Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.

In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.

“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.

The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
 

Is it safe?

Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.

Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.

The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).

They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.

The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.

The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
 

Immune-related proteins

The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.

A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.

The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.

The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.

Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.

Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.

“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
 

Timing of expression patterns

During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”

“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”

Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.

The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.

Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.

In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.

“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.

The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
 

Is it safe?

Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.

Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.

The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).

They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.

The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.

The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
 

Immune-related proteins

The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.

A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.

The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.

The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.

Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.

Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.

“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
 

Timing of expression patterns

During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”

“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”

Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.

The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.

Stopping nucleoside analog therapy in patients with hepatitis B viral (HBV) infections results in sustained viral suppression in only a minority of patients, but a new study suggests there are immune signatures that may serve as predictive biomarkers to help clinicians determine how to improve immune responses in these patients, according to investigators.

In a study of 359 patients enrolled in clinical trials of antiviral therapy for HBV infections, there were 29 immune-related proteins that were found in significantly higher levels among patients who continued to have viral suppression 24 weeks after the end of treatment, compared with patients who did not maintain viral suppression, reported Henry L.Y. Chan, MD, from the Chinese University of Hong Kong.

“In this study, plasma proteomics shows that sustained HBV suppression following treatment discontinuation is associated with higher levels of innate and adaptive immune responses during treatment, but whether these signatures vary by specific treatment regimens remains to be determined,” he said in an oral session at the meeting sponsored by the European Association for the Study of the Liver.

The clustering of proteins differed between patients treated with nucleoside analogs and those who received pegylated interferon (PEG-IFN), Dr. Chan noted.
 

Is it safe?

Although current international guidelines say that clinicians may consider stopping nucleoside analogs in certain patient populations with the goal of promoting sustained off-treatment responses, pooled data from four large phase 3 studies showed that only 10% of patients had sustained HBV DNA suppression, and only 32% had persistent low-level viremia, Dr. Chan said, citing a presentation from ILC in 2019.

Dr. Chan and colleagues sought to identify immune biomarkers that at the end of treatment predict HBV off-treatment response. This is important because existing treatments do not kill the virus which – even if suppressed – can lead to hepatocellular carcinoma.

The researchers examined plasma samples from patients with chronic hepatitis B who were enrolled in two studies: a registrational study comparing tenofovir disoproxil fumarate with adefovir followed by tenofovir maintenance (GS-US-174-0102) and one comparing TDF plus PEG-IFN with either drug alone (GS-US-174-0149).

They identified a total of 359 patients who had at least two treatment-free follow-up visits, were positive for the hepatitis B S antigen (HBsAg) at the end of the treatment, including patients who had antigen loss on treatment but subsequently seroverted, and had available plasma samples collected before the end of treatment.

The study outcomes were sustained viral suppression 24 weeks after the end of treatment, defined as HBV DNA less than 29 IU/mL, and a low replicative state defined as HBV DNA below 2,000 IU/mL with ALT levels at or below the upper limit of normal.

The median patient age was 39 years. In all, 67% of the population was male, and 70% were Asian.
 

Immune-related proteins

The investigators performed proteomic analyses looking for expression levels in serum or plasma proteins at the end of treatment.

A total of 25 patients had HBV DNA suppression at posttreatment week 24, 111 patients had a low replicative states, and 4 had HBsAg loss.

The patients with HBV DNA suppression had significantly higher expression of 29 immune-related proteins, the majority of which were related to the host immune response.

The proteins included myeloid cell markers, leukocyte-trafficking chemokines, natural killer cell markers, and extracellular matrix and/or extracellular matrix–associated proteins.

Among patients with HBV suppression, there was evidence of enrichment for extracellular remodeling pathways, as well as pathways involved in innate immune response to viral infections and immune regulation.

Among patients with low viral replication, there was a trend toward higher CD8a expression levels at the 24-week follow-up, but there were no proteins with significantly elevated expression levels.

“Assessment of unique protein signatures associated with HBsAg loss following treatment discontinuation is ongoing,” Dr. Chan said.
 

Timing of expression patterns

During the question-and-answer session following his presentation, comoderator Pablo Sarobe, MD, from the Clinica Universidad de Navarra (Spain), said: “I’ve seen that you have compared the different proteins which are detected in your cell samples 24 weeks after stopping treatment. Do you think that these differences are already relevant just at the end of treatment, or that these proteins are being expressed [during] the 24 weeks between the end of treatment and your determination?”

“We only have one time-point sample, so it’s hard to say,” Dr. Chan replied, but he speculated that the delay would not have a direct impact on protein expression, “so probably this expression should last after treatment has stopped. But we only have only posttreatment 24-week data, and we believe that some of the outcome measures may change with longer follow-up. After 1 year some patients in suppression may relapse.”

Asked by an audience member whether the investigators had performed a subanalysis of patients treated with nucleoside analogs, Dr. Chan noted that such an analysis was under consideration, although the patient numbers were relatively small. He did add, however, that protein expression patterns differed among patients treated with nucleoside analogs and PEG-IFN.

The study was funded by Gilead Sciences. Dr. Chan disclosed sponsored lecture activities and consulting for Gilead and others. Dr. Sarobe reported no conflicts of interest.

Human placental allograft

For case reports involving Revita and for more information, visit https://www.stimlabs.com/revita.

FDA approval for cytology processor

For more information, visit: https://www.hologic.com/.

Cell-free RNA testing for pregnancy complications

Currently, Mirvie is recruiting for their Miracle of Life study, which requests that single gestation pregnant mothers who are not scheduled for cesarean delivery provide a blood sample during their second trimester. Women can see if they are eligible for study participation by visiting https://www.curebase.com/study/miracle/home.

For more information, visit: https://mirvie.com/.

Male fertility platform

For more information, visit: https://posterityhealth.com/.

Human placental allograft

For case reports involving Revita and for more information, visit https://www.stimlabs.com/revita.

FDA approval for cytology processor

For more information, visit: https://www.hologic.com/.

Cell-free RNA testing for pregnancy complications

Currently, Mirvie is recruiting for their Miracle of Life study, which requests that single gestation pregnant mothers who are not scheduled for cesarean delivery provide a blood sample during their second trimester. Women can see if they are eligible for study participation by visiting https://www.curebase.com/study/miracle/home.

For more information, visit: https://mirvie.com/.

Male fertility platform

For more information, visit: https://posterityhealth.com/.

Human placental allograft

For case reports involving Revita and for more information, visit https://www.stimlabs.com/revita.

FDA approval for cytology processor

For more information, visit: https://www.hologic.com/.

Cell-free RNA testing for pregnancy complications

Currently, Mirvie is recruiting for their Miracle of Life study, which requests that single gestation pregnant mothers who are not scheduled for cesarean delivery provide a blood sample during their second trimester. Women can see if they are eligible for study participation by visiting https://www.curebase.com/study/miracle/home.

For more information, visit: https://mirvie.com/.

Male fertility platform

For more information, visit: https://posterityhealth.com/.

Pregnancy and the postpartum period are times of increased risk for venous thromboembolism (VTE). While VTE is a rare event overall, it is responsible for more than 9% of maternal deaths in the United States.¹ The increased risk of VTE exists throughout pregnancy, rising in the third trimester.² The highest-risk period is the first 6 weeks postpartum, likely peaking in the first 2 to 3 weeks and returning to baseline at about 12 weeks postpartum.^2,3

To reduce this source of maternal harm, the National Partnership for Maternal Safety and the Council on Patient Safety in Women’s Health Care recommend the use of VTE prevention bundles. Bundles include standard assessment of risk during prenatal care, any admission to the hospital, and postpartum coupled with standard recommendations for treatment.^4-6 Multiple published guidelines are available for prevention of VTE in pregnancy, and they provide varying recommendations on patient selection and treatment. Many of these recommendations are based on low quality of evidence, making the choice of standard practice difficult.

In this article, I attempt to simplify patient selection and treatment based on currently published guidelines from the American College of Obstetricians and Gynecologists (ACOG), Royal College of Obstetricians and Gynaecologists (RCOG), American College of Chest Physicians (CHEST), American Society of Hematology (ASH), and expert opinion.

Determining VTE risk and need for prophylaxis

CASE 1 Woman with factor V Leiden

A 25-year-old woman (G1P0) presents for her initial prenatal visit. She says she is a carrier for factor V Leiden but has never had a clot. She was tested after her sister had a VTE. She asks, does she need VTE prophylaxis before her delivery?

What are the considerations and options for this patient?

Options for VTE prophylaxis

Before considering patients at risk for VTE, it is helpful to review the options for prophylaxis. Patients can undergo clinical surveillance or routine care with attention to VTE symptoms and a low threshold for workup.

There are 3 categories of chemoprophylaxis for prevention of VTE. (TABLE 1 offers examples of dosing regimens.) No strategy has been proven optimal over another:

• prophylactic-dose: the lowest, fixed dose.
• intermediate-dose: lacks a standard definition and is any dose higher than prophylactic-dose but lower than therapeutic-dose. This includes fixed twice-daily doses, weight-based doses, and incrementally increasing doses.
• therapeutic-dose: typically used for treatment but mentioned here since patients with high-risk conditions may use it for prevention of VTE.

The preferred agent for VTE chemoprophylaxis is low molecular weight heparin (LMWH; dalteparin, enoxaparin). LMWH has a lower risk of complications than unfractionated heparin (UFH) and can be injected once daily. LMWH and UFH do not cross the placenta. LMWH and UFH are safe in breastfeeding. Oral direct thrombin inhibitors and anti-Xa inhibitors are not recommended in pregnancy or lactation at this time. Warfarin is avoided in pregnancy except in situations with mechanical heart valves, which will not be addressed here. Patients taking warfarin for long-term anticoagulation can transition back while breastfeeding with appropriate bridging.

Continue to: Risk factors for VTE...

Risk factors for VTE

History of VTE. The most important risk factor for VTE is a personal history of prior VTE.⁶ Recurrence risks have been widely reported and depend on the factors surrounding the initial event. For patients with a prior provoked deep vein thrombosis (DVT; associated with trauma or surgery), the antepartum VTE risk likely is less than 1%, and VTE chemoprophylaxis is not recommended antepartum.⁷

For patients with a prior VTE that was not associated with surgery or trauma (unprovoked), the risk is approximately 3%; for prior VTE related to pregnancy or hormonal contraception, the risk is approximately 6%.⁷ For both of these groups, prophylactic-dose antepartum is recommended. Patients with recurrent VTE are often taking long-term anticoagulation. Anyone on long-term anticoagulation should be placed on therapeutic-dose antepartum. For patients not receiving long-term anticoagulation, consider a hematology consultation when available, and begin an intermediate-dose or therapeutic-dose regimen after assessing other risk factors and the risk of bleeding and discussing treatment with the patient.

Thrombophilias. The next most important risk factor is the presence of inherited thrombophilias.⁶ Factor V homozygote, prothrombin G20210A mutation homozygote, antithrombin deficiency, and combined factor V heterozygote and prothrombin G20210A heterozygote (also called compound heterozygote) have the strongest association with VTE in pregnancy.⁸ It is recommended that patients with these high-risk thrombophilias receive prophylactic-dose antepartum.⁸

Factor V heterozygote, prothrombin G20210A mutation heterozygote, and protein C or protein S deficiency are considered low-risk thrombophilias. Patients with low-risk thrombophilias and no personal history of VTE or first-degree relative with VTE can be monitored with clinical surveillance antepartum. However, if a family history of VTE or other risk factors for VTE are present, antepartum prophylactic-dose is recommended. Clinical factors to consider antepartum include obesity, age older than 35 years, parity of 3 or higher, varicose veins, immobility, smoking, assisted reproductive technology use, multiple gestation, and preeclampsia.¹⁰

Antiphospholipid syndrome (APS) is another high-risk condition. For patients not taking long-term anticoagulation antepartum, prophylactic-dose is recommended. For patients on long-term anticoagulation, therapeutic-dose is recommended.

Other medical conditions. Patients with medical conditions that place them at high risk for VTE may warrant prophylactic-dose antepartum. These include active cancer, active systemic lupus erythematosus, sickle cell disease, nephropathy, and inflammatory bowel disease.¹⁰ This decision can be made in conjunction with other specialists caring for the patient.

Antepartum prophylactic-dose is not recommended for low-risk patients as there is less than 1% risk of VTE.⁷ (TABLE 2 summarizes antepartum chemoprophylaxis recommendations.)

CASE 1 continued Patient develops another VTE risk factor

The patient is being followed with clinical surveillance. At 19 weeks’ gestation, she presents to the emergency department with shortness of breath and fever. She is diagnosed with COVID-19 and is admitted by a medicine service. They call the OB team to ask for recommendations regarding anticoagulation.

What should the next steps include?

Hospitalization and nonobstetric surgery are risk factors for VTE. Many hospitals use a standardized assessment for all inpatients, such as the Padua or Caprini VTE risk assessment scores. These can be modified for use in pregnant patients, although neither scoring system is currently validated for use in pregnancy.⁵ For any pregnant patient admitted to the hospital, mechanical prophylaxis is recommended.

COVID-19. Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome, COVID-19, is associated with increased rates of VTE. Recommendations for pregnant patients with COVID-19 are the same as for the general population. During hospitalization for COVID-19, pregnant patients should be placed on prophylactic-dose chemoprophylaxis. Patients should not be discharged home on chemoprophylaxis, and patients managed as outpatients for their disease do not need chemoprophylaxis.¹¹

Management approach. Prophylactic-dose administration is recommended during hospital stay for all patients admitted with anticipated length of stay of 3 days or longer and who are not at high risk for bleeding or delivery.¹⁰ Both LMWH and UFH are options for inpatients. For any nonobstetric surgery or admission, LMWH may be most appropriate. However, as most obstetrics admissions are at increased risk for delivery, UFH 5,000 U twice daily to 3 times daily is the best option to increase the chances for neuraxial anesthesia. (I review anesthesia considerations for delivery later in this article.) For patients at high risk for bleeding or delivery, mechanical prophylaxis alone, with elastic stockings or pneumatic compression devices, can be used.

Continue to: CASE 1 continued Patient is discharged home...

CASE 1 continued Patient is discharged home

The patient received enoxaparin while she was in the hospital. She is now discharged and doing well. She asks, will she need anticoagulation prophylaxis after delivery?

How would you counsel her?

Chemoprophylaxis in the postpartum period

With no risk of fetal harm and a higher risk of VTE per day, the threshold for chemoprophylaxis is lower in the postpartum period. The risk of postpartum bleeding is less than 1%, with the most common complication being wound hematomas (0.61%).⁹ For this case patient, the COVID-19 diagnosis does not alter the recommendations for postpartum chemoprophylaxis. Additionally, as the need for neuraxial anesthesia has passed, the use of intermediate-dose chemoprophylaxis over prophylactic-dose is advocated in the postpartum period, especially in obese patients.¹²

As mentioned previously, there is no standard definition of intermediate-dose. Data suggest that a weight-based intermediate-dose is most likely to achieve therapeutic levels of anti-Xa in this high-risk population compared with a fixed dose.^13,14 For example, enoxaparin 0.5 mg/kg twice daily is recommended for patients with class 3 obesity or higher by the Society for Maternal-Fetal Medicine.¹²

As a rule, anyone who was on chemoprophylaxis antepartum should be continued on at least an equivalent dose for 6 weeks postpartum. Postpartum, patients with any prior DVT should take prophylactic-dose or intermediate-dose chemoprophylaxis for 6 weeks. Patients with a known high-risk thrombophilia should receive prophylactic-dose or intermediate-dose chemoprophylaxis postpartum for 6 weeks. For patients with a low-risk thrombophilia, prophylactic-dose or intermediate-dose chemoprophylaxis is recommended for 6 weeks.

For low-risk patients without prior VTE or thrombophilia, standardized risk assessment is recommended.

Cesarean delivery

Cesarean delivery (CD) is a risk factor for postpartum VTE.⁹ A universal chemoprophylaxis strategy has not been proven in this patient population. Mechanical prophylaxis with sequential compression devices is recommended for all patients undergoing CD pre-procedure and until patients are fully ambulatory.^8,9 Early ambulation also should be encouraged.

Many risk assessment models are available for postoperative VTE prevention, and they have widely different chemoprophylaxis rates. Studies have shown chemoprophylaxis rates of 85% by RCOG, 1% by ACOG, 35% by CHEST, 94% by Caprini, and less than 1% by Padua.^15,16 In addition to the antepartum patient-specific risk factors mentioned, postpartum risk factors include infection, postpartum hemorrhage, and transfusion. Based on data extrapolated from the nonobstetric literature, chemoprophylaxis is recommended until discharge from the hospital unless risk factors are expected to continue.⁹

Neuraxial anesthesia

For patients who require postpartum chemoprophylaxis, the Society for Obstetric Anesthesia and Perinatology (SOAP) offers evidence-based guidelines for use after neuraxial anesthesia. UFH can be initiated 1 hour or longer after a neuraxial procedure and 1 hour or longer after catheter removal. Prophylactic-dose LMWH can be restarted at 12 hours or longer after a neuraxial procedure and at 4 to 6 hours or longer after catheter removal. For patients restarting intermediate-dose or therapeutic-dose, the recommendations are to wait 24 hours or longer after a neuraxial procedure and 4 hours or longer after catheter removal.¹⁷ Timing can be individualized based on the patient’s risk of hemorrhage and surgical bleeding. Although it may be tempting to delay chemoprophylaxis in the setting of bleeding, postpartum hemorrhage and transfusion increase the risks of VTE. In this setting, it is best to consider the use of UFH, which safely can be started earlier than LMWH.

For patients without neuraxial anesthesia, ACOG recommends chemoprophylaxis 4 to 6 hours after vaginal delivery and 6 to 12 hours after CD.⁸ (TABLE 3 summarizes recommendations for postpartum chemoprophylaxis.)

Continue to: Adjusting the anticoagulation regimen...

CASE 2 Pregnant woman with prior VTE

A 36-year-old woman (G1P0) with prior VTE is taking enoxaparin 40 mg daily. She asks, does she need any blood work for her anticoagulation?

What would you test for?

Increased renal clearance of LMWH and increased volume of distribution during pregnancy has led to the consideration of monitoring anti-Xa levels. There are no published standards or recommendations for dose adjustment. At this time, anti-Xa level monitoring antepartum is not recommended, but it may be considered when a patient is at the extremes of weight. With a weight-based strategy in the postpartum period, monitoring is not recommended as studies show a higher likelihood of therapeutic anti-Xa levels with this approach.^13,14 This is an active area of research, and these recommendations may change.

For prophylactic-dose or intermediate-dose anticoagulation, a peak anti-Xa level of 0.2 to 0.6 U/mL is generally accepted as the target. For therapeutic-dose, a peak anti-Xa level of 0.6 to 1.2 U/mL is generally accepted as the therapeutic range. This blood draw must be collected 4 hours after the third dose.

CASE 2 continued Anticoagulation considerations nearing delivery

The patient is now at 36 weeks’ gestation, and she asks, what should be done regarding her anticoagulation prior to delivery?

What would be an appropriate approach?

Traditionally, patients were transitioned to UFH at 36 weeks and allowed to present in spontaneous labor to increase the likelihood of neuraxial anesthesia. The alternative is to continue prophylactic-dose LMWH until a scheduled delivery. While the SOAP guidelines establish the timeframe that is safe to proceed with neuraxial anesthesia, there is variation in practice, so consider discussing this with your anesthesia providers.

SOAP considers prophylactic-dose UFH to be 5,000 U 2 to 3 times per day. In this setting, neuraxial anesthesia can be placed more than 4 to 6 hours from the last dose.¹⁷ But due to the pharmacokinetics of pregnancy, ACOG recommends 10,000 U in the third trimester.⁸ This dose is considered intermediate-dose by SOAP, and 12 hours or longer plus a normal activated partial thromboplastin time (aPTT) or undetectable anti-Xa level are required prior to neuraxial anesthesia. This is the same time allowed for prophylactic-dose LMWH without lab work. Prophylactic-dose LMWH is considered to be enoxaparin 40 mg or less daily or 30 mg twice daily, and dalteparin 5,000 U daily. For therapeutic-dose LMWH or UFH, 24 hours or more from last dose is recommended prior to neuraxial anesthesia. For intermediate-dose LMWH, data are limited to recommend anything between 12 and 24 hours.¹⁷

In my practice, we favor a shared decision-making approach with patients. We discuss the likelihood of labor prior to 39 weeks based on a patient’s history, the importance of neuraxial anesthesia to the patient, and the importance of the number of daily injections. Most patients continue enoxaparin until a scheduled induction, and they are instructed to skip their dose if labor symptoms begin. Patients at high risk for preterm delivery can be transitioned to heparin earlier than 36 weeks. ●

Pregnancy and the postpartum period are times of increased risk for venous thromboembolism (VTE). While VTE is a rare event overall, it is responsible for more than 9% of maternal deaths in the United States.¹ The increased risk of VTE exists throughout pregnancy, rising in the third trimester.² The highest-risk period is the first 6 weeks postpartum, likely peaking in the first 2 to 3 weeks and returning to baseline at about 12 weeks postpartum.^2,3

To reduce this source of maternal harm, the National Partnership for Maternal Safety and the Council on Patient Safety in Women’s Health Care recommend the use of VTE prevention bundles. Bundles include standard assessment of risk during prenatal care, any admission to the hospital, and postpartum coupled with standard recommendations for treatment.^4-6 Multiple published guidelines are available for prevention of VTE in pregnancy, and they provide varying recommendations on patient selection and treatment. Many of these recommendations are based on low quality of evidence, making the choice of standard practice difficult.

In this article, I attempt to simplify patient selection and treatment based on currently published guidelines from the American College of Obstetricians and Gynecologists (ACOG), Royal College of Obstetricians and Gynaecologists (RCOG), American College of Chest Physicians (CHEST), American Society of Hematology (ASH), and expert opinion.

Determining VTE risk and need for prophylaxis

CASE 1 Woman with factor V Leiden

A 25-year-old woman (G1P0) presents for her initial prenatal visit. She says she is a carrier for factor V Leiden but has never had a clot. She was tested after her sister had a VTE. She asks, does she need VTE prophylaxis before her delivery?

What are the considerations and options for this patient?

Options for VTE prophylaxis

Before considering patients at risk for VTE, it is helpful to review the options for prophylaxis. Patients can undergo clinical surveillance or routine care with attention to VTE symptoms and a low threshold for workup.

There are 3 categories of chemoprophylaxis for prevention of VTE. (TABLE 1 offers examples of dosing regimens.) No strategy has been proven optimal over another:

• prophylactic-dose: the lowest, fixed dose.
• intermediate-dose: lacks a standard definition and is any dose higher than prophylactic-dose but lower than therapeutic-dose. This includes fixed twice-daily doses, weight-based doses, and incrementally increasing doses.
• therapeutic-dose: typically used for treatment but mentioned here since patients with high-risk conditions may use it for prevention of VTE.

The preferred agent for VTE chemoprophylaxis is low molecular weight heparin (LMWH; dalteparin, enoxaparin). LMWH has a lower risk of complications than unfractionated heparin (UFH) and can be injected once daily. LMWH and UFH do not cross the placenta. LMWH and UFH are safe in breastfeeding. Oral direct thrombin inhibitors and anti-Xa inhibitors are not recommended in pregnancy or lactation at this time. Warfarin is avoided in pregnancy except in situations with mechanical heart valves, which will not be addressed here. Patients taking warfarin for long-term anticoagulation can transition back while breastfeeding with appropriate bridging.

Continue to: Risk factors for VTE...

Risk factors for VTE

History of VTE. The most important risk factor for VTE is a personal history of prior VTE.⁶ Recurrence risks have been widely reported and depend on the factors surrounding the initial event. For patients with a prior provoked deep vein thrombosis (DVT; associated with trauma or surgery), the antepartum VTE risk likely is less than 1%, and VTE chemoprophylaxis is not recommended antepartum.⁷

For patients with a prior VTE that was not associated with surgery or trauma (unprovoked), the risk is approximately 3%; for prior VTE related to pregnancy or hormonal contraception, the risk is approximately 6%.⁷ For both of these groups, prophylactic-dose antepartum is recommended. Patients with recurrent VTE are often taking long-term anticoagulation. Anyone on long-term anticoagulation should be placed on therapeutic-dose antepartum. For patients not receiving long-term anticoagulation, consider a hematology consultation when available, and begin an intermediate-dose or therapeutic-dose regimen after assessing other risk factors and the risk of bleeding and discussing treatment with the patient.

Thrombophilias. The next most important risk factor is the presence of inherited thrombophilias.⁶ Factor V homozygote, prothrombin G20210A mutation homozygote, antithrombin deficiency, and combined factor V heterozygote and prothrombin G20210A heterozygote (also called compound heterozygote) have the strongest association with VTE in pregnancy.⁸ It is recommended that patients with these high-risk thrombophilias receive prophylactic-dose antepartum.⁸

Factor V heterozygote, prothrombin G20210A mutation heterozygote, and protein C or protein S deficiency are considered low-risk thrombophilias. Patients with low-risk thrombophilias and no personal history of VTE or first-degree relative with VTE can be monitored with clinical surveillance antepartum. However, if a family history of VTE or other risk factors for VTE are present, antepartum prophylactic-dose is recommended. Clinical factors to consider antepartum include obesity, age older than 35 years, parity of 3 or higher, varicose veins, immobility, smoking, assisted reproductive technology use, multiple gestation, and preeclampsia.¹⁰

Antiphospholipid syndrome (APS) is another high-risk condition. For patients not taking long-term anticoagulation antepartum, prophylactic-dose is recommended. For patients on long-term anticoagulation, therapeutic-dose is recommended.

Other medical conditions. Patients with medical conditions that place them at high risk for VTE may warrant prophylactic-dose antepartum. These include active cancer, active systemic lupus erythematosus, sickle cell disease, nephropathy, and inflammatory bowel disease.¹⁰ This decision can be made in conjunction with other specialists caring for the patient.

Antepartum prophylactic-dose is not recommended for low-risk patients as there is less than 1% risk of VTE.⁷ (TABLE 2 summarizes antepartum chemoprophylaxis recommendations.)

CASE 1 continued Patient develops another VTE risk factor

The patient is being followed with clinical surveillance. At 19 weeks’ gestation, she presents to the emergency department with shortness of breath and fever. She is diagnosed with COVID-19 and is admitted by a medicine service. They call the OB team to ask for recommendations regarding anticoagulation.

What should the next steps include?

Hospitalization and nonobstetric surgery are risk factors for VTE. Many hospitals use a standardized assessment for all inpatients, such as the Padua or Caprini VTE risk assessment scores. These can be modified for use in pregnant patients, although neither scoring system is currently validated for use in pregnancy.⁵ For any pregnant patient admitted to the hospital, mechanical prophylaxis is recommended.

COVID-19. Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome, COVID-19, is associated with increased rates of VTE. Recommendations for pregnant patients with COVID-19 are the same as for the general population. During hospitalization for COVID-19, pregnant patients should be placed on prophylactic-dose chemoprophylaxis. Patients should not be discharged home on chemoprophylaxis, and patients managed as outpatients for their disease do not need chemoprophylaxis.¹¹

Management approach. Prophylactic-dose administration is recommended during hospital stay for all patients admitted with anticipated length of stay of 3 days or longer and who are not at high risk for bleeding or delivery.¹⁰ Both LMWH and UFH are options for inpatients. For any nonobstetric surgery or admission, LMWH may be most appropriate. However, as most obstetrics admissions are at increased risk for delivery, UFH 5,000 U twice daily to 3 times daily is the best option to increase the chances for neuraxial anesthesia. (I review anesthesia considerations for delivery later in this article.) For patients at high risk for bleeding or delivery, mechanical prophylaxis alone, with elastic stockings or pneumatic compression devices, can be used.

Continue to: CASE 1 continued Patient is discharged home...

CASE 1 continued Patient is discharged home

The patient received enoxaparin while she was in the hospital. She is now discharged and doing well. She asks, will she need anticoagulation prophylaxis after delivery?

How would you counsel her?

Chemoprophylaxis in the postpartum period

With no risk of fetal harm and a higher risk of VTE per day, the threshold for chemoprophylaxis is lower in the postpartum period. The risk of postpartum bleeding is less than 1%, with the most common complication being wound hematomas (0.61%).⁹ For this case patient, the COVID-19 diagnosis does not alter the recommendations for postpartum chemoprophylaxis. Additionally, as the need for neuraxial anesthesia has passed, the use of intermediate-dose chemoprophylaxis over prophylactic-dose is advocated in the postpartum period, especially in obese patients.¹²

As mentioned previously, there is no standard definition of intermediate-dose. Data suggest that a weight-based intermediate-dose is most likely to achieve therapeutic levels of anti-Xa in this high-risk population compared with a fixed dose.^13,14 For example, enoxaparin 0.5 mg/kg twice daily is recommended for patients with class 3 obesity or higher by the Society for Maternal-Fetal Medicine.¹²

As a rule, anyone who was on chemoprophylaxis antepartum should be continued on at least an equivalent dose for 6 weeks postpartum. Postpartum, patients with any prior DVT should take prophylactic-dose or intermediate-dose chemoprophylaxis for 6 weeks. Patients with a known high-risk thrombophilia should receive prophylactic-dose or intermediate-dose chemoprophylaxis postpartum for 6 weeks. For patients with a low-risk thrombophilia, prophylactic-dose or intermediate-dose chemoprophylaxis is recommended for 6 weeks.

For low-risk patients without prior VTE or thrombophilia, standardized risk assessment is recommended.

Cesarean delivery

Cesarean delivery (CD) is a risk factor for postpartum VTE.⁹ A universal chemoprophylaxis strategy has not been proven in this patient population. Mechanical prophylaxis with sequential compression devices is recommended for all patients undergoing CD pre-procedure and until patients are fully ambulatory.^8,9 Early ambulation also should be encouraged.

Many risk assessment models are available for postoperative VTE prevention, and they have widely different chemoprophylaxis rates. Studies have shown chemoprophylaxis rates of 85% by RCOG, 1% by ACOG, 35% by CHEST, 94% by Caprini, and less than 1% by Padua.^15,16 In addition to the antepartum patient-specific risk factors mentioned, postpartum risk factors include infection, postpartum hemorrhage, and transfusion. Based on data extrapolated from the nonobstetric literature, chemoprophylaxis is recommended until discharge from the hospital unless risk factors are expected to continue.⁹

Neuraxial anesthesia

For patients who require postpartum chemoprophylaxis, the Society for Obstetric Anesthesia and Perinatology (SOAP) offers evidence-based guidelines for use after neuraxial anesthesia. UFH can be initiated 1 hour or longer after a neuraxial procedure and 1 hour or longer after catheter removal. Prophylactic-dose LMWH can be restarted at 12 hours or longer after a neuraxial procedure and at 4 to 6 hours or longer after catheter removal. For patients restarting intermediate-dose or therapeutic-dose, the recommendations are to wait 24 hours or longer after a neuraxial procedure and 4 hours or longer after catheter removal.¹⁷ Timing can be individualized based on the patient’s risk of hemorrhage and surgical bleeding. Although it may be tempting to delay chemoprophylaxis in the setting of bleeding, postpartum hemorrhage and transfusion increase the risks of VTE. In this setting, it is best to consider the use of UFH, which safely can be started earlier than LMWH.

For patients without neuraxial anesthesia, ACOG recommends chemoprophylaxis 4 to 6 hours after vaginal delivery and 6 to 12 hours after CD.⁸ (TABLE 3 summarizes recommendations for postpartum chemoprophylaxis.)

Continue to: Adjusting the anticoagulation regimen...

CASE 2 Pregnant woman with prior VTE

A 36-year-old woman (G1P0) with prior VTE is taking enoxaparin 40 mg daily. She asks, does she need any blood work for her anticoagulation?

What would you test for?

Increased renal clearance of LMWH and increased volume of distribution during pregnancy has led to the consideration of monitoring anti-Xa levels. There are no published standards or recommendations for dose adjustment. At this time, anti-Xa level monitoring antepartum is not recommended, but it may be considered when a patient is at the extremes of weight. With a weight-based strategy in the postpartum period, monitoring is not recommended as studies show a higher likelihood of therapeutic anti-Xa levels with this approach.^13,14 This is an active area of research, and these recommendations may change.

For prophylactic-dose or intermediate-dose anticoagulation, a peak anti-Xa level of 0.2 to 0.6 U/mL is generally accepted as the target. For therapeutic-dose, a peak anti-Xa level of 0.6 to 1.2 U/mL is generally accepted as the therapeutic range. This blood draw must be collected 4 hours after the third dose.

CASE 2 continued Anticoagulation considerations nearing delivery

The patient is now at 36 weeks’ gestation, and she asks, what should be done regarding her anticoagulation prior to delivery?

What would be an appropriate approach?

Traditionally, patients were transitioned to UFH at 36 weeks and allowed to present in spontaneous labor to increase the likelihood of neuraxial anesthesia. The alternative is to continue prophylactic-dose LMWH until a scheduled delivery. While the SOAP guidelines establish the timeframe that is safe to proceed with neuraxial anesthesia, there is variation in practice, so consider discussing this with your anesthesia providers.

SOAP considers prophylactic-dose UFH to be 5,000 U 2 to 3 times per day. In this setting, neuraxial anesthesia can be placed more than 4 to 6 hours from the last dose.¹⁷ But due to the pharmacokinetics of pregnancy, ACOG recommends 10,000 U in the third trimester.⁸ This dose is considered intermediate-dose by SOAP, and 12 hours or longer plus a normal activated partial thromboplastin time (aPTT) or undetectable anti-Xa level are required prior to neuraxial anesthesia. This is the same time allowed for prophylactic-dose LMWH without lab work. Prophylactic-dose LMWH is considered to be enoxaparin 40 mg or less daily or 30 mg twice daily, and dalteparin 5,000 U daily. For therapeutic-dose LMWH or UFH, 24 hours or more from last dose is recommended prior to neuraxial anesthesia. For intermediate-dose LMWH, data are limited to recommend anything between 12 and 24 hours.¹⁷

In my practice, we favor a shared decision-making approach with patients. We discuss the likelihood of labor prior to 39 weeks based on a patient’s history, the importance of neuraxial anesthesia to the patient, and the importance of the number of daily injections. Most patients continue enoxaparin until a scheduled induction, and they are instructed to skip their dose if labor symptoms begin. Patients at high risk for preterm delivery can be transitioned to heparin earlier than 36 weeks. ●

Pregnancy and the postpartum period are times of increased risk for venous thromboembolism (VTE). While VTE is a rare event overall, it is responsible for more than 9% of maternal deaths in the United States.¹ The increased risk of VTE exists throughout pregnancy, rising in the third trimester.² The highest-risk period is the first 6 weeks postpartum, likely peaking in the first 2 to 3 weeks and returning to baseline at about 12 weeks postpartum.^2,3

To reduce this source of maternal harm, the National Partnership for Maternal Safety and the Council on Patient Safety in Women’s Health Care recommend the use of VTE prevention bundles. Bundles include standard assessment of risk during prenatal care, any admission to the hospital, and postpartum coupled with standard recommendations for treatment.^4-6 Multiple published guidelines are available for prevention of VTE in pregnancy, and they provide varying recommendations on patient selection and treatment. Many of these recommendations are based on low quality of evidence, making the choice of standard practice difficult.

In this article, I attempt to simplify patient selection and treatment based on currently published guidelines from the American College of Obstetricians and Gynecologists (ACOG), Royal College of Obstetricians and Gynaecologists (RCOG), American College of Chest Physicians (CHEST), American Society of Hematology (ASH), and expert opinion.

Determining VTE risk and need for prophylaxis

CASE 1 Woman with factor V Leiden

A 25-year-old woman (G1P0) presents for her initial prenatal visit. She says she is a carrier for factor V Leiden but has never had a clot. She was tested after her sister had a VTE. She asks, does she need VTE prophylaxis before her delivery?

What are the considerations and options for this patient?

Options for VTE prophylaxis

Before considering patients at risk for VTE, it is helpful to review the options for prophylaxis. Patients can undergo clinical surveillance or routine care with attention to VTE symptoms and a low threshold for workup.

There are 3 categories of chemoprophylaxis for prevention of VTE. (TABLE 1 offers examples of dosing regimens.) No strategy has been proven optimal over another:

• prophylactic-dose: the lowest, fixed dose.
• intermediate-dose: lacks a standard definition and is any dose higher than prophylactic-dose but lower than therapeutic-dose. This includes fixed twice-daily doses, weight-based doses, and incrementally increasing doses.
• therapeutic-dose: typically used for treatment but mentioned here since patients with high-risk conditions may use it for prevention of VTE.

The preferred agent for VTE chemoprophylaxis is low molecular weight heparin (LMWH; dalteparin, enoxaparin). LMWH has a lower risk of complications than unfractionated heparin (UFH) and can be injected once daily. LMWH and UFH do not cross the placenta. LMWH and UFH are safe in breastfeeding. Oral direct thrombin inhibitors and anti-Xa inhibitors are not recommended in pregnancy or lactation at this time. Warfarin is avoided in pregnancy except in situations with mechanical heart valves, which will not be addressed here. Patients taking warfarin for long-term anticoagulation can transition back while breastfeeding with appropriate bridging.

Continue to: Risk factors for VTE...

Risk factors for VTE

History of VTE. The most important risk factor for VTE is a personal history of prior VTE.⁶ Recurrence risks have been widely reported and depend on the factors surrounding the initial event. For patients with a prior provoked deep vein thrombosis (DVT; associated with trauma or surgery), the antepartum VTE risk likely is less than 1%, and VTE chemoprophylaxis is not recommended antepartum.⁷

For patients with a prior VTE that was not associated with surgery or trauma (unprovoked), the risk is approximately 3%; for prior VTE related to pregnancy or hormonal contraception, the risk is approximately 6%.⁷ For both of these groups, prophylactic-dose antepartum is recommended. Patients with recurrent VTE are often taking long-term anticoagulation. Anyone on long-term anticoagulation should be placed on therapeutic-dose antepartum. For patients not receiving long-term anticoagulation, consider a hematology consultation when available, and begin an intermediate-dose or therapeutic-dose regimen after assessing other risk factors and the risk of bleeding and discussing treatment with the patient.

Thrombophilias. The next most important risk factor is the presence of inherited thrombophilias.⁶ Factor V homozygote, prothrombin G20210A mutation homozygote, antithrombin deficiency, and combined factor V heterozygote and prothrombin G20210A heterozygote (also called compound heterozygote) have the strongest association with VTE in pregnancy.⁸ It is recommended that patients with these high-risk thrombophilias receive prophylactic-dose antepartum.⁸

Factor V heterozygote, prothrombin G20210A mutation heterozygote, and protein C or protein S deficiency are considered low-risk thrombophilias. Patients with low-risk thrombophilias and no personal history of VTE or first-degree relative with VTE can be monitored with clinical surveillance antepartum. However, if a family history of VTE or other risk factors for VTE are present, antepartum prophylactic-dose is recommended. Clinical factors to consider antepartum include obesity, age older than 35 years, parity of 3 or higher, varicose veins, immobility, smoking, assisted reproductive technology use, multiple gestation, and preeclampsia.¹⁰

Antiphospholipid syndrome (APS) is another high-risk condition. For patients not taking long-term anticoagulation antepartum, prophylactic-dose is recommended. For patients on long-term anticoagulation, therapeutic-dose is recommended.

Other medical conditions. Patients with medical conditions that place them at high risk for VTE may warrant prophylactic-dose antepartum. These include active cancer, active systemic lupus erythematosus, sickle cell disease, nephropathy, and inflammatory bowel disease.¹⁰ This decision can be made in conjunction with other specialists caring for the patient.

Antepartum prophylactic-dose is not recommended for low-risk patients as there is less than 1% risk of VTE.⁷ (TABLE 2 summarizes antepartum chemoprophylaxis recommendations.)

CASE 1 continued Patient develops another VTE risk factor

The patient is being followed with clinical surveillance. At 19 weeks’ gestation, she presents to the emergency department with shortness of breath and fever. She is diagnosed with COVID-19 and is admitted by a medicine service. They call the OB team to ask for recommendations regarding anticoagulation.

What should the next steps include?

Hospitalization and nonobstetric surgery are risk factors for VTE. Many hospitals use a standardized assessment for all inpatients, such as the Padua or Caprini VTE risk assessment scores. These can be modified for use in pregnant patients, although neither scoring system is currently validated for use in pregnancy.⁵ For any pregnant patient admitted to the hospital, mechanical prophylaxis is recommended.

COVID-19. Infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated clinical syndrome, COVID-19, is associated with increased rates of VTE. Recommendations for pregnant patients with COVID-19 are the same as for the general population. During hospitalization for COVID-19, pregnant patients should be placed on prophylactic-dose chemoprophylaxis. Patients should not be discharged home on chemoprophylaxis, and patients managed as outpatients for their disease do not need chemoprophylaxis.¹¹

Management approach. Prophylactic-dose administration is recommended during hospital stay for all patients admitted with anticipated length of stay of 3 days or longer and who are not at high risk for bleeding or delivery.¹⁰ Both LMWH and UFH are options for inpatients. For any nonobstetric surgery or admission, LMWH may be most appropriate. However, as most obstetrics admissions are at increased risk for delivery, UFH 5,000 U twice daily to 3 times daily is the best option to increase the chances for neuraxial anesthesia. (I review anesthesia considerations for delivery later in this article.) For patients at high risk for bleeding or delivery, mechanical prophylaxis alone, with elastic stockings or pneumatic compression devices, can be used.

Continue to: CASE 1 continued Patient is discharged home...

CASE 1 continued Patient is discharged home

The patient received enoxaparin while she was in the hospital. She is now discharged and doing well. She asks, will she need anticoagulation prophylaxis after delivery?

How would you counsel her?

Chemoprophylaxis in the postpartum period

With no risk of fetal harm and a higher risk of VTE per day, the threshold for chemoprophylaxis is lower in the postpartum period. The risk of postpartum bleeding is less than 1%, with the most common complication being wound hematomas (0.61%).⁹ For this case patient, the COVID-19 diagnosis does not alter the recommendations for postpartum chemoprophylaxis. Additionally, as the need for neuraxial anesthesia has passed, the use of intermediate-dose chemoprophylaxis over prophylactic-dose is advocated in the postpartum period, especially in obese patients.¹²

As mentioned previously, there is no standard definition of intermediate-dose. Data suggest that a weight-based intermediate-dose is most likely to achieve therapeutic levels of anti-Xa in this high-risk population compared with a fixed dose.^13,14 For example, enoxaparin 0.5 mg/kg twice daily is recommended for patients with class 3 obesity or higher by the Society for Maternal-Fetal Medicine.¹²

As a rule, anyone who was on chemoprophylaxis antepartum should be continued on at least an equivalent dose for 6 weeks postpartum. Postpartum, patients with any prior DVT should take prophylactic-dose or intermediate-dose chemoprophylaxis for 6 weeks. Patients with a known high-risk thrombophilia should receive prophylactic-dose or intermediate-dose chemoprophylaxis postpartum for 6 weeks. For patients with a low-risk thrombophilia, prophylactic-dose or intermediate-dose chemoprophylaxis is recommended for 6 weeks.

For low-risk patients without prior VTE or thrombophilia, standardized risk assessment is recommended.

Cesarean delivery

Cesarean delivery (CD) is a risk factor for postpartum VTE.⁹ A universal chemoprophylaxis strategy has not been proven in this patient population. Mechanical prophylaxis with sequential compression devices is recommended for all patients undergoing CD pre-procedure and until patients are fully ambulatory.^8,9 Early ambulation also should be encouraged.

Many risk assessment models are available for postoperative VTE prevention, and they have widely different chemoprophylaxis rates. Studies have shown chemoprophylaxis rates of 85% by RCOG, 1% by ACOG, 35% by CHEST, 94% by Caprini, and less than 1% by Padua.^15,16 In addition to the antepartum patient-specific risk factors mentioned, postpartum risk factors include infection, postpartum hemorrhage, and transfusion. Based on data extrapolated from the nonobstetric literature, chemoprophylaxis is recommended until discharge from the hospital unless risk factors are expected to continue.⁹

Neuraxial anesthesia

For patients who require postpartum chemoprophylaxis, the Society for Obstetric Anesthesia and Perinatology (SOAP) offers evidence-based guidelines for use after neuraxial anesthesia. UFH can be initiated 1 hour or longer after a neuraxial procedure and 1 hour or longer after catheter removal. Prophylactic-dose LMWH can be restarted at 12 hours or longer after a neuraxial procedure and at 4 to 6 hours or longer after catheter removal. For patients restarting intermediate-dose or therapeutic-dose, the recommendations are to wait 24 hours or longer after a neuraxial procedure and 4 hours or longer after catheter removal.¹⁷ Timing can be individualized based on the patient’s risk of hemorrhage and surgical bleeding. Although it may be tempting to delay chemoprophylaxis in the setting of bleeding, postpartum hemorrhage and transfusion increase the risks of VTE. In this setting, it is best to consider the use of UFH, which safely can be started earlier than LMWH.

For patients without neuraxial anesthesia, ACOG recommends chemoprophylaxis 4 to 6 hours after vaginal delivery and 6 to 12 hours after CD.⁸ (TABLE 3 summarizes recommendations for postpartum chemoprophylaxis.)

Continue to: Adjusting the anticoagulation regimen...

CASE 2 Pregnant woman with prior VTE

A 36-year-old woman (G1P0) with prior VTE is taking enoxaparin 40 mg daily. She asks, does she need any blood work for her anticoagulation?

What would you test for?

Increased renal clearance of LMWH and increased volume of distribution during pregnancy has led to the consideration of monitoring anti-Xa levels. There are no published standards or recommendations for dose adjustment. At this time, anti-Xa level monitoring antepartum is not recommended, but it may be considered when a patient is at the extremes of weight. With a weight-based strategy in the postpartum period, monitoring is not recommended as studies show a higher likelihood of therapeutic anti-Xa levels with this approach.^13,14 This is an active area of research, and these recommendations may change.

For prophylactic-dose or intermediate-dose anticoagulation, a peak anti-Xa level of 0.2 to 0.6 U/mL is generally accepted as the target. For therapeutic-dose, a peak anti-Xa level of 0.6 to 1.2 U/mL is generally accepted as the therapeutic range. This blood draw must be collected 4 hours after the third dose.

CASE 2 continued Anticoagulation considerations nearing delivery

The patient is now at 36 weeks’ gestation, and she asks, what should be done regarding her anticoagulation prior to delivery?

What would be an appropriate approach?

Traditionally, patients were transitioned to UFH at 36 weeks and allowed to present in spontaneous labor to increase the likelihood of neuraxial anesthesia. The alternative is to continue prophylactic-dose LMWH until a scheduled delivery. While the SOAP guidelines establish the timeframe that is safe to proceed with neuraxial anesthesia, there is variation in practice, so consider discussing this with your anesthesia providers.

SOAP considers prophylactic-dose UFH to be 5,000 U 2 to 3 times per day. In this setting, neuraxial anesthesia can be placed more than 4 to 6 hours from the last dose.¹⁷ But due to the pharmacokinetics of pregnancy, ACOG recommends 10,000 U in the third trimester.⁸ This dose is considered intermediate-dose by SOAP, and 12 hours or longer plus a normal activated partial thromboplastin time (aPTT) or undetectable anti-Xa level are required prior to neuraxial anesthesia. This is the same time allowed for prophylactic-dose LMWH without lab work. Prophylactic-dose LMWH is considered to be enoxaparin 40 mg or less daily or 30 mg twice daily, and dalteparin 5,000 U daily. For therapeutic-dose LMWH or UFH, 24 hours or more from last dose is recommended prior to neuraxial anesthesia. For intermediate-dose LMWH, data are limited to recommend anything between 12 and 24 hours.¹⁷

In my practice, we favor a shared decision-making approach with patients. We discuss the likelihood of labor prior to 39 weeks based on a patient’s history, the importance of neuraxial anesthesia to the patient, and the importance of the number of daily injections. Most patients continue enoxaparin until a scheduled induction, and they are instructed to skip their dose if labor symptoms begin. Patients at high risk for preterm delivery can be transitioned to heparin earlier than 36 weeks. ●

CASE Pregnant woman with positive hepatitis B surface antigen

A 27-year-old primigravida at 9 weeks 3 days of gestation tests positive for the hepatitis B surface antigen at her first prenatal appointment. She is completely asymptomatic.

• What additional tests are indicated?

• Does she pose a risk to her sexual partner, and is her newborn at risk for acquiring hepatitis B?

• Can anything be done to protect her partner and newborn from infection?

Meet our perpetrator

Hepatitis is one of the more common viral infections that may occur during pregnancy. Two forms of hepatitis, notably hepatitis A and E, pose a primary threat to the mother. Three forms (B, C, and D) present dangers for the mother, fetus, and newborn. This article will review the epidemiology, clinical manifestations, perinatal implications, and management of the various forms of viral hepatitis. (TABLE 1).

Hepatitis A

Hepatitis A is caused by an RNA virus that is transmitted by fecal-oral contact. The disease is most prevalent in areas with poor sanitation and close living conditions. The incubation period ranges from 15 to 50 days. Most children who acquire this disease are asymptomatic. By contrast, most infected adults are acutely symptomatic. Clinical manifestations typically include low-grade fever, malaise, anorexia, right upper quadrant pain and tenderness, jaundice, and claycolored stools.^1,2

The diagnosis of acute hepatitis A infection is best confirmed by detection of immunoglobulin M (IgM)-specific antibodies. The serum transaminase concentrations and the serum bilirubin concentrations usually are significantly elevated. The international normalized ratio, prothrombin time, and partial thromboplastin time also may be elevated.^1,2

The treatment for acute hepatitis A largely is supportive care: maintaining hydration, optimizing nutrition, and correcting coagulation abnormalities. The appropriate measures for prevention of hepatitis A are adoption of sound sanitation practices, particularly water purification; minimizing overcrowded living conditions; and administering the hepatitis A vaccine for both pre and postexposure prophylaxis.^3,4 The hepatitis A vaccine is preferred over administration of immune globulin because it provides lifelong immunity.

The hepatitis A vaccine is produced in 2 monovalent formulations: Havrix (GlaxoSmithKline) and Vaqta (Merck & Co, Inc). The vaccine should be administered intramuscularly in 2 doses 6 to 12 months apart. The wholesale cost of the vaccine varies from $66 to $119 (according to http://www.goodrx.com). The vaccine also is available in a bivalent form, with recombinant hepatitis B vaccine (Twinrix, GlaxoSmithKline). When used in this form, 3 vaccine administrations are given—at 0, 1, and 6 months apart. The cost of the vaccine is approximately $150 (according to http://www.goodrx.com). TABLE 2 lists the individuals who are appropriate candidates for the hepatitis A vaccine.^3,4

Hepatitis B

Hepatitis B is caused by a DNA virus that is transmitted parenterally or perinatally or through sexual contact. Four genotypes have been identified: A, B, C, and D.

Acute hepatitis B affects 1 to 2 of 1,000 pregnancies in the United States. Approximately 6 to 10 patients per 1,000 pregnancies are asymptomatic but chronically infected.⁴ The natural history of hepatitis B infection is shown in the FIGURE. The diagnosis of acute and chronic hepatitis B is best established by serology and polymerase chain reaction (PCR; TABLE 3).

Continue to: Hepatitis C...

Hepatitis C

Hepatitis C is caused by an RNA virus that has 6 genotypes. The most common genotype is HCV1, which affects 79% of patients; approximately 13% of patients have HCV2, and 6% have HCV3.⁹ Of note, the 3 individuals who discovered this virus—Drs. Harvey Alter, Michael Houghton, and Charles Rice—received the 2020 Nobel Prize in Medicine.¹⁰

Hepatitis C is transmitted via sexual contact, parenterally, and perinatally. In many patient populations in the United States, hepatitis C is now more prevalent than hepatitis B. Only about half of all infected persons are aware of their infection. If patients go untreated, approximately 15% to 30% eventually develop cirrhosis. Of these individuals, 1% to 3% develop hepatocellular cancer. Chronic hepatitis C is now the most common indication for liver transplantation in the United States.^1,9

In the initial stages of infection, hepatitis C usually is asymptomatic. The best screening test is detection of hepatitis C antibody. Because of the increasing prevalence of this disease, the seriousness of the infection, and the recent availability of remarkably effective treatment, routine screening, rather than screening on the basis of risk factors, for hepatitis C in pregnancy is now indicated.^11,12

The best tests for confirmation of infection are detection of antibody by enzyme immunoassay and recombinant immuno-blot assay and detection of viral RNA in serum by PCR. Seroconversion may not occur for up to 16 weeks after infection. Therefore, in at-risk patients who initially test negative, retesting is advisable. Patients with positive test results should have tests to identify the specific genotype, determine the viral load, and assess liver function.¹

In patients who have undetectable viral loads and who do not have coexisting HIV infection, the risk of perinatal transmission of hepatitis C is less than 5%. If HIV infection is present, the risk of perinatal transmission approaches 20%.^1,13,14

If the patient is coinfected with HIV, a scheduled cesarean delivery should be performed at 38 weeks’ gestation.¹ If the viral load is undetectable, vaginal delivery is appropriate. If the viral load is high, however (arbitrarily defined as >2.5 millioncopies/mL), the optimal method of delivery is controversial. Several small, nonrandomized noncontrolled cohort studies support elective cesarean delivery in such patients.¹⁴

There is no contraindication to breastfeeding in women with hepatitis C unless they are coinfected with HIV. In such a circumstance, formula feeding should be chosen. After delivery, patients with hepatitis C should be referred to a gastroenterology specialist to receive antiviral treatment. Multiple new single-agent and combination regimens have produced cures in more than 90% of patients. These regimens usually require 8 to 12 weeks of treatment, and they are very expensive. They have not been widely tested in pregnant women.¹

Hepatitis D

Hepatitis D, or delta hepatitis, is caused by an RNA virus. This virus is unique because it is incapable of independent replication. It must be present in association with hepatitis B to replicate and cause clinical infection. Therefore, the epidemiology of hepatitis D closely mirrors that of hepatitis B.^1,2

Patients with hepatitis D typically present in one of two ways. Some individuals are acutely infected with hepatitis D at the same time that they acquire hepatitis B (coinfection). The natural history of this infection usually is spontaneous resolution without sequelae. Other patients have chronic hepatitis D superimposed on chronic hepatitis B (superinfection). Unfortunately, patients with the latter condition are at a notably increased risk for developing severe persistent liver disease.^1,2

The diagnosis of hepatitis D may be confirmed by identifying the delta antigen in serum or in liver tissue obtained by biopsy or by identifying IgM- and IgG-specific antibodies in serum. In conjunction with hepatitis B, the delta virus can cause a chronic carrier state. Perinatal transmission is possible but uncommon. Of greatest importance, the immunoprophylaxis described for hepatitis B is almost perfectly protective against perinatal transmission of hepatitis D.^1,2

Continue to: Hepatitis E...

Hepatitis E

Hepatitis E is an RNA virus that has 1 serotype and 4 genotypes. Its epidemiology is similar to that of hepatitis A. It is the most common waterborne illness in the world. The incubation period varies from 21 to 56 days. This disease is quite rare in the United States but is endemic in developing nations. In those countries, maternal infection has an alarmingly high mortality rate (5%–25%). For example, in Bangladesh, hepatitis E is responsible for more than 1,000 deaths per year in pregnant women. When hepatitis E is identified in more affluent countries, the individual cases and small outbreaks usually are linked to consumption of undercooked pork or wild game.^1,15-17

The clinical presentation of acute hepatitis E also is similar to that of hepatitis A. The usual manifestations are fever, malaise, anorexia, nausea, right upper quadrant pain and tenderness, jaundice, darkened urine, and clay-colored stools. The most useful diagnostic tests are serologic detection of viral-specific antibodies (positive IgM or a 4-fold increase in the prior IgG titer) and PCR-RNA.^1,17

Hepatitis E usually does not cause a chronic carrier state, and perinatal transmission is rare. Fortunately, a highly effective vaccine was recently developed (Hecolin, Xiamen Innovax Biotech). This recombinant vaccine is specifically directed against the hepatitis E genotype 1. In the initial efficacy study, healthy adults aged 16 to 65 years were randomly assigned to receive either the hepatitis E vaccine or the hepatitis B vaccine. The vaccine was administered at time point 0, and 1 and 6 months later. Patients were followed for up to 4.5 years to assess efficacy, immunogenicity, and safety. During the study period, 7 cases of hepatitis E occurred in the vaccine group, compared with 53 in the control group. Approximately 56,000 patients were included in each group. The efficacy of the vaccine was 86.8% (P<.001).¹⁸

Hepatitis G

Hepatitis G is caused by 2 single-stranded RNA viruses that are virtually identical—hepatitis G virus and GB virus type C. The viruses share approximately 30% homology with hepatitis C virus. The organism is present throughout the world and infects approximately 1.5% to 2.0% of the population. The virus is transmitted by blood and sexual contact. It replicates preferentially in mononuclear cells and the bone marrow rather than in the liver.^19-21

Hepatitis G is much less virulent than hepatitis C. Hepatitis G often coexists with hepatitis A, B, and C, as well as with HIV. Coinfection with hepatitis G does not adversely affect the clinical course of the other conditions.^22,23

Most patients with hepatitis G are asymptomatic, and no treatment is indicated. The virus can cause a chronic carrier state. Perinatal transmission is distinctly uncommon. When it does occur, however, injury to mother, fetus, or neonate is unlikely.^1,24

The diagnosis of hepatitis G can be established by detection of virus with PCR and by the identification of antibody by enzyme immunoassay. Routine screening for this infection in pregnancy is not indicated.^1,2

CASE Resolved

Hepatitis B is highly contagious and can be transmitted from the patient to her sexual partner and neonate. Testing for hepatitis B surface antigen and antibody is indicated in her partner. If these tests are negative, the partner should immediately receive hepatitis B immune globulin and then be started on the 3-dose hepatitis B vaccination series. The patient’s newborn also should receive hepatitis B immune globulin within 12 hours of delivery and should receive the first dose of the hepatitis B vaccine prior to discharge from the hospital. The second and third doses should be administered 1 and 6 months after delivery.

The patient also should have the following tests:

• liver function tests

-serum transaminases

-direct and indirect bilirubin

-coagulation profile

• hepatitis D antigen

• hepatitis B genotype

• hepatitis B viral load

• HIV serology.

If the hepatitis B viral load exceeds 1 million copies/mL, the patient should be treated with tenofovir 200 mg daily from 28 weeks’ gestation until delivery. In addition, she should be referred to a liver disease specialist after delivery for consideration of treatment with directly-acting antiviral agents. ●

CASE Pregnant woman with positive hepatitis B surface antigen

A 27-year-old primigravida at 9 weeks 3 days of gestation tests positive for the hepatitis B surface antigen at her first prenatal appointment. She is completely asymptomatic.

• What additional tests are indicated?

• Does she pose a risk to her sexual partner, and is her newborn at risk for acquiring hepatitis B?

• Can anything be done to protect her partner and newborn from infection?

Meet our perpetrator

Hepatitis is one of the more common viral infections that may occur during pregnancy. Two forms of hepatitis, notably hepatitis A and E, pose a primary threat to the mother. Three forms (B, C, and D) present dangers for the mother, fetus, and newborn. This article will review the epidemiology, clinical manifestations, perinatal implications, and management of the various forms of viral hepatitis. (TABLE 1).

Hepatitis A

Hepatitis A is caused by an RNA virus that is transmitted by fecal-oral contact. The disease is most prevalent in areas with poor sanitation and close living conditions. The incubation period ranges from 15 to 50 days. Most children who acquire this disease are asymptomatic. By contrast, most infected adults are acutely symptomatic. Clinical manifestations typically include low-grade fever, malaise, anorexia, right upper quadrant pain and tenderness, jaundice, and claycolored stools.^1,2

The diagnosis of acute hepatitis A infection is best confirmed by detection of immunoglobulin M (IgM)-specific antibodies. The serum transaminase concentrations and the serum bilirubin concentrations usually are significantly elevated. The international normalized ratio, prothrombin time, and partial thromboplastin time also may be elevated.^1,2

The treatment for acute hepatitis A largely is supportive care: maintaining hydration, optimizing nutrition, and correcting coagulation abnormalities. The appropriate measures for prevention of hepatitis A are adoption of sound sanitation practices, particularly water purification; minimizing overcrowded living conditions; and administering the hepatitis A vaccine for both pre and postexposure prophylaxis.^3,4 The hepatitis A vaccine is preferred over administration of immune globulin because it provides lifelong immunity.

The hepatitis A vaccine is produced in 2 monovalent formulations: Havrix (GlaxoSmithKline) and Vaqta (Merck & Co, Inc). The vaccine should be administered intramuscularly in 2 doses 6 to 12 months apart. The wholesale cost of the vaccine varies from $66 to $119 (according to http://www.goodrx.com). The vaccine also is available in a bivalent form, with recombinant hepatitis B vaccine (Twinrix, GlaxoSmithKline). When used in this form, 3 vaccine administrations are given—at 0, 1, and 6 months apart. The cost of the vaccine is approximately $150 (according to http://www.goodrx.com). TABLE 2 lists the individuals who are appropriate candidates for the hepatitis A vaccine.^3,4

Hepatitis B

Hepatitis B is caused by a DNA virus that is transmitted parenterally or perinatally or through sexual contact. Four genotypes have been identified: A, B, C, and D.

Acute hepatitis B affects 1 to 2 of 1,000 pregnancies in the United States. Approximately 6 to 10 patients per 1,000 pregnancies are asymptomatic but chronically infected.⁴ The natural history of hepatitis B infection is shown in the FIGURE. The diagnosis of acute and chronic hepatitis B is best established by serology and polymerase chain reaction (PCR; TABLE 3).

Continue to: Hepatitis C...

Hepatitis C

Hepatitis C is caused by an RNA virus that has 6 genotypes. The most common genotype is HCV1, which affects 79% of patients; approximately 13% of patients have HCV2, and 6% have HCV3.⁹ Of note, the 3 individuals who discovered this virus—Drs. Harvey Alter, Michael Houghton, and Charles Rice—received the 2020 Nobel Prize in Medicine.¹⁰

Hepatitis C is transmitted via sexual contact, parenterally, and perinatally. In many patient populations in the United States, hepatitis C is now more prevalent than hepatitis B. Only about half of all infected persons are aware of their infection. If patients go untreated, approximately 15% to 30% eventually develop cirrhosis. Of these individuals, 1% to 3% develop hepatocellular cancer. Chronic hepatitis C is now the most common indication for liver transplantation in the United States.^1,9

In the initial stages of infection, hepatitis C usually is asymptomatic. The best screening test is detection of hepatitis C antibody. Because of the increasing prevalence of this disease, the seriousness of the infection, and the recent availability of remarkably effective treatment, routine screening, rather than screening on the basis of risk factors, for hepatitis C in pregnancy is now indicated.^11,12

The best tests for confirmation of infection are detection of antibody by enzyme immunoassay and recombinant immuno-blot assay and detection of viral RNA in serum by PCR. Seroconversion may not occur for up to 16 weeks after infection. Therefore, in at-risk patients who initially test negative, retesting is advisable. Patients with positive test results should have tests to identify the specific genotype, determine the viral load, and assess liver function.¹

In patients who have undetectable viral loads and who do not have coexisting HIV infection, the risk of perinatal transmission of hepatitis C is less than 5%. If HIV infection is present, the risk of perinatal transmission approaches 20%.^1,13,14

If the patient is coinfected with HIV, a scheduled cesarean delivery should be performed at 38 weeks’ gestation.¹ If the viral load is undetectable, vaginal delivery is appropriate. If the viral load is high, however (arbitrarily defined as >2.5 millioncopies/mL), the optimal method of delivery is controversial. Several small, nonrandomized noncontrolled cohort studies support elective cesarean delivery in such patients.¹⁴

There is no contraindication to breastfeeding in women with hepatitis C unless they are coinfected with HIV. In such a circumstance, formula feeding should be chosen. After delivery, patients with hepatitis C should be referred to a gastroenterology specialist to receive antiviral treatment. Multiple new single-agent and combination regimens have produced cures in more than 90% of patients. These regimens usually require 8 to 12 weeks of treatment, and they are very expensive. They have not been widely tested in pregnant women.¹

Hepatitis D

Hepatitis D, or delta hepatitis, is caused by an RNA virus. This virus is unique because it is incapable of independent replication. It must be present in association with hepatitis B to replicate and cause clinical infection. Therefore, the epidemiology of hepatitis D closely mirrors that of hepatitis B.^1,2

Patients with hepatitis D typically present in one of two ways. Some individuals are acutely infected with hepatitis D at the same time that they acquire hepatitis B (coinfection). The natural history of this infection usually is spontaneous resolution without sequelae. Other patients have chronic hepatitis D superimposed on chronic hepatitis B (superinfection). Unfortunately, patients with the latter condition are at a notably increased risk for developing severe persistent liver disease.^1,2

The diagnosis of hepatitis D may be confirmed by identifying the delta antigen in serum or in liver tissue obtained by biopsy or by identifying IgM- and IgG-specific antibodies in serum. In conjunction with hepatitis B, the delta virus can cause a chronic carrier state. Perinatal transmission is possible but uncommon. Of greatest importance, the immunoprophylaxis described for hepatitis B is almost perfectly protective against perinatal transmission of hepatitis D.^1,2

Continue to: Hepatitis E...

Hepatitis E

Hepatitis E is an RNA virus that has 1 serotype and 4 genotypes. Its epidemiology is similar to that of hepatitis A. It is the most common waterborne illness in the world. The incubation period varies from 21 to 56 days. This disease is quite rare in the United States but is endemic in developing nations. In those countries, maternal infection has an alarmingly high mortality rate (5%–25%). For example, in Bangladesh, hepatitis E is responsible for more than 1,000 deaths per year in pregnant women. When hepatitis E is identified in more affluent countries, the individual cases and small outbreaks usually are linked to consumption of undercooked pork or wild game.^1,15-17

The clinical presentation of acute hepatitis E also is similar to that of hepatitis A. The usual manifestations are fever, malaise, anorexia, nausea, right upper quadrant pain and tenderness, jaundice, darkened urine, and clay-colored stools. The most useful diagnostic tests are serologic detection of viral-specific antibodies (positive IgM or a 4-fold increase in the prior IgG titer) and PCR-RNA.^1,17

Hepatitis E usually does not cause a chronic carrier state, and perinatal transmission is rare. Fortunately, a highly effective vaccine was recently developed (Hecolin, Xiamen Innovax Biotech). This recombinant vaccine is specifically directed against the hepatitis E genotype 1. In the initial efficacy study, healthy adults aged 16 to 65 years were randomly assigned to receive either the hepatitis E vaccine or the hepatitis B vaccine. The vaccine was administered at time point 0, and 1 and 6 months later. Patients were followed for up to 4.5 years to assess efficacy, immunogenicity, and safety. During the study period, 7 cases of hepatitis E occurred in the vaccine group, compared with 53 in the control group. Approximately 56,000 patients were included in each group. The efficacy of the vaccine was 86.8% (P<.001).¹⁸

Hepatitis G

Hepatitis G is caused by 2 single-stranded RNA viruses that are virtually identical—hepatitis G virus and GB virus type C. The viruses share approximately 30% homology with hepatitis C virus. The organism is present throughout the world and infects approximately 1.5% to 2.0% of the population. The virus is transmitted by blood and sexual contact. It replicates preferentially in mononuclear cells and the bone marrow rather than in the liver.^19-21

Hepatitis G is much less virulent than hepatitis C. Hepatitis G often coexists with hepatitis A, B, and C, as well as with HIV. Coinfection with hepatitis G does not adversely affect the clinical course of the other conditions.^22,23

Most patients with hepatitis G are asymptomatic, and no treatment is indicated. The virus can cause a chronic carrier state. Perinatal transmission is distinctly uncommon. When it does occur, however, injury to mother, fetus, or neonate is unlikely.^1,24

The diagnosis of hepatitis G can be established by detection of virus with PCR and by the identification of antibody by enzyme immunoassay. Routine screening for this infection in pregnancy is not indicated.^1,2

CASE Resolved

Hepatitis B is highly contagious and can be transmitted from the patient to her sexual partner and neonate. Testing for hepatitis B surface antigen and antibody is indicated in her partner. If these tests are negative, the partner should immediately receive hepatitis B immune globulin and then be started on the 3-dose hepatitis B vaccination series. The patient’s newborn also should receive hepatitis B immune globulin within 12 hours of delivery and should receive the first dose of the hepatitis B vaccine prior to discharge from the hospital. The second and third doses should be administered 1 and 6 months after delivery.

The patient also should have the following tests:

• liver function tests

-serum transaminases

-direct and indirect bilirubin

-coagulation profile

• hepatitis D antigen

• hepatitis B genotype

• hepatitis B viral load

• HIV serology.

If the hepatitis B viral load exceeds 1 million copies/mL, the patient should be treated with tenofovir 200 mg daily from 28 weeks’ gestation until delivery. In addition, she should be referred to a liver disease specialist after delivery for consideration of treatment with directly-acting antiviral agents. ●

CASE Pregnant woman with positive hepatitis B surface antigen

A 27-year-old primigravida at 9 weeks 3 days of gestation tests positive for the hepatitis B surface antigen at her first prenatal appointment. She is completely asymptomatic.

• What additional tests are indicated?

• Does she pose a risk to her sexual partner, and is her newborn at risk for acquiring hepatitis B?

• Can anything be done to protect her partner and newborn from infection?

Meet our perpetrator

Hepatitis is one of the more common viral infections that may occur during pregnancy. Two forms of hepatitis, notably hepatitis A and E, pose a primary threat to the mother. Three forms (B, C, and D) present dangers for the mother, fetus, and newborn. This article will review the epidemiology, clinical manifestations, perinatal implications, and management of the various forms of viral hepatitis. (TABLE 1).

Hepatitis A

Hepatitis A is caused by an RNA virus that is transmitted by fecal-oral contact. The disease is most prevalent in areas with poor sanitation and close living conditions. The incubation period ranges from 15 to 50 days. Most children who acquire this disease are asymptomatic. By contrast, most infected adults are acutely symptomatic. Clinical manifestations typically include low-grade fever, malaise, anorexia, right upper quadrant pain and tenderness, jaundice, and claycolored stools.^1,2

The diagnosis of acute hepatitis A infection is best confirmed by detection of immunoglobulin M (IgM)-specific antibodies. The serum transaminase concentrations and the serum bilirubin concentrations usually are significantly elevated. The international normalized ratio, prothrombin time, and partial thromboplastin time also may be elevated.^1,2

The treatment for acute hepatitis A largely is supportive care: maintaining hydration, optimizing nutrition, and correcting coagulation abnormalities. The appropriate measures for prevention of hepatitis A are adoption of sound sanitation practices, particularly water purification; minimizing overcrowded living conditions; and administering the hepatitis A vaccine for both pre and postexposure prophylaxis.^3,4 The hepatitis A vaccine is preferred over administration of immune globulin because it provides lifelong immunity.

The hepatitis A vaccine is produced in 2 monovalent formulations: Havrix (GlaxoSmithKline) and Vaqta (Merck & Co, Inc). The vaccine should be administered intramuscularly in 2 doses 6 to 12 months apart. The wholesale cost of the vaccine varies from $66 to $119 (according to http://www.goodrx.com). The vaccine also is available in a bivalent form, with recombinant hepatitis B vaccine (Twinrix, GlaxoSmithKline). When used in this form, 3 vaccine administrations are given—at 0, 1, and 6 months apart. The cost of the vaccine is approximately $150 (according to http://www.goodrx.com). TABLE 2 lists the individuals who are appropriate candidates for the hepatitis A vaccine.^3,4

Hepatitis B

Hepatitis B is caused by a DNA virus that is transmitted parenterally or perinatally or through sexual contact. Four genotypes have been identified: A, B, C, and D.

Acute hepatitis B affects 1 to 2 of 1,000 pregnancies in the United States. Approximately 6 to 10 patients per 1,000 pregnancies are asymptomatic but chronically infected.⁴ The natural history of hepatitis B infection is shown in the FIGURE. The diagnosis of acute and chronic hepatitis B is best established by serology and polymerase chain reaction (PCR; TABLE 3).

Continue to: Hepatitis C...

Hepatitis C

Hepatitis C is caused by an RNA virus that has 6 genotypes. The most common genotype is HCV1, which affects 79% of patients; approximately 13% of patients have HCV2, and 6% have HCV3.⁹ Of note, the 3 individuals who discovered this virus—Drs. Harvey Alter, Michael Houghton, and Charles Rice—received the 2020 Nobel Prize in Medicine.¹⁰

Hepatitis C is transmitted via sexual contact, parenterally, and perinatally. In many patient populations in the United States, hepatitis C is now more prevalent than hepatitis B. Only about half of all infected persons are aware of their infection. If patients go untreated, approximately 15% to 30% eventually develop cirrhosis. Of these individuals, 1% to 3% develop hepatocellular cancer. Chronic hepatitis C is now the most common indication for liver transplantation in the United States.^1,9

In the initial stages of infection, hepatitis C usually is asymptomatic. The best screening test is detection of hepatitis C antibody. Because of the increasing prevalence of this disease, the seriousness of the infection, and the recent availability of remarkably effective treatment, routine screening, rather than screening on the basis of risk factors, for hepatitis C in pregnancy is now indicated.^11,12

The best tests for confirmation of infection are detection of antibody by enzyme immunoassay and recombinant immuno-blot assay and detection of viral RNA in serum by PCR. Seroconversion may not occur for up to 16 weeks after infection. Therefore, in at-risk patients who initially test negative, retesting is advisable. Patients with positive test results should have tests to identify the specific genotype, determine the viral load, and assess liver function.¹

In patients who have undetectable viral loads and who do not have coexisting HIV infection, the risk of perinatal transmission of hepatitis C is less than 5%. If HIV infection is present, the risk of perinatal transmission approaches 20%.^1,13,14

If the patient is coinfected with HIV, a scheduled cesarean delivery should be performed at 38 weeks’ gestation.¹ If the viral load is undetectable, vaginal delivery is appropriate. If the viral load is high, however (arbitrarily defined as >2.5 millioncopies/mL), the optimal method of delivery is controversial. Several small, nonrandomized noncontrolled cohort studies support elective cesarean delivery in such patients.¹⁴

There is no contraindication to breastfeeding in women with hepatitis C unless they are coinfected with HIV. In such a circumstance, formula feeding should be chosen. After delivery, patients with hepatitis C should be referred to a gastroenterology specialist to receive antiviral treatment. Multiple new single-agent and combination regimens have produced cures in more than 90% of patients. These regimens usually require 8 to 12 weeks of treatment, and they are very expensive. They have not been widely tested in pregnant women.¹

Hepatitis D

Hepatitis D, or delta hepatitis, is caused by an RNA virus. This virus is unique because it is incapable of independent replication. It must be present in association with hepatitis B to replicate and cause clinical infection. Therefore, the epidemiology of hepatitis D closely mirrors that of hepatitis B.^1,2

Patients with hepatitis D typically present in one of two ways. Some individuals are acutely infected with hepatitis D at the same time that they acquire hepatitis B (coinfection). The natural history of this infection usually is spontaneous resolution without sequelae. Other patients have chronic hepatitis D superimposed on chronic hepatitis B (superinfection). Unfortunately, patients with the latter condition are at a notably increased risk for developing severe persistent liver disease.^1,2

The diagnosis of hepatitis D may be confirmed by identifying the delta antigen in serum or in liver tissue obtained by biopsy or by identifying IgM- and IgG-specific antibodies in serum. In conjunction with hepatitis B, the delta virus can cause a chronic carrier state. Perinatal transmission is possible but uncommon. Of greatest importance, the immunoprophylaxis described for hepatitis B is almost perfectly protective against perinatal transmission of hepatitis D.^1,2

Continue to: Hepatitis E...

Hepatitis E

Hepatitis E is an RNA virus that has 1 serotype and 4 genotypes. Its epidemiology is similar to that of hepatitis A. It is the most common waterborne illness in the world. The incubation period varies from 21 to 56 days. This disease is quite rare in the United States but is endemic in developing nations. In those countries, maternal infection has an alarmingly high mortality rate (5%–25%). For example, in Bangladesh, hepatitis E is responsible for more than 1,000 deaths per year in pregnant women. When hepatitis E is identified in more affluent countries, the individual cases and small outbreaks usually are linked to consumption of undercooked pork or wild game.^1,15-17

The clinical presentation of acute hepatitis E also is similar to that of hepatitis A. The usual manifestations are fever, malaise, anorexia, nausea, right upper quadrant pain and tenderness, jaundice, darkened urine, and clay-colored stools. The most useful diagnostic tests are serologic detection of viral-specific antibodies (positive IgM or a 4-fold increase in the prior IgG titer) and PCR-RNA.^1,17

Hepatitis E usually does not cause a chronic carrier state, and perinatal transmission is rare. Fortunately, a highly effective vaccine was recently developed (Hecolin, Xiamen Innovax Biotech). This recombinant vaccine is specifically directed against the hepatitis E genotype 1. In the initial efficacy study, healthy adults aged 16 to 65 years were randomly assigned to receive either the hepatitis E vaccine or the hepatitis B vaccine. The vaccine was administered at time point 0, and 1 and 6 months later. Patients were followed for up to 4.5 years to assess efficacy, immunogenicity, and safety. During the study period, 7 cases of hepatitis E occurred in the vaccine group, compared with 53 in the control group. Approximately 56,000 patients were included in each group. The efficacy of the vaccine was 86.8% (P<.001).¹⁸

Hepatitis G

Hepatitis G is caused by 2 single-stranded RNA viruses that are virtually identical—hepatitis G virus and GB virus type C. The viruses share approximately 30% homology with hepatitis C virus. The organism is present throughout the world and infects approximately 1.5% to 2.0% of the population. The virus is transmitted by blood and sexual contact. It replicates preferentially in mononuclear cells and the bone marrow rather than in the liver.^19-21

Hepatitis G is much less virulent than hepatitis C. Hepatitis G often coexists with hepatitis A, B, and C, as well as with HIV. Coinfection with hepatitis G does not adversely affect the clinical course of the other conditions.^22,23

Most patients with hepatitis G are asymptomatic, and no treatment is indicated. The virus can cause a chronic carrier state. Perinatal transmission is distinctly uncommon. When it does occur, however, injury to mother, fetus, or neonate is unlikely.^1,24

The diagnosis of hepatitis G can be established by detection of virus with PCR and by the identification of antibody by enzyme immunoassay. Routine screening for this infection in pregnancy is not indicated.^1,2

CASE Resolved

Hepatitis B is highly contagious and can be transmitted from the patient to her sexual partner and neonate. Testing for hepatitis B surface antigen and antibody is indicated in her partner. If these tests are negative, the partner should immediately receive hepatitis B immune globulin and then be started on the 3-dose hepatitis B vaccination series. The patient’s newborn also should receive hepatitis B immune globulin within 12 hours of delivery and should receive the first dose of the hepatitis B vaccine prior to discharge from the hospital. The second and third doses should be administered 1 and 6 months after delivery.

The patient also should have the following tests:

• liver function tests

-serum transaminases

-direct and indirect bilirubin

-coagulation profile

• hepatitis D antigen

• hepatitis B genotype

• hepatitis B viral load

• HIV serology.

If the hepatitis B viral load exceeds 1 million copies/mL, the patient should be treated with tenofovir 200 mg daily from 28 weeks’ gestation until delivery. In addition, she should be referred to a liver disease specialist after delivery for consideration of treatment with directly-acting antiviral agents. ●

Sentilhes L, Senat MV, Le Lous M, et al; Groupe de Recherche en Obstetrique et Gynecologie. Tranexamic acid for the prevention of blood loss after cesarean delivery. N Engl J Med. 2021;384:1623-1634. doi: 10.1056/NEJMoa2028788.

EXPERT COMMENTARY

Postpartum hemorrhage is the leading cause of maternal mortality worldwide.¹ Many preventive strategies, including tranexamic acid administration, have been studied in an attempt to reduce the risk of PPH. Tranexamic acid prevents the conversion of plasminogen to plasmin, preventing the breakdown of fibrin, and ultimately stabilizing the fibrin matrix of clot.² It has been shown to be an effective approach to treating hemorrhage in patients after trauma as well as cardiac surgery.^3,4 The use of tranexamic acid in obstetric hemorrhage has reduced mortality in previous trials,⁵ but its prophylactic use has had mixed results in preventing obstetric hemorrhage.^6-8

Recently, Sentilhes and colleagues published the largest prospective study to date addressing the efficacy of tranexamic acid for the primary prevention of PPH.

Details of the study

Multiple hospitals throughout France participated in the investigators’ double-blind randomized, placebo-controlled trial. Women undergoing CD at 34 or more weeks’ gestation (N = 4,551) were randomly assigned to receive 1 g of intravenous (IV) tranexamic acid or placebo after cord clamping. Both groups received IV prophylactic uterotonics. The primary outcome was PPH, defined by estimated blood loss (EBL) greater than 1 L or receipt of red blood cell transfusion within the first 2 days after surgery.

Results. The rate of PPH was significantly lower in women who received tranexamic acid compared with those who received placebo. Yet, the mean EBL between the 2 groups differed by only 100 mL. The rates of blood transfusions, additional uterotonic administration, arterial embolization, and hysterectomy did not differ between groups.

The clinicians responsible for the care of these patients did not observe a difference in the rate of “clinically significant” PPH between those who received tranexamic acid and those who received placebo. Women who received tranexamic acid were more likely to experience nausea and vomiting, but they did not have any increased risk of venous thromboembolic disease.

Study strengths and limitations

Sentilhes and colleagues’ study findings contradict those of an earlier meta-analysis on the topic.⁹ This may be due to the effect of publication bias on meta-analyses, which makes them prone to supporting the findings of published positive trials while missing data from negative trials that did not reach publication. The gold standard for addressing a research question such as this is a randomized controlled trial (RCT). The study reviewed here is an excellent example of a well-designed and executed RCT.

There may be a benefit to prophylactic tranexamic acid in certain populations not well captured among these study participants. The inclusion criteria were broad, including both prelabor and intrapartum CDs, making the results generalizable. However, the population studied, with a mean body mass index of 26 kg/m² and age of 33, may not resemble some readers’ patient population. Prespecified subgroup analyses did not find a benefit to tranexamic acid in patients considered at high risk for PPH or in those undergoing intrapartum CD. ●

Sentilhes L, Senat MV, Le Lous M, et al; Groupe de Recherche en Obstetrique et Gynecologie. Tranexamic acid for the prevention of blood loss after cesarean delivery. N Engl J Med. 2021;384:1623-1634. doi: 10.1056/NEJMoa2028788.

EXPERT COMMENTARY

Postpartum hemorrhage is the leading cause of maternal mortality worldwide.¹ Many preventive strategies, including tranexamic acid administration, have been studied in an attempt to reduce the risk of PPH. Tranexamic acid prevents the conversion of plasminogen to plasmin, preventing the breakdown of fibrin, and ultimately stabilizing the fibrin matrix of clot.² It has been shown to be an effective approach to treating hemorrhage in patients after trauma as well as cardiac surgery.^3,4 The use of tranexamic acid in obstetric hemorrhage has reduced mortality in previous trials,⁵ but its prophylactic use has had mixed results in preventing obstetric hemorrhage.^6-8

Recently, Sentilhes and colleagues published the largest prospective study to date addressing the efficacy of tranexamic acid for the primary prevention of PPH.

Details of the study

Multiple hospitals throughout France participated in the investigators’ double-blind randomized, placebo-controlled trial. Women undergoing CD at 34 or more weeks’ gestation (N = 4,551) were randomly assigned to receive 1 g of intravenous (IV) tranexamic acid or placebo after cord clamping. Both groups received IV prophylactic uterotonics. The primary outcome was PPH, defined by estimated blood loss (EBL) greater than 1 L or receipt of red blood cell transfusion within the first 2 days after surgery.

Results. The rate of PPH was significantly lower in women who received tranexamic acid compared with those who received placebo. Yet, the mean EBL between the 2 groups differed by only 100 mL. The rates of blood transfusions, additional uterotonic administration, arterial embolization, and hysterectomy did not differ between groups.

The clinicians responsible for the care of these patients did not observe a difference in the rate of “clinically significant” PPH between those who received tranexamic acid and those who received placebo. Women who received tranexamic acid were more likely to experience nausea and vomiting, but they did not have any increased risk of venous thromboembolic disease.

Study strengths and limitations

Sentilhes and colleagues’ study findings contradict those of an earlier meta-analysis on the topic.⁹ This may be due to the effect of publication bias on meta-analyses, which makes them prone to supporting the findings of published positive trials while missing data from negative trials that did not reach publication. The gold standard for addressing a research question such as this is a randomized controlled trial (RCT). The study reviewed here is an excellent example of a well-designed and executed RCT.

There may be a benefit to prophylactic tranexamic acid in certain populations not well captured among these study participants. The inclusion criteria were broad, including both prelabor and intrapartum CDs, making the results generalizable. However, the population studied, with a mean body mass index of 26 kg/m² and age of 33, may not resemble some readers’ patient population. Prespecified subgroup analyses did not find a benefit to tranexamic acid in patients considered at high risk for PPH or in those undergoing intrapartum CD. ●

Sentilhes L, Senat MV, Le Lous M, et al; Groupe de Recherche en Obstetrique et Gynecologie. Tranexamic acid for the prevention of blood loss after cesarean delivery. N Engl J Med. 2021;384:1623-1634. doi: 10.1056/NEJMoa2028788.

EXPERT COMMENTARY

Postpartum hemorrhage is the leading cause of maternal mortality worldwide.¹ Many preventive strategies, including tranexamic acid administration, have been studied in an attempt to reduce the risk of PPH. Tranexamic acid prevents the conversion of plasminogen to plasmin, preventing the breakdown of fibrin, and ultimately stabilizing the fibrin matrix of clot.² It has been shown to be an effective approach to treating hemorrhage in patients after trauma as well as cardiac surgery.^3,4 The use of tranexamic acid in obstetric hemorrhage has reduced mortality in previous trials,⁵ but its prophylactic use has had mixed results in preventing obstetric hemorrhage.^6-8

Recently, Sentilhes and colleagues published the largest prospective study to date addressing the efficacy of tranexamic acid for the primary prevention of PPH.

Details of the study

Multiple hospitals throughout France participated in the investigators’ double-blind randomized, placebo-controlled trial. Women undergoing CD at 34 or more weeks’ gestation (N = 4,551) were randomly assigned to receive 1 g of intravenous (IV) tranexamic acid or placebo after cord clamping. Both groups received IV prophylactic uterotonics. The primary outcome was PPH, defined by estimated blood loss (EBL) greater than 1 L or receipt of red blood cell transfusion within the first 2 days after surgery.

Results. The rate of PPH was significantly lower in women who received tranexamic acid compared with those who received placebo. Yet, the mean EBL between the 2 groups differed by only 100 mL. The rates of blood transfusions, additional uterotonic administration, arterial embolization, and hysterectomy did not differ between groups.

The clinicians responsible for the care of these patients did not observe a difference in the rate of “clinically significant” PPH between those who received tranexamic acid and those who received placebo. Women who received tranexamic acid were more likely to experience nausea and vomiting, but they did not have any increased risk of venous thromboembolic disease.

Study strengths and limitations

Sentilhes and colleagues’ study findings contradict those of an earlier meta-analysis on the topic.⁹ This may be due to the effect of publication bias on meta-analyses, which makes them prone to supporting the findings of published positive trials while missing data from negative trials that did not reach publication. The gold standard for addressing a research question such as this is a randomized controlled trial (RCT). The study reviewed here is an excellent example of a well-designed and executed RCT.

There may be a benefit to prophylactic tranexamic acid in certain populations not well captured among these study participants. The inclusion criteria were broad, including both prelabor and intrapartum CDs, making the results generalizable. However, the population studied, with a mean body mass index of 26 kg/m² and age of 33, may not resemble some readers’ patient population. Prespecified subgroup analyses did not find a benefit to tranexamic acid in patients considered at high risk for PPH or in those undergoing intrapartum CD. ●

Patient:

Alone in the Emergency Dept, breathless, I wait for you

“The Hospitalist will admit you” says the nurse, “she will come in a few.”

Muffled voices – masked faces bustle in & out of the room

Loud beeping machines & the rushed pace, fill me with gloom



You walk in the room, lean in to introduce

You tell me your name and what you will do

For a moment I’m more than a diagnosis, an H&P,

and then the fleeting connection passes, can’t you see?

You listen, seem hurried, but I think you care

Would you sit with me while my story I share?

Physician:

I do see you, I feel your fear & anguish

A moment to know you too, is all that I wish

How do I convince you that I truly care?

When, with all my tasks I have only minutes to spare

Patient:

You diligently ask questions from your checklist of H.P.I.,

Finalizing the diagnosis, when I hear your pager beep.

An admission awaits I know, but please sit by my side

Could we make our new-found meeting, a little more deep?

Physician:

The minute our day begins, it’s go-go-go

There isn’t a second to pause, inhale, or be slow

Missed lunch, it’s 6 p.m., bite to eat I dare?

My shift ended 3 hrs. back but I’m still here

Notes, DC summaries, calls to your PCP

Advocating for you, is more than a job to me.



Tirelessly I work, giving patients my all

Drained, exhausted yet, for you, standing tall

Our bond albeit short lived, is very important to me

Watching you get better each day, is fulfilling for me!

Patient:

You take time to ask about my family, about what I like to do

I tell you all about Beatles & my sweet grandkids

You sit & ask me “what matters most to you”

I reply: getting well for the wedding of my daughter “Sue”

Physician:

I sense loneliness engulfing you at times

Your fear and anxiety, I promise to help overcome

I will help you navigate this complex hospital stay

Together we will fight this virus or anything that comes our way

Each passing minute the line between doctor and patient disappears

That’s when we win over this virus, and hope replaces fear

Patient:

Every day you come see me, tell me my numbers are improving

I notice your warm and kind eyes behind that stifling mask

When they light up as you tell me I’m going home soon

I feel assured I mean more to you, than a mere task

Physician:

Each day I visit, together we hum “here comes the sun”

I too open up and share with you, my favorite Beatles song

Our visits cover much more than clinical medicine

True connection & mutual soul healing begins, before long.

Patient:

Today is the day, grateful to go home,

My body may be healed due to all the medicine & potions,

But my bruised soul was healed due to all your kind emotions.



Time to bid adieu Dear Doc – If I meet you at our local grocery store,

I promise I’ll remember those kind eyes, and wave

After all, you stood between me and death

I’m indebted to you, it’s my life that you did save!
 

Dr. Mehta is a hospitalist and director of quality and performance and patient experience at Vituity in Emeryville, Calif. She is chair of the SHM patient experience executive council and executive board member of the SHM San Francisco Bay Area chapter.
 

Patient:

Alone in the Emergency Dept, breathless, I wait for you

“The Hospitalist will admit you” says the nurse, “she will come in a few.”

Muffled voices – masked faces bustle in & out of the room

Loud beeping machines & the rushed pace, fill me with gloom



You walk in the room, lean in to introduce

You tell me your name and what you will do

For a moment I’m more than a diagnosis, an H&P,

and then the fleeting connection passes, can’t you see?

You listen, seem hurried, but I think you care

Would you sit with me while my story I share?

Physician:

I do see you, I feel your fear & anguish

A moment to know you too, is all that I wish

How do I convince you that I truly care?

When, with all my tasks I have only minutes to spare

Patient:

You diligently ask questions from your checklist of H.P.I.,

Finalizing the diagnosis, when I hear your pager beep.

An admission awaits I know, but please sit by my side

Could we make our new-found meeting, a little more deep?

Physician:

The minute our day begins, it’s go-go-go

There isn’t a second to pause, inhale, or be slow

Missed lunch, it’s 6 p.m., bite to eat I dare?

My shift ended 3 hrs. back but I’m still here

Notes, DC summaries, calls to your PCP

Advocating for you, is more than a job to me.



Tirelessly I work, giving patients my all

Drained, exhausted yet, for you, standing tall

Our bond albeit short lived, is very important to me

Watching you get better each day, is fulfilling for me!

Patient:

You take time to ask about my family, about what I like to do

I tell you all about Beatles & my sweet grandkids

You sit & ask me “what matters most to you”

I reply: getting well for the wedding of my daughter “Sue”

Physician:

I sense loneliness engulfing you at times

Your fear and anxiety, I promise to help overcome

I will help you navigate this complex hospital stay

Together we will fight this virus or anything that comes our way

Each passing minute the line between doctor and patient disappears

That’s when we win over this virus, and hope replaces fear

Patient:

Every day you come see me, tell me my numbers are improving

I notice your warm and kind eyes behind that stifling mask

When they light up as you tell me I’m going home soon

I feel assured I mean more to you, than a mere task

Physician:

Each day I visit, together we hum “here comes the sun”

I too open up and share with you, my favorite Beatles song

Our visits cover much more than clinical medicine

True connection & mutual soul healing begins, before long.

Patient:

Today is the day, grateful to go home,

My body may be healed due to all the medicine & potions,

But my bruised soul was healed due to all your kind emotions.



Time to bid adieu Dear Doc – If I meet you at our local grocery store,

I promise I’ll remember those kind eyes, and wave

After all, you stood between me and death

I’m indebted to you, it’s my life that you did save!
 

Dr. Mehta is a hospitalist and director of quality and performance and patient experience at Vituity in Emeryville, Calif. She is chair of the SHM patient experience executive council and executive board member of the SHM San Francisco Bay Area chapter.
 

Patient:

Alone in the Emergency Dept, breathless, I wait for you

“The Hospitalist will admit you” says the nurse, “she will come in a few.”

Muffled voices – masked faces bustle in & out of the room

Loud beeping machines & the rushed pace, fill me with gloom



You walk in the room, lean in to introduce

You tell me your name and what you will do

For a moment I’m more than a diagnosis, an H&P,

and then the fleeting connection passes, can’t you see?

You listen, seem hurried, but I think you care

Would you sit with me while my story I share?

Physician:

I do see you, I feel your fear & anguish

A moment to know you too, is all that I wish

How do I convince you that I truly care?

When, with all my tasks I have only minutes to spare

Patient:

You diligently ask questions from your checklist of H.P.I.,

Finalizing the diagnosis, when I hear your pager beep.

An admission awaits I know, but please sit by my side

Could we make our new-found meeting, a little more deep?

Physician:

The minute our day begins, it’s go-go-go

There isn’t a second to pause, inhale, or be slow

Missed lunch, it’s 6 p.m., bite to eat I dare?

My shift ended 3 hrs. back but I’m still here

Notes, DC summaries, calls to your PCP

Advocating for you, is more than a job to me.



Tirelessly I work, giving patients my all

Drained, exhausted yet, for you, standing tall

Our bond albeit short lived, is very important to me

Watching you get better each day, is fulfilling for me!

Patient:

You take time to ask about my family, about what I like to do

I tell you all about Beatles & my sweet grandkids

You sit & ask me “what matters most to you”

I reply: getting well for the wedding of my daughter “Sue”

Physician:

I sense loneliness engulfing you at times

Your fear and anxiety, I promise to help overcome

I will help you navigate this complex hospital stay

Together we will fight this virus or anything that comes our way

Each passing minute the line between doctor and patient disappears

That’s when we win over this virus, and hope replaces fear

Patient:

Every day you come see me, tell me my numbers are improving

I notice your warm and kind eyes behind that stifling mask

When they light up as you tell me I’m going home soon

I feel assured I mean more to you, than a mere task

Physician:

Each day I visit, together we hum “here comes the sun”

I too open up and share with you, my favorite Beatles song

Our visits cover much more than clinical medicine

True connection & mutual soul healing begins, before long.

Patient:

Today is the day, grateful to go home,

My body may be healed due to all the medicine & potions,

But my bruised soul was healed due to all your kind emotions.



Time to bid adieu Dear Doc – If I meet you at our local grocery store,

I promise I’ll remember those kind eyes, and wave

After all, you stood between me and death

I’m indebted to you, it’s my life that you did save!
 

Dr. Mehta is a hospitalist and director of quality and performance and patient experience at Vituity in Emeryville, Calif. She is chair of the SHM patient experience executive council and executive board member of the SHM San Francisco Bay Area chapter.
 

The Diagnosis: Dowling-Degos Disease

Histopathology demonstrated elongation of the epidermal rete ridges with increased basal pigmentation, suprapapillary epithelial thinning, dermal melanophages, and a mild lymphocytic infiltrate (Figure). Given the clinical and histologic findings, a diagnosis of Dowling-Degos disease (DDD) was made. The patient was counseled on the increased risk for her children developing DDD. Treatment with the erbium:YAG (Er:YAG) laser subsequently was initiated.

Dowling-Degos disease (also known as reticulate pigmented anomaly of the flexures) is an uncommon autosomal-dominant condition characterized by reticular hyperpigmentation involving the flexural and intertriginous sites. Classic DDD commonly is caused by lossof-function mutations in the keratin 5 gene, KRT5¹; however, DDD also may result from loss-of-function mutations in the protein O-fucosyltransferase 1, POFUT1, and protein O-glucosyltransferase 1, POGLUT1, genes.²

Rare cases of DDD associated with hidradenitis suppurativa are caused by mutations in the presenilin enhancer protein 2 gene, PSENEN.³

Of note, a missense mutation in KRT5 is implicated in epidermolysis bullosa simplex with mottled pigmentation. Onset of DDD typically occurs during the third to fourth decades of life. Reticulated hyperpigmented macules initially occur in the axillae and groin and progressively increase over time to involve the neck, inframammary folds, trunk, and flexural surfaces of the arms and thighs. Patients additionally may present with pitted perioral scars, comedolike lesions on the back and neck, epidermoid cysts, and hidradenitis suppurativa. Keratoacanthoma and squamous cell carcinoma rarely have been reported in association with classic DDD.^4,5

Dowling-Degos disease usually is asymptomatic, though pruritus seldom may occur in the affected flexural areas. Histologically, the epidermal rete ridges are elongated in a filiform or antlerlike pattern with increased pigmentation of the basal layer and thinning of the suprapapillary epithelium. Dermal melanosis and a mild perivascular lymphohistiocytic infiltrate also are present with no increase in the number of melanocytes.^6,7 Galli-Galli disease is a variant of DDD that shares similar clinical and histologic features of DDD but is distinguished from DDD by suprabasilar nondyskeratotic acantholysis on histology.⁸

Regarding other differential diagnoses for our patient, acanthosis nigricans may be distinguished clinically by the presence of velvety and/or verrucous plaques, commonly in the neck folds and axillae. Histologically, acanthosis nigricans is distinct from DDD and involves hyperkeratosis, acanthosis, and epidermal papillomatosis. Our patient had no history of diabetes mellitus or insulin resistance. Granular parakeratosis presents with hyperpigmented hyperkeratotic papules and plaques classically confined to the axillary region; however, the involvement of other intertriginous areas may occur. Histologically, granular parakeratosis demonstrates compact parakeratosis with small bluish keratohyalin granules within the stratum corneum. Confluent and reticulated papillomatosis presents with red-brown keratotic papules that initially appear in the intermammary region and spread laterally forming a reticulated pattern. Histology is similar to acanthosis nigricans and demonstrates hyperkeratosis, acanthosis, and papillomatosis. Inverse psoriasis presents with symmetric and sharply demarcated, erythematous, nonscaly plaques in the intertriginous areas. The plaques of inverse psoriasis may be pruritic and/or sore and occasionally may become macerated. Inverse psoriasis shares similar histologic findings compared to classic plaque psoriasis but may have less confluent parakeratosis.

Treatment of DDD essentially is reserved for cosmetic reasons. Topical hydroquinone, tretinoin, and corticosteroids have been used with limited to no success.^5,9 Beneficial results after treatment with the Er:YAG laser have been reported.¹⁰

The Diagnosis: Dowling-Degos Disease

Histopathology demonstrated elongation of the epidermal rete ridges with increased basal pigmentation, suprapapillary epithelial thinning, dermal melanophages, and a mild lymphocytic infiltrate (Figure). Given the clinical and histologic findings, a diagnosis of Dowling-Degos disease (DDD) was made. The patient was counseled on the increased risk for her children developing DDD. Treatment with the erbium:YAG (Er:YAG) laser subsequently was initiated.

Dowling-Degos disease (also known as reticulate pigmented anomaly of the flexures) is an uncommon autosomal-dominant condition characterized by reticular hyperpigmentation involving the flexural and intertriginous sites. Classic DDD commonly is caused by lossof-function mutations in the keratin 5 gene, KRT5¹; however, DDD also may result from loss-of-function mutations in the protein O-fucosyltransferase 1, POFUT1, and protein O-glucosyltransferase 1, POGLUT1, genes.²

Rare cases of DDD associated with hidradenitis suppurativa are caused by mutations in the presenilin enhancer protein 2 gene, PSENEN.³

Of note, a missense mutation in KRT5 is implicated in epidermolysis bullosa simplex with mottled pigmentation. Onset of DDD typically occurs during the third to fourth decades of life. Reticulated hyperpigmented macules initially occur in the axillae and groin and progressively increase over time to involve the neck, inframammary folds, trunk, and flexural surfaces of the arms and thighs. Patients additionally may present with pitted perioral scars, comedolike lesions on the back and neck, epidermoid cysts, and hidradenitis suppurativa. Keratoacanthoma and squamous cell carcinoma rarely have been reported in association with classic DDD.^4,5

Dowling-Degos disease usually is asymptomatic, though pruritus seldom may occur in the affected flexural areas. Histologically, the epidermal rete ridges are elongated in a filiform or antlerlike pattern with increased pigmentation of the basal layer and thinning of the suprapapillary epithelium. Dermal melanosis and a mild perivascular lymphohistiocytic infiltrate also are present with no increase in the number of melanocytes.^6,7 Galli-Galli disease is a variant of DDD that shares similar clinical and histologic features of DDD but is distinguished from DDD by suprabasilar nondyskeratotic acantholysis on histology.⁸

Regarding other differential diagnoses for our patient, acanthosis nigricans may be distinguished clinically by the presence of velvety and/or verrucous plaques, commonly in the neck folds and axillae. Histologically, acanthosis nigricans is distinct from DDD and involves hyperkeratosis, acanthosis, and epidermal papillomatosis. Our patient had no history of diabetes mellitus or insulin resistance. Granular parakeratosis presents with hyperpigmented hyperkeratotic papules and plaques classically confined to the axillary region; however, the involvement of other intertriginous areas may occur. Histologically, granular parakeratosis demonstrates compact parakeratosis with small bluish keratohyalin granules within the stratum corneum. Confluent and reticulated papillomatosis presents with red-brown keratotic papules that initially appear in the intermammary region and spread laterally forming a reticulated pattern. Histology is similar to acanthosis nigricans and demonstrates hyperkeratosis, acanthosis, and papillomatosis. Inverse psoriasis presents with symmetric and sharply demarcated, erythematous, nonscaly plaques in the intertriginous areas. The plaques of inverse psoriasis may be pruritic and/or sore and occasionally may become macerated. Inverse psoriasis shares similar histologic findings compared to classic plaque psoriasis but may have less confluent parakeratosis.

Treatment of DDD essentially is reserved for cosmetic reasons. Topical hydroquinone, tretinoin, and corticosteroids have been used with limited to no success.^5,9 Beneficial results after treatment with the Er:YAG laser have been reported.¹⁰

The Diagnosis: Dowling-Degos Disease

Histopathology demonstrated elongation of the epidermal rete ridges with increased basal pigmentation, suprapapillary epithelial thinning, dermal melanophages, and a mild lymphocytic infiltrate (Figure). Given the clinical and histologic findings, a diagnosis of Dowling-Degos disease (DDD) was made. The patient was counseled on the increased risk for her children developing DDD. Treatment with the erbium:YAG (Er:YAG) laser subsequently was initiated.

Dowling-Degos disease (also known as reticulate pigmented anomaly of the flexures) is an uncommon autosomal-dominant condition characterized by reticular hyperpigmentation involving the flexural and intertriginous sites. Classic DDD commonly is caused by lossof-function mutations in the keratin 5 gene, KRT5¹; however, DDD also may result from loss-of-function mutations in the protein O-fucosyltransferase 1, POFUT1, and protein O-glucosyltransferase 1, POGLUT1, genes.²

Rare cases of DDD associated with hidradenitis suppurativa are caused by mutations in the presenilin enhancer protein 2 gene, PSENEN.³

Of note, a missense mutation in KRT5 is implicated in epidermolysis bullosa simplex with mottled pigmentation. Onset of DDD typically occurs during the third to fourth decades of life. Reticulated hyperpigmented macules initially occur in the axillae and groin and progressively increase over time to involve the neck, inframammary folds, trunk, and flexural surfaces of the arms and thighs. Patients additionally may present with pitted perioral scars, comedolike lesions on the back and neck, epidermoid cysts, and hidradenitis suppurativa. Keratoacanthoma and squamous cell carcinoma rarely have been reported in association with classic DDD.^4,5

Dowling-Degos disease usually is asymptomatic, though pruritus seldom may occur in the affected flexural areas. Histologically, the epidermal rete ridges are elongated in a filiform or antlerlike pattern with increased pigmentation of the basal layer and thinning of the suprapapillary epithelium. Dermal melanosis and a mild perivascular lymphohistiocytic infiltrate also are present with no increase in the number of melanocytes.^6,7 Galli-Galli disease is a variant of DDD that shares similar clinical and histologic features of DDD but is distinguished from DDD by suprabasilar nondyskeratotic acantholysis on histology.⁸

Regarding other differential diagnoses for our patient, acanthosis nigricans may be distinguished clinically by the presence of velvety and/or verrucous plaques, commonly in the neck folds and axillae. Histologically, acanthosis nigricans is distinct from DDD and involves hyperkeratosis, acanthosis, and epidermal papillomatosis. Our patient had no history of diabetes mellitus or insulin resistance. Granular parakeratosis presents with hyperpigmented hyperkeratotic papules and plaques classically confined to the axillary region; however, the involvement of other intertriginous areas may occur. Histologically, granular parakeratosis demonstrates compact parakeratosis with small bluish keratohyalin granules within the stratum corneum. Confluent and reticulated papillomatosis presents with red-brown keratotic papules that initially appear in the intermammary region and spread laterally forming a reticulated pattern. Histology is similar to acanthosis nigricans and demonstrates hyperkeratosis, acanthosis, and papillomatosis. Inverse psoriasis presents with symmetric and sharply demarcated, erythematous, nonscaly plaques in the intertriginous areas. The plaques of inverse psoriasis may be pruritic and/or sore and occasionally may become macerated. Inverse psoriasis shares similar histologic findings compared to classic plaque psoriasis but may have less confluent parakeratosis.

Treatment of DDD essentially is reserved for cosmetic reasons. Topical hydroquinone, tretinoin, and corticosteroids have been used with limited to no success.^5,9 Beneficial results after treatment with the Er:YAG laser have been reported.¹⁰

The U.S. Food and Drug Administration has declined to approve the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals, despite narrow endorsement in a 10-7 vote in favor of approval by one of its advisory panels in May.

According to the company, the FDA did not cite any clinical deficiencies related to the efficacy and safety data packages submitted as part of the biologics license application for teplizumab.

Rather, the sticking point appears to be a study in healthy volunteers that had been raised as an issue with Provention Bio in April.

That study was designed to compare the planned commercial product with the product originally manufactured for clinical trials, but the former was not pharmacologically comparable to the latter, the FDA said in its complete response letter, issued on July 2.

The company expects, later this quarter, to obtain data from a substudy in patients receiving 12 days of therapy in the ongoing PROTECT trial of newly diagnosed patients with type 1 diabetes, which it hopes will help alleviate the FDA’s concerns.

“Upon review of the results from this substudy, the company will determine whether to submit these data to the FDA for its review ... to support pharmacokinetic comparability or otherwise justify why pharmacokinetic comparability is not necessary,” it said in its statement.

The FDA’s complete response letter had also mentioned additional issues related to product quality that Provention believes it has or will be able to address in the short term.

Teplizumab delays type 1 diabetes onset by years

Phase 2 data showing that a 14-day teplizumab infusion delayed the onset of type 1 diabetes by 2 years in high-risk relatives of people with the condition were called “game-changing” when presented at the American Diabetes Association 2019 Scientific Sessions and simultaneously published in the New England Journal of Medicine. These were the data considered by the FDA advisory panel in May.

In response to the FDA decision, the type 1 diabetes research and advocacy organization JDRF said: “It is unfortunate that the FDA has not approved teplizumab at this time and instead has requested additional information from the sponsor. We look forward to Provention Bio addressing the issues outlined in the Complete Response Letter and working with the FDA to bring this option to market safely.”

Teplizumab is one of several potential disease-modifying therapies being studied for type 1 diabetes administered either soon after diagnosis or to asymptomatic individuals with high-risk autoantibodies.

“Disease-modifying therapies such as teplizumab will help address the unmet needs of people with type 1 diabetes and those at risk for developing the disease. In the meantime, our organization will continue to support the research of other disease-modifying therapies that put us on the critical pathway to preventing and ultimately curing type 1 diabetes,” JDRF said in a statement.

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

The U.S. Food and Drug Administration has declined to approve the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals, despite narrow endorsement in a 10-7 vote in favor of approval by one of its advisory panels in May.

According to the company, the FDA did not cite any clinical deficiencies related to the efficacy and safety data packages submitted as part of the biologics license application for teplizumab.

Rather, the sticking point appears to be a study in healthy volunteers that had been raised as an issue with Provention Bio in April.

That study was designed to compare the planned commercial product with the product originally manufactured for clinical trials, but the former was not pharmacologically comparable to the latter, the FDA said in its complete response letter, issued on July 2.

The company expects, later this quarter, to obtain data from a substudy in patients receiving 12 days of therapy in the ongoing PROTECT trial of newly diagnosed patients with type 1 diabetes, which it hopes will help alleviate the FDA’s concerns.

“Upon review of the results from this substudy, the company will determine whether to submit these data to the FDA for its review ... to support pharmacokinetic comparability or otherwise justify why pharmacokinetic comparability is not necessary,” it said in its statement.

The FDA’s complete response letter had also mentioned additional issues related to product quality that Provention believes it has or will be able to address in the short term.

Teplizumab delays type 1 diabetes onset by years

Phase 2 data showing that a 14-day teplizumab infusion delayed the onset of type 1 diabetes by 2 years in high-risk relatives of people with the condition were called “game-changing” when presented at the American Diabetes Association 2019 Scientific Sessions and simultaneously published in the New England Journal of Medicine. These were the data considered by the FDA advisory panel in May.

In response to the FDA decision, the type 1 diabetes research and advocacy organization JDRF said: “It is unfortunate that the FDA has not approved teplizumab at this time and instead has requested additional information from the sponsor. We look forward to Provention Bio addressing the issues outlined in the Complete Response Letter and working with the FDA to bring this option to market safely.”

Teplizumab is one of several potential disease-modifying therapies being studied for type 1 diabetes administered either soon after diagnosis or to asymptomatic individuals with high-risk autoantibodies.

“Disease-modifying therapies such as teplizumab will help address the unmet needs of people with type 1 diabetes and those at risk for developing the disease. In the meantime, our organization will continue to support the research of other disease-modifying therapies that put us on the critical pathway to preventing and ultimately curing type 1 diabetes,” JDRF said in a statement.

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

The U.S. Food and Drug Administration has declined to approve the anti-CD3 monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals, despite narrow endorsement in a 10-7 vote in favor of approval by one of its advisory panels in May.

According to the company, the FDA did not cite any clinical deficiencies related to the efficacy and safety data packages submitted as part of the biologics license application for teplizumab.

Rather, the sticking point appears to be a study in healthy volunteers that had been raised as an issue with Provention Bio in April.

That study was designed to compare the planned commercial product with the product originally manufactured for clinical trials, but the former was not pharmacologically comparable to the latter, the FDA said in its complete response letter, issued on July 2.

The company expects, later this quarter, to obtain data from a substudy in patients receiving 12 days of therapy in the ongoing PROTECT trial of newly diagnosed patients with type 1 diabetes, which it hopes will help alleviate the FDA’s concerns.

“Upon review of the results from this substudy, the company will determine whether to submit these data to the FDA for its review ... to support pharmacokinetic comparability or otherwise justify why pharmacokinetic comparability is not necessary,” it said in its statement.

The FDA’s complete response letter had also mentioned additional issues related to product quality that Provention believes it has or will be able to address in the short term.

Teplizumab delays type 1 diabetes onset by years

Phase 2 data showing that a 14-day teplizumab infusion delayed the onset of type 1 diabetes by 2 years in high-risk relatives of people with the condition were called “game-changing” when presented at the American Diabetes Association 2019 Scientific Sessions and simultaneously published in the New England Journal of Medicine. These were the data considered by the FDA advisory panel in May.

In response to the FDA decision, the type 1 diabetes research and advocacy organization JDRF said: “It is unfortunate that the FDA has not approved teplizumab at this time and instead has requested additional information from the sponsor. We look forward to Provention Bio addressing the issues outlined in the Complete Response Letter and working with the FDA to bring this option to market safely.”

Teplizumab is one of several potential disease-modifying therapies being studied for type 1 diabetes administered either soon after diagnosis or to asymptomatic individuals with high-risk autoantibodies.

“Disease-modifying therapies such as teplizumab will help address the unmet needs of people with type 1 diabetes and those at risk for developing the disease. In the meantime, our organization will continue to support the research of other disease-modifying therapies that put us on the critical pathway to preventing and ultimately curing type 1 diabetes,” JDRF said in a statement.

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

More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.

Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.

Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.

The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.

--

Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.

More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.

Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.

Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.

The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.

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Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.

More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.

Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.

Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.

The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.

--

Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.

Violin and viola players can pay a price for the music they create: Many suffer from skin irritation and inflammation where the instruments touch their necks and upper bodies. Now, a new literature review offers insight into this common condition, known as “fiddler’s neck.”

Hill Street Studios/Stone/Getty Images

“These skin conditions are disfiguring, and they also carry so much psychological burden. Not only are these patients under constant pressure to perform at their maximum at all times, it really is troublesome when there is a barrier between you and performing art that you absolutely love,” lead author Henry Lim, an osteopathic medical student at the University of North Texas Health Science Center at Fort Worth, said in an interview.

The results of the literature review were presented in a poster at the Inaugural Symposium for Inflammatory Skin Disease.

Mr. Lim, who has a special interest in skin, said his own musical experience inspired the research. “Throughout my experience as a violinist, I faced many dermatologic issues because of my violin, and it affected my performance,” he said. “As time went on, I recognized that many other stringed instrumentalists were dealing with similar issues but chose to live with it because it came with the territory.”

One physician told Mr. Lim that he needed to quit in order to permanently treat his skin problems. He didn’t accept this answer and instead launched the literature review with colleagues Marshall Hall, MPH, also an osteopathic medical student with an interest in dermatology, and Sajid Surve, DO, codirector of the UNT Texas Center for Performing Arts Health.

Mr. Lim and colleagues evaluated 23 articles, which included case studies and literature reviews, about dermatitis in violinists, violists, cellists, bassists, guitarists and harpists. “Stringed instrumentalists are the highest at-risk population compared to performers who play other types of instruments,” Mr. Lim said.

The poster he presented at the meeting largely focuses on fiddler’s neck, which he defined as “simply dermatitis related to friction and allergic irritation from playing violin or viola.” Many people, he noted, are allergic to nickel, and the bracket that secures the violin’s chin rest “most often contains nickel. Even a very small concentration of nickel can cause massive reactions, and we found that the C string of a viola – the thickest, lowest-sounding string – contains a nickel concentration of up to 37%.”

Gold-coated strings are an alternative option, he said, but they’re more expensive.

Stringed instrumentalists may also be allergic to rosin applied to “bow hairs,” which is the hair – typically from horses – that is used to string bows, also described in the poster. “We found that there is an overall common allergy to the main ingredient called colophony,” Mr. Lim said. The legendary violin maker Antonio Stradivari “was rumored to have used colophony and another irritating ingredient called propolis in the wood varnish of his instruments. Because he was such a great influence on the art of violin crafting, his technique is still used in the modern era, which may be another contributing factor to the allergic reactions seen in stringed instrumentalists.”

(In the poster, the authors refer to one of the articles in the review, which described a violin maker allergic to colophony and propolis, who was treated with cetirizine, mild corticosteroids, and avoidance.)

What should dermatologists know about skin conditions in these musicians? Mr. Hall, one of the coauthors of the report, suggested they invite the patients to play their instruments during a visit. “The musicians may not understand that they are doing certain things with their movements, but looking from a clinical lens, we are able to see how their biomechanics and posture [are] contributing to their dermatitis,” he said.

Dr. Surve, the other coauthor, also suggested speaking to the patient’s teacher, coach, or mentor. “Keeping that person in the loop regarding what you are seeing and recommending will go a long way towards helping your patient,” he said. “If the teacher doesn’t understand or agree with what you’re trying to accomplish, they may try to undermine your plan of care. But if they are on board, they become a valuable tool for facilitating and reinforcing it.”

As for treatments, avoidance of the instruments is the most effective, but is simply not feasible for many musicians. “Certain interventions like creating a barrier between the musician and the instrument can reduce the risk of contact dermatitis without compromising the quality [of playing] as much,” Mr. Hall said. The poster reported that a handkerchief was used for this purpose in one case attributed to nickel sulfate in a 16-year-old .

Purchasing more expensive instrument materials to prevent reactions is another option, he said, and players can also purchase stands. But musicians may be resistant to any treatment that changes how the instruments sound or forces them to adjust the way they do things, he cautioned.

No funding for the study or author disclosures were reported.

Violin and viola players can pay a price for the music they create: Many suffer from skin irritation and inflammation where the instruments touch their necks and upper bodies. Now, a new literature review offers insight into this common condition, known as “fiddler’s neck.”

Hill Street Studios/Stone/Getty Images

“These skin conditions are disfiguring, and they also carry so much psychological burden. Not only are these patients under constant pressure to perform at their maximum at all times, it really is troublesome when there is a barrier between you and performing art that you absolutely love,” lead author Henry Lim, an osteopathic medical student at the University of North Texas Health Science Center at Fort Worth, said in an interview.

The results of the literature review were presented in a poster at the Inaugural Symposium for Inflammatory Skin Disease.

Mr. Lim, who has a special interest in skin, said his own musical experience inspired the research. “Throughout my experience as a violinist, I faced many dermatologic issues because of my violin, and it affected my performance,” he said. “As time went on, I recognized that many other stringed instrumentalists were dealing with similar issues but chose to live with it because it came with the territory.”

One physician told Mr. Lim that he needed to quit in order to permanently treat his skin problems. He didn’t accept this answer and instead launched the literature review with colleagues Marshall Hall, MPH, also an osteopathic medical student with an interest in dermatology, and Sajid Surve, DO, codirector of the UNT Texas Center for Performing Arts Health.

Mr. Lim and colleagues evaluated 23 articles, which included case studies and literature reviews, about dermatitis in violinists, violists, cellists, bassists, guitarists and harpists. “Stringed instrumentalists are the highest at-risk population compared to performers who play other types of instruments,” Mr. Lim said.

The poster he presented at the meeting largely focuses on fiddler’s neck, which he defined as “simply dermatitis related to friction and allergic irritation from playing violin or viola.” Many people, he noted, are allergic to nickel, and the bracket that secures the violin’s chin rest “most often contains nickel. Even a very small concentration of nickel can cause massive reactions, and we found that the C string of a viola – the thickest, lowest-sounding string – contains a nickel concentration of up to 37%.”

Gold-coated strings are an alternative option, he said, but they’re more expensive.

Stringed instrumentalists may also be allergic to rosin applied to “bow hairs,” which is the hair – typically from horses – that is used to string bows, also described in the poster. “We found that there is an overall common allergy to the main ingredient called colophony,” Mr. Lim said. The legendary violin maker Antonio Stradivari “was rumored to have used colophony and another irritating ingredient called propolis in the wood varnish of his instruments. Because he was such a great influence on the art of violin crafting, his technique is still used in the modern era, which may be another contributing factor to the allergic reactions seen in stringed instrumentalists.”

(In the poster, the authors refer to one of the articles in the review, which described a violin maker allergic to colophony and propolis, who was treated with cetirizine, mild corticosteroids, and avoidance.)

What should dermatologists know about skin conditions in these musicians? Mr. Hall, one of the coauthors of the report, suggested they invite the patients to play their instruments during a visit. “The musicians may not understand that they are doing certain things with their movements, but looking from a clinical lens, we are able to see how their biomechanics and posture [are] contributing to their dermatitis,” he said.

Dr. Surve, the other coauthor, also suggested speaking to the patient’s teacher, coach, or mentor. “Keeping that person in the loop regarding what you are seeing and recommending will go a long way towards helping your patient,” he said. “If the teacher doesn’t understand or agree with what you’re trying to accomplish, they may try to undermine your plan of care. But if they are on board, they become a valuable tool for facilitating and reinforcing it.”

As for treatments, avoidance of the instruments is the most effective, but is simply not feasible for many musicians. “Certain interventions like creating a barrier between the musician and the instrument can reduce the risk of contact dermatitis without compromising the quality [of playing] as much,” Mr. Hall said. The poster reported that a handkerchief was used for this purpose in one case attributed to nickel sulfate in a 16-year-old .

Purchasing more expensive instrument materials to prevent reactions is another option, he said, and players can also purchase stands. But musicians may be resistant to any treatment that changes how the instruments sound or forces them to adjust the way they do things, he cautioned.

No funding for the study or author disclosures were reported.

Violin and viola players can pay a price for the music they create: Many suffer from skin irritation and inflammation where the instruments touch their necks and upper bodies. Now, a new literature review offers insight into this common condition, known as “fiddler’s neck.”

Hill Street Studios/Stone/Getty Images

“These skin conditions are disfiguring, and they also carry so much psychological burden. Not only are these patients under constant pressure to perform at their maximum at all times, it really is troublesome when there is a barrier between you and performing art that you absolutely love,” lead author Henry Lim, an osteopathic medical student at the University of North Texas Health Science Center at Fort Worth, said in an interview.

The results of the literature review were presented in a poster at the Inaugural Symposium for Inflammatory Skin Disease.

Mr. Lim, who has a special interest in skin, said his own musical experience inspired the research. “Throughout my experience as a violinist, I faced many dermatologic issues because of my violin, and it affected my performance,” he said. “As time went on, I recognized that many other stringed instrumentalists were dealing with similar issues but chose to live with it because it came with the territory.”

One physician told Mr. Lim that he needed to quit in order to permanently treat his skin problems. He didn’t accept this answer and instead launched the literature review with colleagues Marshall Hall, MPH, also an osteopathic medical student with an interest in dermatology, and Sajid Surve, DO, codirector of the UNT Texas Center for Performing Arts Health.

Mr. Lim and colleagues evaluated 23 articles, which included case studies and literature reviews, about dermatitis in violinists, violists, cellists, bassists, guitarists and harpists. “Stringed instrumentalists are the highest at-risk population compared to performers who play other types of instruments,” Mr. Lim said.

The poster he presented at the meeting largely focuses on fiddler’s neck, which he defined as “simply dermatitis related to friction and allergic irritation from playing violin or viola.” Many people, he noted, are allergic to nickel, and the bracket that secures the violin’s chin rest “most often contains nickel. Even a very small concentration of nickel can cause massive reactions, and we found that the C string of a viola – the thickest, lowest-sounding string – contains a nickel concentration of up to 37%.”

Gold-coated strings are an alternative option, he said, but they’re more expensive.

Stringed instrumentalists may also be allergic to rosin applied to “bow hairs,” which is the hair – typically from horses – that is used to string bows, also described in the poster. “We found that there is an overall common allergy to the main ingredient called colophony,” Mr. Lim said. The legendary violin maker Antonio Stradivari “was rumored to have used colophony and another irritating ingredient called propolis in the wood varnish of his instruments. Because he was such a great influence on the art of violin crafting, his technique is still used in the modern era, which may be another contributing factor to the allergic reactions seen in stringed instrumentalists.”

(In the poster, the authors refer to one of the articles in the review, which described a violin maker allergic to colophony and propolis, who was treated with cetirizine, mild corticosteroids, and avoidance.)

What should dermatologists know about skin conditions in these musicians? Mr. Hall, one of the coauthors of the report, suggested they invite the patients to play their instruments during a visit. “The musicians may not understand that they are doing certain things with their movements, but looking from a clinical lens, we are able to see how their biomechanics and posture [are] contributing to their dermatitis,” he said.

Dr. Surve, the other coauthor, also suggested speaking to the patient’s teacher, coach, or mentor. “Keeping that person in the loop regarding what you are seeing and recommending will go a long way towards helping your patient,” he said. “If the teacher doesn’t understand or agree with what you’re trying to accomplish, they may try to undermine your plan of care. But if they are on board, they become a valuable tool for facilitating and reinforcing it.”

As for treatments, avoidance of the instruments is the most effective, but is simply not feasible for many musicians. “Certain interventions like creating a barrier between the musician and the instrument can reduce the risk of contact dermatitis without compromising the quality [of playing] as much,” Mr. Hall said. The poster reported that a handkerchief was used for this purpose in one case attributed to nickel sulfate in a 16-year-old .

Purchasing more expensive instrument materials to prevent reactions is another option, he said, and players can also purchase stands. But musicians may be resistant to any treatment that changes how the instruments sound or forces them to adjust the way they do things, he cautioned.

No funding for the study or author disclosures were reported.