects on menstruation, he continued. “Most women experience resumption of normal intervals 1 month following vaccination. Further, there is no credible evidence that links the vaccine to infertility.

“Nevertheless, research in this area is vital and underway,” he added.
 

Physicians can help with stress

Menstrual cycle disruption is especially frustrating for women trying to build a family, said Ms. Malloy. Providers may be observing more menstrual irregularity in their patient populations, and seeing more patients struggle to conceive on their own, turning to ART.

Providers can’t make COVID-19 go away, but they could help patients by doing a better job of integrating mental health screening, connecting patients to treatments that optimize conception and fertility treatment outcomes, said Ms. Malloy.

The survey was limited in that its questions didn’t consider proper diagnostic criteria for irregularity, versus self-reported changes. But it does highlight the need for more research on the pandemic’s affect on menstruation and the vaccine on menstruation, said Ms. Malloy. “The National Institutes of Health in August committed $1.6 million to explore this connection. We’re looking forward to seeing what their results are.” 

Dr. Trolice and Ms. Malloy had no disclosures.