Obstetrics

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

Deligiannidis KM, Meltzer-Brody S, Maximos B, et al. Zuranolone for the treatment of postpartum depression. Am J Psychiatry. 2023;180:668-675. doi:10.1176/appi.ajp.20220785.

EXPERT COMMENTARY

Postpartum depression affects approximately 17.2% of patients in the peripartum period.¹ Typical pharmacologic treatment of PPD includes selective serotonin reuptake inhibitors (SSRIs), which may take up to 12 weeks to take effect. Postpartum depression is thought to be secondary to maladaptation to hormonal fluctuations in the peripartum period, including allopregnanolone, a positive allosteric modulator of GABA_A (γ-aminobutyric acid type A)receptors and a metabolite of progesterone, levels of which increase in pregnancy and abruptly decrease following delivery.¹ In 2019, the GABA_A receptor modulator brexanalone was approved by the US Food and Drug Administration (FDA) to treat PPD through continuous intravenous infusion over 60 hours in the hospital setting.

Zuranolone, an allosteric modulator of GABA_A receptors, also has been studied as an investigational medication for rapid treatment of PPD. Prior studies demonstrated the efficacy of oral zuranolone 30 mg daily for the treatment of PPD² and 50 mg for the treatment of major depression in nonpregnant patients.³ Deligiannidis and colleagues conducted a trial to investigate the 50-mg dose of zuranolone for the treatment of PPD. (Notably, in August 2023, the FDA approved oral zuranolone once daily for 14 days for the treatment of PPD.) Following the FDA approval, the American College of Obstetricians and Gynecologists (ACOG) released a Practice Advisory recommending consideration of zuranolone for PPD that takes into account balancing the benefits and risks, including known sedative effects, potential need for decreasing the dose due to adverse effects, lack of safety data in lactation, and unknown long-term efficacy.⁴

Details of the study

This randomized, double-blind, placebo-controlled study included 196 patients with an episode of major depression, characterized as a baseline score of 26 or greater on the Hamilton Depression Rating Scale (HAM-D) beginning in the third trimester or within the first 4 weeks postpartum. Patients were randomly assigned in a 1:1 ratio to receive zuranolone 50 mg daily or placebo, with stratification by stable concurrent antidepressant use. Treatment duration was for 14 days, with follow-up through day 45.

The study’s primary outcome was a change in the baseline HAM-D score at day 15. Changes in HAM-D score also were recorded at days 3, 28, and 45.

The 2 study groups were well balanced by demographic and baseline characteristics. In both groups, the majority of patients experienced the onset of their major depressive episodes within the first 4 weeks postpartum. Completion rates of the 14-day treatment course and 45-day follow-up were high and similar in both groups; 170 patients completed the study. The rate of concurrent psychiatric medications taken, most of which were SSRIs, was similar between the 2 groups at approximately 15% of patients.

Results. A statistically significant improvement in the primary outcome (the change in HAM-D score) at day 15 occurred in patients who received zuranolone versus placebo (P = .001). Additionally, there were statistically significant improvements in the secondary outcomes HAM-D scores at days 3, 28, and 45. Initial response, as measured by changes in HAM-D scores, occurred at a median duration of 9 days in the zuranolone group and 43 days in the placebo group. More patients in the zuranolone group achieved a reduction in HAM-D score at 15 days (57.0% vs 38.9%; P = .02). Zuranolone was associated with a higher rate of HAM-D remission at day 45 (44.0% vs 29.4%; P = .02).

With regard to safety, 16.3% of patients (17) in the zuranolone group (vs 1% in the placebo group) experienced an adverse event, most commonly somnolence, dizziness, and sedation, which led to a dose reduction. However, 15 of these 17 patients still completed the study, and there were no serious adverse events.

Study strengths and limitations

This study’s strengths include the double-blinded design that was continued throughout the duration of the follow-up. Additionally, the study population was heterogeneous andreflective of patients from diverse racial and ethnic backgrounds. Lastly, only minor and moderate adverse events were reported and, despite this, nearly all patients who experienced adverse events completed the study.

Limitations of the study include the lack of generalizability, as patients with bipolar disorder and mild or moderate PPD were excluded. Additionally, the majority of patients had depressive episodes within the first 4 weeks postpartum, thereby excluding patients with depressive episodes at other time points in the peripartum period. Further, as breastfeeding was prohibited, safety in lactating patients using zuranolone is unknown. Lastly, the study follow-up period was 45 days; therefore, the long-term efficacy of zuranolone treatment is unclear. ●

The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.

At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.

courtesy UNC-Chapel Hill

What is zuranolone?

Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABA_A receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABA_A receptor to GABA.

Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
 

What does zuranolone treat?

Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.

How does zuranolone work?

courtesy UNC-Chapel Hill

Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.

How was it studied?

Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.

The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
 

When will we be able to start using it?

It is anticipated that zuranolone will become commercially available in early 2024.

Who can prescribe it?

courtesy UNC-Chapel Hill

Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.

How much will it cost?

The manufacturers have not released this information as of August 2023.

What sort of doses and duration is recommended?

The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.

What happens if the patient relapses after a 14-day trial?

While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.

What are the side effects?

courtesy UNC-Chapel Hill

Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.

Are there any boxed warnings?

Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.

Can it be used with other medications?

Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.

Are there any medicines to avoid?

We recommend caution with other medications which may increase sedation, such as benzodiazepines.

Can it be used with birth control?

Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.

Can it be used in pregnancy?

As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
 

Long-term side effects?

Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.

Breastfeeding?

Use in lactation has not yet been studied. Continued research is needed.

Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?

The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.

Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?

Zuranolone is currently only approved for the treatment of postpartum depression. It has not received FDA approval for major depression outside of the perinatal period at this time. Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.

Anxiety?

Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.

However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
 

Insomnia?

In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.

How is it different from brexanolone?

The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.

Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
 

When would you consider zuranolone vs. brexanolone vs. other antidepressants?

Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).

Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
 

Where can I find more information?

Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.

We plan to update this entry upon market release and access to new information.

Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.

References

Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.

Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.

Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.

Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.

FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression

ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf

The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.

At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.

courtesy UNC-Chapel Hill

What is zuranolone?

Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABA_A receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABA_A receptor to GABA.

Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
 

What does zuranolone treat?

Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.

How does zuranolone work?

courtesy UNC-Chapel Hill

Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.

How was it studied?

Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.

The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
 

When will we be able to start using it?

It is anticipated that zuranolone will become commercially available in early 2024.

Who can prescribe it?

courtesy UNC-Chapel Hill

Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.

How much will it cost?

The manufacturers have not released this information as of August 2023.

What sort of doses and duration is recommended?

The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.

What happens if the patient relapses after a 14-day trial?

While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.

What are the side effects?

courtesy UNC-Chapel Hill

Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.

Are there any boxed warnings?

Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.

Can it be used with other medications?

Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.

Are there any medicines to avoid?

We recommend caution with other medications which may increase sedation, such as benzodiazepines.

Can it be used with birth control?

Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.

Can it be used in pregnancy?

As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
 

Long-term side effects?

Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.

Breastfeeding?

Use in lactation has not yet been studied. Continued research is needed.

Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?

The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.

Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?

Zuranolone is currently only approved for the treatment of postpartum depression. It has not received FDA approval for major depression outside of the perinatal period at this time. Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.

Anxiety?

Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.

However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
 

Insomnia?

In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.

How is it different from brexanolone?

The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.

Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
 

When would you consider zuranolone vs. brexanolone vs. other antidepressants?

Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).

Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
 

Where can I find more information?

Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.

We plan to update this entry upon market release and access to new information.

Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.

References

Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.

Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.

Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.

Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.

FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression

ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf

The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.

At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.

courtesy UNC-Chapel Hill

What is zuranolone?

Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABA_A receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABA_A receptor to GABA.

Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
 

What does zuranolone treat?

Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.

How does zuranolone work?

courtesy UNC-Chapel Hill

Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.

How was it studied?

Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.

The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
 

When will we be able to start using it?

It is anticipated that zuranolone will become commercially available in early 2024.

Who can prescribe it?

courtesy UNC-Chapel Hill

Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.

How much will it cost?

The manufacturers have not released this information as of August 2023.

What sort of doses and duration is recommended?

The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.

What happens if the patient relapses after a 14-day trial?

While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.

What are the side effects?

courtesy UNC-Chapel Hill

Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.

Are there any boxed warnings?

Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.

Can it be used with other medications?

Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.

Are there any medicines to avoid?

We recommend caution with other medications which may increase sedation, such as benzodiazepines.

Can it be used with birth control?

Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.

Can it be used in pregnancy?

As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
 

Long-term side effects?

Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.

Breastfeeding?

Use in lactation has not yet been studied. Continued research is needed.

Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?

The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.

Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?

Zuranolone is currently only approved for the treatment of postpartum depression. It has not received FDA approval for major depression outside of the perinatal period at this time. Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.

Anxiety?

Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.

However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
 

Insomnia?

In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.

How is it different from brexanolone?

The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.

Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
 

When would you consider zuranolone vs. brexanolone vs. other antidepressants?

Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).

Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
 

Where can I find more information?

Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.

We plan to update this entry upon market release and access to new information.

Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.

References

Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.

Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.

Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.

Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.

FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression

ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf

TOPLINE:

Approximately one-third of women with rheumatic diseases develop anemia by the third trimester of pregnancy, and two-thirds are iron deficient, according to findings from a longitudinal cohort study.

METHODOLOGY:

• Researchers analyzed data from 368 pregnancies in women with rheumatic diseases during the period 2014-2022; nearly two-thirds (62%) had a connective tissue disease, 16% had rheumatoid arthritis or juvenile idiopathic arthritis, 14% had spondyloarthritis, 3% had vasculitis, and 7% had other diseases.
• Patients were aged 17-44 years, with a median age of 32 years at the time of birth.
• Researchers examined the frequency of anemia and iron deficiency and the impact of anemia on adverse maternal and child outcomes.

TAKEAWAY:

• The prevalence of iron deficiency was 28%, 51%, and 62% in the first, second, and third trimesters, respectively.
• The prevalence of anemia was 18%, 27%, and 33% in the first, second, and third trimesters, respectively.
• There was an increased risk for fetal complications such as malformation, infections, small for gestational age, neonatal lupus, preterm birth, and abortion or stillbirth in association with maternal connective tissue disease (odds ratio, 2.14) and also with low maternal hemoglobin levels and maternal iron deficiency (ORs, 0.52 and 0.86, respectively).
• Lower maternal hemoglobin levels were associated with an increased risk for maternal complications (OR, 1.47) such as flare with adaption of rheumatic medication and pregnancy-related adverse events (preeclampsia, gestational diabetes, bleeding complications, and thromboembolism), but patients with connective tissue disease had a lower risk for maternal complications (OR, 0.51); mean serum ferritin had no significant impact on maternal complications (OR, 1.02).

IN PRACTICE:

“Patients with rheumatic diseases suffer more often and already in early pregnancy from iron deficiency,” the researchers write. Therefore, early identification of anemia and iron deficiency in this population could inform prepregnancy counseling.

SOURCE:

The lead author on the study was Ann-Christin Pecher, MD, of University Hospital Tübingen, Germany. The study was published online in Joint Bone Spine.

LIMITATIONS:

The findings were limited by the use of a single dataset that might not be representative of all pregnant patients with rheumatic diseases. Other limitations included the lack of a standardized approach to iron supplementation.

DISCLOSURES:

The study was supported by a grant from the Medical Faculty of Tübingen Clinician-Scientist to the lead author. The researchers report no relevant financial relationships.

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

TOPLINE:

Approximately one-third of women with rheumatic diseases develop anemia by the third trimester of pregnancy, and two-thirds are iron deficient, according to findings from a longitudinal cohort study.

METHODOLOGY:

• Researchers analyzed data from 368 pregnancies in women with rheumatic diseases during the period 2014-2022; nearly two-thirds (62%) had a connective tissue disease, 16% had rheumatoid arthritis or juvenile idiopathic arthritis, 14% had spondyloarthritis, 3% had vasculitis, and 7% had other diseases.
• Patients were aged 17-44 years, with a median age of 32 years at the time of birth.
• Researchers examined the frequency of anemia and iron deficiency and the impact of anemia on adverse maternal and child outcomes.

TAKEAWAY:

• The prevalence of iron deficiency was 28%, 51%, and 62% in the first, second, and third trimesters, respectively.
• The prevalence of anemia was 18%, 27%, and 33% in the first, second, and third trimesters, respectively.
• There was an increased risk for fetal complications such as malformation, infections, small for gestational age, neonatal lupus, preterm birth, and abortion or stillbirth in association with maternal connective tissue disease (odds ratio, 2.14) and also with low maternal hemoglobin levels and maternal iron deficiency (ORs, 0.52 and 0.86, respectively).
• Lower maternal hemoglobin levels were associated with an increased risk for maternal complications (OR, 1.47) such as flare with adaption of rheumatic medication and pregnancy-related adverse events (preeclampsia, gestational diabetes, bleeding complications, and thromboembolism), but patients with connective tissue disease had a lower risk for maternal complications (OR, 0.51); mean serum ferritin had no significant impact on maternal complications (OR, 1.02).

IN PRACTICE:

“Patients with rheumatic diseases suffer more often and already in early pregnancy from iron deficiency,” the researchers write. Therefore, early identification of anemia and iron deficiency in this population could inform prepregnancy counseling.

SOURCE:

The lead author on the study was Ann-Christin Pecher, MD, of University Hospital Tübingen, Germany. The study was published online in Joint Bone Spine.

LIMITATIONS:

The findings were limited by the use of a single dataset that might not be representative of all pregnant patients with rheumatic diseases. Other limitations included the lack of a standardized approach to iron supplementation.

DISCLOSURES:

The study was supported by a grant from the Medical Faculty of Tübingen Clinician-Scientist to the lead author. The researchers report no relevant financial relationships.

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

TOPLINE:

Approximately one-third of women with rheumatic diseases develop anemia by the third trimester of pregnancy, and two-thirds are iron deficient, according to findings from a longitudinal cohort study.

METHODOLOGY:

• Researchers analyzed data from 368 pregnancies in women with rheumatic diseases during the period 2014-2022; nearly two-thirds (62%) had a connective tissue disease, 16% had rheumatoid arthritis or juvenile idiopathic arthritis, 14% had spondyloarthritis, 3% had vasculitis, and 7% had other diseases.
• Patients were aged 17-44 years, with a median age of 32 years at the time of birth.
• Researchers examined the frequency of anemia and iron deficiency and the impact of anemia on adverse maternal and child outcomes.

TAKEAWAY:

• The prevalence of iron deficiency was 28%, 51%, and 62% in the first, second, and third trimesters, respectively.
• The prevalence of anemia was 18%, 27%, and 33% in the first, second, and third trimesters, respectively.
• There was an increased risk for fetal complications such as malformation, infections, small for gestational age, neonatal lupus, preterm birth, and abortion or stillbirth in association with maternal connective tissue disease (odds ratio, 2.14) and also with low maternal hemoglobin levels and maternal iron deficiency (ORs, 0.52 and 0.86, respectively).
• Lower maternal hemoglobin levels were associated with an increased risk for maternal complications (OR, 1.47) such as flare with adaption of rheumatic medication and pregnancy-related adverse events (preeclampsia, gestational diabetes, bleeding complications, and thromboembolism), but patients with connective tissue disease had a lower risk for maternal complications (OR, 0.51); mean serum ferritin had no significant impact on maternal complications (OR, 1.02).

IN PRACTICE:

“Patients with rheumatic diseases suffer more often and already in early pregnancy from iron deficiency,” the researchers write. Therefore, early identification of anemia and iron deficiency in this population could inform prepregnancy counseling.

SOURCE:

The lead author on the study was Ann-Christin Pecher, MD, of University Hospital Tübingen, Germany. The study was published online in Joint Bone Spine.

LIMITATIONS:

The findings were limited by the use of a single dataset that might not be representative of all pregnant patients with rheumatic diseases. Other limitations included the lack of a standardized approach to iron supplementation.

DISCLOSURES:

The study was supported by a grant from the Medical Faculty of Tübingen Clinician-Scientist to the lead author. The researchers report no relevant financial relationships.

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

Maternal pertussis vaccinations, given during pregnancy, prevent an estimated 65% of pertussis infections in infants, new research indicates.

The study, led by Annette K. Regan, PhD, MPH, a perinatal and pediatric infectious disease epidemiologist at Curtin University, Perth, Australia, was published online in Pediatrics.

Dr. Regan – who is also with the University of San Francisco and the University of California, Los Angeles – and colleagues reviewed data on 279,418 infants born to 252,444 mothers in Australia.

There, about 52% of the women in this study received the Tdap vaccine through a maternal pertussis vaccination program.

Duration of effectiveness in infants was one of the main questions the study sought to answer.

The authors wrote that they assessed vaccine effectiveness through 18 months of age. “We observed significant protection against disease until at least 8 months of age, 2 months longer than reported in previous studies.” From 70% to 90% of all pertussis-attributable hospitalizations and death occur in infancy.
 

Answering the ‘blunting’ question

This study also set out to clarify an important clinical question regarding a potential “blunting” effect in infants. Previous work had suggested that maternal antibodies from the vaccination could interfere with the effectiveness of infants’ DtaP (the version of Tdap for infants) and other vaccines.

Dr. Regan and colleagues found that, “although we observed slightly lower VE [vaccine effectiveness] point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs. 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% confidence interval, 0.61-3.39).
 

Best time to give mothers the vaccine

Another clinical debate has centered on when to give the mother the vaccine during pregnancy. The authors concluded: “Our findings support the infant health benefits of recommendations to administer a booster dose of pertussis vaccine near 28 weeks of gestational age.”

That 28-week mark was associated with lower risk of infection in infants through 8 months of age, they wrote.
 

Positive results in the United States

In an invited commentary, Kathryn M. Edwards, MD, with the division of infectious diseases, department of pediatrics, at Vanderbilt University Medical Center, Nashville, Tenn., highlighted similar positive findings for maternal pertussis vaccination in the United States.

The Centers for Disease Control and Prevention did an ecologic study of infant pertussis cases reported between Jan. 1, 2000, and Dec. 31, 2019. Rates were compared for the years before maternal Tdap vaccinations were recommended against the 7-year period after they were implemented.

That study found that in the period before maternal Tdap vaccination, annual pertussis incidence did not change among infants younger than 2 months and increased slightly in infants 6-12 months.

However, during the period after maternal Tdap vaccination had started (2012-2019), pertussis incidence significantly decreased in infants younger than 2 months and was unchanged in infants 6-12 months.

“As with the Australian data, the U.S. data support the overall benefit of the maternal Tdap program and, as with the Australian data, do not suggest that blunting has led to an increase in cases within the first year of life,” Dr. Edwards wrote.

The CDC notes that pertussis cases are rising and outbreaks are happening across the United States.

“On average, about 1,000 infants are hospitalized and typically between 5 and 15 infants die each year in the United States due to pertussis,” the CDC states.
 

Uptake low despite positive data

Dr. Edwards noted that, despite positive data supporting maternal vaccination to reduce pertussis, uptake rates are low – between 50% and 60% in Australia, the United Kingdom, and the United States. “Active engagement to increase these rates should be implemented.”

Maternal vaccination might also be implemented soon to protect against other diseases including respiratory syncytial virus and group B streptococcal disease after promising study data, she said.

As with pertussis, the potential “blunting” effect will need to be carefully monitored, she said, “as was done in the carefully conducted study of pertussis reported in this issue of Pediatrics.”

One coauthor has received institutional honoraria for participation in advisory groups for Merck Sharpe & Dohme and Pfizer unrelated to this work. Another coauthor was supported by scholarships provided by the Wesfarmers Centre of Vaccines and Infectious Disease at the Telethon Kids Institute. Dr. Edwards reported receiving grants from the CDC and consulting for Bionet, Dynavax, and IBM. She is a member of the data safety and monitoring board for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, and Brighton Collaboration.

Maternal pertussis vaccinations, given during pregnancy, prevent an estimated 65% of pertussis infections in infants, new research indicates.

The study, led by Annette K. Regan, PhD, MPH, a perinatal and pediatric infectious disease epidemiologist at Curtin University, Perth, Australia, was published online in Pediatrics.

Dr. Regan – who is also with the University of San Francisco and the University of California, Los Angeles – and colleagues reviewed data on 279,418 infants born to 252,444 mothers in Australia.

There, about 52% of the women in this study received the Tdap vaccine through a maternal pertussis vaccination program.

Duration of effectiveness in infants was one of the main questions the study sought to answer.

The authors wrote that they assessed vaccine effectiveness through 18 months of age. “We observed significant protection against disease until at least 8 months of age, 2 months longer than reported in previous studies.” From 70% to 90% of all pertussis-attributable hospitalizations and death occur in infancy.
 

Answering the ‘blunting’ question

This study also set out to clarify an important clinical question regarding a potential “blunting” effect in infants. Previous work had suggested that maternal antibodies from the vaccination could interfere with the effectiveness of infants’ DtaP (the version of Tdap for infants) and other vaccines.

Dr. Regan and colleagues found that, “although we observed slightly lower VE [vaccine effectiveness] point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs. 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% confidence interval, 0.61-3.39).
 

Best time to give mothers the vaccine

Another clinical debate has centered on when to give the mother the vaccine during pregnancy. The authors concluded: “Our findings support the infant health benefits of recommendations to administer a booster dose of pertussis vaccine near 28 weeks of gestational age.”

That 28-week mark was associated with lower risk of infection in infants through 8 months of age, they wrote.
 

Positive results in the United States

In an invited commentary, Kathryn M. Edwards, MD, with the division of infectious diseases, department of pediatrics, at Vanderbilt University Medical Center, Nashville, Tenn., highlighted similar positive findings for maternal pertussis vaccination in the United States.

The Centers for Disease Control and Prevention did an ecologic study of infant pertussis cases reported between Jan. 1, 2000, and Dec. 31, 2019. Rates were compared for the years before maternal Tdap vaccinations were recommended against the 7-year period after they were implemented.

That study found that in the period before maternal Tdap vaccination, annual pertussis incidence did not change among infants younger than 2 months and increased slightly in infants 6-12 months.

However, during the period after maternal Tdap vaccination had started (2012-2019), pertussis incidence significantly decreased in infants younger than 2 months and was unchanged in infants 6-12 months.

“As with the Australian data, the U.S. data support the overall benefit of the maternal Tdap program and, as with the Australian data, do not suggest that blunting has led to an increase in cases within the first year of life,” Dr. Edwards wrote.

The CDC notes that pertussis cases are rising and outbreaks are happening across the United States.

“On average, about 1,000 infants are hospitalized and typically between 5 and 15 infants die each year in the United States due to pertussis,” the CDC states.
 

Uptake low despite positive data

Dr. Edwards noted that, despite positive data supporting maternal vaccination to reduce pertussis, uptake rates are low – between 50% and 60% in Australia, the United Kingdom, and the United States. “Active engagement to increase these rates should be implemented.”

Maternal vaccination might also be implemented soon to protect against other diseases including respiratory syncytial virus and group B streptococcal disease after promising study data, she said.

As with pertussis, the potential “blunting” effect will need to be carefully monitored, she said, “as was done in the carefully conducted study of pertussis reported in this issue of Pediatrics.”

One coauthor has received institutional honoraria for participation in advisory groups for Merck Sharpe & Dohme and Pfizer unrelated to this work. Another coauthor was supported by scholarships provided by the Wesfarmers Centre of Vaccines and Infectious Disease at the Telethon Kids Institute. Dr. Edwards reported receiving grants from the CDC and consulting for Bionet, Dynavax, and IBM. She is a member of the data safety and monitoring board for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, and Brighton Collaboration.

Maternal pertussis vaccinations, given during pregnancy, prevent an estimated 65% of pertussis infections in infants, new research indicates.

The study, led by Annette K. Regan, PhD, MPH, a perinatal and pediatric infectious disease epidemiologist at Curtin University, Perth, Australia, was published online in Pediatrics.

Dr. Regan – who is also with the University of San Francisco and the University of California, Los Angeles – and colleagues reviewed data on 279,418 infants born to 252,444 mothers in Australia.

There, about 52% of the women in this study received the Tdap vaccine through a maternal pertussis vaccination program.

Duration of effectiveness in infants was one of the main questions the study sought to answer.

The authors wrote that they assessed vaccine effectiveness through 18 months of age. “We observed significant protection against disease until at least 8 months of age, 2 months longer than reported in previous studies.” From 70% to 90% of all pertussis-attributable hospitalizations and death occur in infancy.
 

Answering the ‘blunting’ question

This study also set out to clarify an important clinical question regarding a potential “blunting” effect in infants. Previous work had suggested that maternal antibodies from the vaccination could interfere with the effectiveness of infants’ DtaP (the version of Tdap for infants) and other vaccines.

Dr. Regan and colleagues found that, “although we observed slightly lower VE [vaccine effectiveness] point estimates for the third dose of infant pertussis vaccine among maternally vaccinated compared with unvaccinated infants (76.5% vs. 92.9%, P = .002), we did not observe higher rates of pertussis infection (hazard ratio, 0.70; 95% confidence interval, 0.61-3.39).
 

Best time to give mothers the vaccine

Another clinical debate has centered on when to give the mother the vaccine during pregnancy. The authors concluded: “Our findings support the infant health benefits of recommendations to administer a booster dose of pertussis vaccine near 28 weeks of gestational age.”

That 28-week mark was associated with lower risk of infection in infants through 8 months of age, they wrote.
 

Positive results in the United States

In an invited commentary, Kathryn M. Edwards, MD, with the division of infectious diseases, department of pediatrics, at Vanderbilt University Medical Center, Nashville, Tenn., highlighted similar positive findings for maternal pertussis vaccination in the United States.

The Centers for Disease Control and Prevention did an ecologic study of infant pertussis cases reported between Jan. 1, 2000, and Dec. 31, 2019. Rates were compared for the years before maternal Tdap vaccinations were recommended against the 7-year period after they were implemented.

That study found that in the period before maternal Tdap vaccination, annual pertussis incidence did not change among infants younger than 2 months and increased slightly in infants 6-12 months.

However, during the period after maternal Tdap vaccination had started (2012-2019), pertussis incidence significantly decreased in infants younger than 2 months and was unchanged in infants 6-12 months.

“As with the Australian data, the U.S. data support the overall benefit of the maternal Tdap program and, as with the Australian data, do not suggest that blunting has led to an increase in cases within the first year of life,” Dr. Edwards wrote.

The CDC notes that pertussis cases are rising and outbreaks are happening across the United States.

“On average, about 1,000 infants are hospitalized and typically between 5 and 15 infants die each year in the United States due to pertussis,” the CDC states.
 

Uptake low despite positive data

Dr. Edwards noted that, despite positive data supporting maternal vaccination to reduce pertussis, uptake rates are low – between 50% and 60% in Australia, the United Kingdom, and the United States. “Active engagement to increase these rates should be implemented.”

Maternal vaccination might also be implemented soon to protect against other diseases including respiratory syncytial virus and group B streptococcal disease after promising study data, she said.

As with pertussis, the potential “blunting” effect will need to be carefully monitored, she said, “as was done in the carefully conducted study of pertussis reported in this issue of Pediatrics.”

One coauthor has received institutional honoraria for participation in advisory groups for Merck Sharpe & Dohme and Pfizer unrelated to this work. Another coauthor was supported by scholarships provided by the Wesfarmers Centre of Vaccines and Infectious Disease at the Telethon Kids Institute. Dr. Edwards reported receiving grants from the CDC and consulting for Bionet, Dynavax, and IBM. She is a member of the data safety and monitoring board for Sanofi, X-4 Pharma, Seqirus, Moderna, Pfizer, Merck, Roche, Novavax, and Brighton Collaboration.

TOPLINE:

Almost one-quarter of pregnant women who have had a heart transplant (HT) will experience severe maternal morbidity (SMM) during their hospital stay for delivery, and they have sevenfold greater risk for preterm birth than do other pregnant women, results of a large study with a nationwide sample suggest.

METHODOLOGY:

• The retrospective cohort study included 2010-2020 information from the Nationwide Readmissions Database (NRD), a large, all-payer administrative dataset that allows for tracking of patient hospital readmissions in the same U.S. state within the same calendar year and includes patient demographics, hospital characteristics, diagnosis and procedure codes (including for cardiac transplants), length of stay, and discharge disposition.
• The primary outcome was nontransfusion SMM which, among other conditions, included acute myocardial infarction, aortic aneurysm, acute renal failure, adult respiratory distress syndrome, amniotic fluid embolism, cardiac arrest/ventricular fibrillation, and heart failure/arrest, during the delivery hospitalization.
• Additional outcomes included rates of all SMMs (including transfusion), a composite cardiovascular SMM (cSMM) outcome that included acute myocardial infarction, aortic aneurysm, cardiac arrest/ventricular fibrillation, cardioversion, and acute heart failure, preterm birth, and readmission rates.

TAKEAWAY:

• From 2010 to 2020, there were 19,399,521 hospital deliveries, of which, 105 were in HT recipients.
• In unadjusted comparisons, rates of all outcomes were higher in HT, compared with non-HT delivery hospitalizations, and after adjusting for age, demographic and facility characteristics, comorbid conditions, and calendar year, HT recipients continued to have higher odds of adverse maternal outcomes. For example, HT recipients had higher rates of nontransfusion SMM (adjusted odds ratio, 28.12; 95% confidence interval, 15.65-50.53), all SMM (aOR, 15.73; 95% CI, 9.17-27.00), cSMM (aOR, 37.7; 95% CI, 17.39-82.01), and preterm birth (aOR, 7.15; 95%, CI 4.75-10.77).
• HT recipients also had longer hospital stays and higher rates of cesarean delivery, although the authors noted that it’s unclear whether this increase was caused by the HT or complications of pregnancy because data were unavailable regarding indication for cesareans.
• Patients with HT were also at increased risk for hospital readmission within the first year after delivery, particularly within the first 6 months, including for HT-related complications, a finding that supports guidelines recommending an initial postpartum visit within 7-14 days of discharge for patients with cardiac conditions, write the authors.

IN PRACTICE:

The findings demonstrate the importance of counseling HT patients at early gestational ages “to provide information about anticipated risks in pregnancy and the postpartum period to allow patients the opportunity to make informed choices regarding their reproductive options,” the authors conclude.

SOURCE:

The study was conducted by Amanda M. Craig, MD, division of maternal fetal medicine, department of obstetrics and gynecology, Duke University Medical Center, Durham, N.C., and colleagues. It was published online in JACC Heart Failure.

LIMITATIONS:

Relying on diagnosis and procedure codes in administrative datasets like NRD may result in underestimation of outcomes. In this study, outcomes were limited to delivery hospitalizations, which may underestimate the true incidence of complications or fail to include pregnancies that didn’t end in a delivery, including pregnancy terminations or spontaneous abortions. Information related to race, ethnicity, hospital regions, and cause of death are not captured in the NRD dataset.

DISCLOSURES:

The authors have no relevant conflicts of interest.

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

TOPLINE:

Almost one-quarter of pregnant women who have had a heart transplant (HT) will experience severe maternal morbidity (SMM) during their hospital stay for delivery, and they have sevenfold greater risk for preterm birth than do other pregnant women, results of a large study with a nationwide sample suggest.

METHODOLOGY:

• The retrospective cohort study included 2010-2020 information from the Nationwide Readmissions Database (NRD), a large, all-payer administrative dataset that allows for tracking of patient hospital readmissions in the same U.S. state within the same calendar year and includes patient demographics, hospital characteristics, diagnosis and procedure codes (including for cardiac transplants), length of stay, and discharge disposition.
• The primary outcome was nontransfusion SMM which, among other conditions, included acute myocardial infarction, aortic aneurysm, acute renal failure, adult respiratory distress syndrome, amniotic fluid embolism, cardiac arrest/ventricular fibrillation, and heart failure/arrest, during the delivery hospitalization.
• Additional outcomes included rates of all SMMs (including transfusion), a composite cardiovascular SMM (cSMM) outcome that included acute myocardial infarction, aortic aneurysm, cardiac arrest/ventricular fibrillation, cardioversion, and acute heart failure, preterm birth, and readmission rates.

TAKEAWAY:

• From 2010 to 2020, there were 19,399,521 hospital deliveries, of which, 105 were in HT recipients.
• In unadjusted comparisons, rates of all outcomes were higher in HT, compared with non-HT delivery hospitalizations, and after adjusting for age, demographic and facility characteristics, comorbid conditions, and calendar year, HT recipients continued to have higher odds of adverse maternal outcomes. For example, HT recipients had higher rates of nontransfusion SMM (adjusted odds ratio, 28.12; 95% confidence interval, 15.65-50.53), all SMM (aOR, 15.73; 95% CI, 9.17-27.00), cSMM (aOR, 37.7; 95% CI, 17.39-82.01), and preterm birth (aOR, 7.15; 95%, CI 4.75-10.77).
• HT recipients also had longer hospital stays and higher rates of cesarean delivery, although the authors noted that it’s unclear whether this increase was caused by the HT or complications of pregnancy because data were unavailable regarding indication for cesareans.
• Patients with HT were also at increased risk for hospital readmission within the first year after delivery, particularly within the first 6 months, including for HT-related complications, a finding that supports guidelines recommending an initial postpartum visit within 7-14 days of discharge for patients with cardiac conditions, write the authors.

IN PRACTICE:

The findings demonstrate the importance of counseling HT patients at early gestational ages “to provide information about anticipated risks in pregnancy and the postpartum period to allow patients the opportunity to make informed choices regarding their reproductive options,” the authors conclude.

SOURCE:

The study was conducted by Amanda M. Craig, MD, division of maternal fetal medicine, department of obstetrics and gynecology, Duke University Medical Center, Durham, N.C., and colleagues. It was published online in JACC Heart Failure.

LIMITATIONS:

Relying on diagnosis and procedure codes in administrative datasets like NRD may result in underestimation of outcomes. In this study, outcomes were limited to delivery hospitalizations, which may underestimate the true incidence of complications or fail to include pregnancies that didn’t end in a delivery, including pregnancy terminations or spontaneous abortions. Information related to race, ethnicity, hospital regions, and cause of death are not captured in the NRD dataset.

DISCLOSURES:

The authors have no relevant conflicts of interest.

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

TOPLINE:

Almost one-quarter of pregnant women who have had a heart transplant (HT) will experience severe maternal morbidity (SMM) during their hospital stay for delivery, and they have sevenfold greater risk for preterm birth than do other pregnant women, results of a large study with a nationwide sample suggest.

METHODOLOGY:

• The retrospective cohort study included 2010-2020 information from the Nationwide Readmissions Database (NRD), a large, all-payer administrative dataset that allows for tracking of patient hospital readmissions in the same U.S. state within the same calendar year and includes patient demographics, hospital characteristics, diagnosis and procedure codes (including for cardiac transplants), length of stay, and discharge disposition.
• The primary outcome was nontransfusion SMM which, among other conditions, included acute myocardial infarction, aortic aneurysm, acute renal failure, adult respiratory distress syndrome, amniotic fluid embolism, cardiac arrest/ventricular fibrillation, and heart failure/arrest, during the delivery hospitalization.
• Additional outcomes included rates of all SMMs (including transfusion), a composite cardiovascular SMM (cSMM) outcome that included acute myocardial infarction, aortic aneurysm, cardiac arrest/ventricular fibrillation, cardioversion, and acute heart failure, preterm birth, and readmission rates.

TAKEAWAY:

• From 2010 to 2020, there were 19,399,521 hospital deliveries, of which, 105 were in HT recipients.
• In unadjusted comparisons, rates of all outcomes were higher in HT, compared with non-HT delivery hospitalizations, and after adjusting for age, demographic and facility characteristics, comorbid conditions, and calendar year, HT recipients continued to have higher odds of adverse maternal outcomes. For example, HT recipients had higher rates of nontransfusion SMM (adjusted odds ratio, 28.12; 95% confidence interval, 15.65-50.53), all SMM (aOR, 15.73; 95% CI, 9.17-27.00), cSMM (aOR, 37.7; 95% CI, 17.39-82.01), and preterm birth (aOR, 7.15; 95%, CI 4.75-10.77).
• HT recipients also had longer hospital stays and higher rates of cesarean delivery, although the authors noted that it’s unclear whether this increase was caused by the HT or complications of pregnancy because data were unavailable regarding indication for cesareans.
• Patients with HT were also at increased risk for hospital readmission within the first year after delivery, particularly within the first 6 months, including for HT-related complications, a finding that supports guidelines recommending an initial postpartum visit within 7-14 days of discharge for patients with cardiac conditions, write the authors.

IN PRACTICE:

The findings demonstrate the importance of counseling HT patients at early gestational ages “to provide information about anticipated risks in pregnancy and the postpartum period to allow patients the opportunity to make informed choices regarding their reproductive options,” the authors conclude.

SOURCE:

The study was conducted by Amanda M. Craig, MD, division of maternal fetal medicine, department of obstetrics and gynecology, Duke University Medical Center, Durham, N.C., and colleagues. It was published online in JACC Heart Failure.

LIMITATIONS:

Relying on diagnosis and procedure codes in administrative datasets like NRD may result in underestimation of outcomes. In this study, outcomes were limited to delivery hospitalizations, which may underestimate the true incidence of complications or fail to include pregnancies that didn’t end in a delivery, including pregnancy terminations or spontaneous abortions. Information related to race, ethnicity, hospital regions, and cause of death are not captured in the NRD dataset.

DISCLOSURES:

The authors have no relevant conflicts of interest.

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

HAMBURG – Initiating metformin treatment at gestational diabetes diagnosis was associated with improved glycemic control and reduced gestational weight gain, according to the results of a randomized, placebo-controlled trial.

Overall, the trial’s primary outcome, a composite of insulin initiation or a fasting glucose level ≥ 5.1 mmol/L (92 mg/dL) at gestation weeks 32 or 38, did not differ between women with gestational diabetes randomly assigned to either placebo or metformin. However, women taking metformin were significantly less likely to require insulin and had significantly lower fasting blood glucose levels at weeks 32 and 38.

“With a composite outcome it’s more difficult to find a positive result ... So, although the primary composite outcome was not positive, the components of the primary outcome that are clinically meaningful were positive,” lead study author Fidelma Dunne, PhD, professor and endocrine consultant at the University of Galway, Ireland, said in an interview.

There were no differences in maternal or neonatal morbidities, but there was a nonsignificant increase in small for gestational age (SGA), a finding that has been seen in some but not all previous studies of metformin use in gestational diabetes.

Dr. Dunne presented the findings on Oct. 3 at the annual meeting of the European Association for the Study of Diabetes. The results were simultaneously published in JAMA.

Current recommendations from the United Kingdom’s National Institute for Health and Care Excellence say metformin is a suitable first-line therapy for gestational diabetes. However, both the American Diabetes Association and the Society of Maternal-Fetal Medicine do not, particularly for pregnancies with hypertension or preeclampsia or in those who are at risk for intrauterine growth restriction.

“Gestational diabetes is now reaching epidemic proportions. And of course, the vast majority of these women are in low- and middle-income countries where insulin might not be available, or the storage may not allow it to be used effectively. If you have a medication that in the majority of women is safe and effective it may actually help a lot of women in [those regions],” Dr. Dunne said.

Moreover, she noted, “women with gestational diabetes are testing their sugar with finger pricks four to seven times per day and we ask them to take insulin one to four times a day. So if you can relieve any of that pain related to treatment of their condition than that is a benefit for the women as well.”

Asked to comment, Katrien Benhalima, MD, PhD, of University Hospital Gasthuisberg, KU Leuven, Belgium, said, “I think it’s an interesting study because they investigated something novel, to initiate immediately metformin or placebo. Normally what we do with gestational diabetes is once we get the diagnosis, we treat them with lifestyle, and if that’s insufficient then we start with medical therapy. So this is a novel approach.”

She also agreed with Dr. Dunne that the lack of significance for the primary outcome “isn’t an issue of power but it is a composite outcome. If you look at the individual outcomes, as can be expected, the women taking metformin had less need for insulin treatment.”

But, Dr. Benhalima said, the study still leaves open the SGA issue. “It wasn’t significant, but it’s still something we are worried about in the sense that we feel we need more data, especially in the long-term for the offspring health ... You really need to follow them for 10 years or longer to see an effect.”

So for now, Dr. Benhalima said that she wouldn’t use metformin as a first-line treatment for gestational diabetes. “Normally if lifestyle isn’t enough we will still start insulin ... Another issue is why would you offer everybody medical treatment when pregnancy outcomes can be met with lifestyle alone?”

Then again, she added, “of course metformin is easier than an injection. Treatment satisfaction is improved, and the cost is less.”
 

Primary outcome didn’t differ, but study findings point toward metformin benefit

The double-blind, placebo-controlled trial was conducted at two sites in Ireland, with 510 individuals (535 gestational diabetes pregnancies) enrolled between June 2017 and September 2022. In addition to usual care, they were randomly assigned 1:1 to either placebo or metformin (maximum 2,500 mg) at the time of gestational diabetes diagnosis and continued until delivery.

The primary outcome, a composite of insulin initiation or a fasting glucose ≥ 5.1 mmol/L at gestation weeks 32 or 38, did not differ significantly between the two groups, with risk ratio 0.89 (P = 0.13).

Insulin initiation occurred in 38.4% of the metformin and 51.1% of the placebo groups (relative risk, 0.75, P = .004). The amount of insulin required at the last assessment prior to delivery did not differ between the two groups (P = .17).

Mean fasting glucose was significantly lower with metformin vs. placebo at gestational week 32 (4.9 vs. 5.0 mmol/L; P = .03) and at gestational week 38 (4.5 vs 4.7 mmol/L; P < .001).

On average, those in the metformin group gained less weight between randomization and delivery (0.8 kg vs. 2.0 kg; P = .003).

Gestational week at delivery didn’t differ between the groups, both 39.1 weeks, nor did preterm births prior to 37 weeks’ gestation (9.2% metformin vs. 6.5% placebo; P = .33) or any other pregnancy-related complications.

More participants in the metformin group said that they would choose the drug compared with placebo (76.2% vs. 67.1%, P = .04).

Mean birth weight was lower in the metformin group compared with placebo, 3,393 g vs. 3,506 g (P = .005), with fewer weighing > 4,000 g (7.6% vs. 14.8%; P = .02) or being large for gestational age, i.e., above the 90th percentile (6.5% vs. 14.9%; P = .003).

Proportions of offspring that were SGA (less than 10th percentile) were 5.7% in the metformin group vs. 2.7% with placebo (P = .13).

There were no other significant differences in neonatal variables.

Dr. Dunne told this news organization that her group has recently received funding for long-term follow-up of the SGA offspring. “As other papers have pointed out, if there’s any hint of SGA that’s really important to follow up. So we’re now beginning our longitudinal follow up of the mother and infants to see if the small number that were SGA will in fact turn out to have an increase in body mass index and weight in their childhood and adolescent years.”

The trial was funded by the Health Review Board (HRB) of Ireland, coordinated by the HRB-Clinical Research Facility Galway, and sponsored by the University of Galway, Ireland. Metformin and matched placebo were provided by Merck Healthcare KGaA, Darmstadt, Germany (operating as EMD Serono in the United States), and blood glucose monitoring strips were provided by Ascensia.

Dr. Dunne reported nonfinancial support from Merck and matched placebo and nonfinancial support from Ascensia during the conduct of the study. Dr. Benhalima receives research funds from Flemish Research Fund, study medication from Novo Nordisk, and devices and unrestricted grants from Medtronic and Dexcom.

A version of this article appeared on Medscape.com.

HAMBURG – Initiating metformin treatment at gestational diabetes diagnosis was associated with improved glycemic control and reduced gestational weight gain, according to the results of a randomized, placebo-controlled trial.

Overall, the trial’s primary outcome, a composite of insulin initiation or a fasting glucose level ≥ 5.1 mmol/L (92 mg/dL) at gestation weeks 32 or 38, did not differ between women with gestational diabetes randomly assigned to either placebo or metformin. However, women taking metformin were significantly less likely to require insulin and had significantly lower fasting blood glucose levels at weeks 32 and 38.

“With a composite outcome it’s more difficult to find a positive result ... So, although the primary composite outcome was not positive, the components of the primary outcome that are clinically meaningful were positive,” lead study author Fidelma Dunne, PhD, professor and endocrine consultant at the University of Galway, Ireland, said in an interview.

There were no differences in maternal or neonatal morbidities, but there was a nonsignificant increase in small for gestational age (SGA), a finding that has been seen in some but not all previous studies of metformin use in gestational diabetes.

Dr. Dunne presented the findings on Oct. 3 at the annual meeting of the European Association for the Study of Diabetes. The results were simultaneously published in JAMA.

Current recommendations from the United Kingdom’s National Institute for Health and Care Excellence say metformin is a suitable first-line therapy for gestational diabetes. However, both the American Diabetes Association and the Society of Maternal-Fetal Medicine do not, particularly for pregnancies with hypertension or preeclampsia or in those who are at risk for intrauterine growth restriction.

“Gestational diabetes is now reaching epidemic proportions. And of course, the vast majority of these women are in low- and middle-income countries where insulin might not be available, or the storage may not allow it to be used effectively. If you have a medication that in the majority of women is safe and effective it may actually help a lot of women in [those regions],” Dr. Dunne said.

Moreover, she noted, “women with gestational diabetes are testing their sugar with finger pricks four to seven times per day and we ask them to take insulin one to four times a day. So if you can relieve any of that pain related to treatment of their condition than that is a benefit for the women as well.”

Asked to comment, Katrien Benhalima, MD, PhD, of University Hospital Gasthuisberg, KU Leuven, Belgium, said, “I think it’s an interesting study because they investigated something novel, to initiate immediately metformin or placebo. Normally what we do with gestational diabetes is once we get the diagnosis, we treat them with lifestyle, and if that’s insufficient then we start with medical therapy. So this is a novel approach.”

She also agreed with Dr. Dunne that the lack of significance for the primary outcome “isn’t an issue of power but it is a composite outcome. If you look at the individual outcomes, as can be expected, the women taking metformin had less need for insulin treatment.”

But, Dr. Benhalima said, the study still leaves open the SGA issue. “It wasn’t significant, but it’s still something we are worried about in the sense that we feel we need more data, especially in the long-term for the offspring health ... You really need to follow them for 10 years or longer to see an effect.”

So for now, Dr. Benhalima said that she wouldn’t use metformin as a first-line treatment for gestational diabetes. “Normally if lifestyle isn’t enough we will still start insulin ... Another issue is why would you offer everybody medical treatment when pregnancy outcomes can be met with lifestyle alone?”

Then again, she added, “of course metformin is easier than an injection. Treatment satisfaction is improved, and the cost is less.”
 

Primary outcome didn’t differ, but study findings point toward metformin benefit

The double-blind, placebo-controlled trial was conducted at two sites in Ireland, with 510 individuals (535 gestational diabetes pregnancies) enrolled between June 2017 and September 2022. In addition to usual care, they were randomly assigned 1:1 to either placebo or metformin (maximum 2,500 mg) at the time of gestational diabetes diagnosis and continued until delivery.

The primary outcome, a composite of insulin initiation or a fasting glucose ≥ 5.1 mmol/L at gestation weeks 32 or 38, did not differ significantly between the two groups, with risk ratio 0.89 (P = 0.13).

Insulin initiation occurred in 38.4% of the metformin and 51.1% of the placebo groups (relative risk, 0.75, P = .004). The amount of insulin required at the last assessment prior to delivery did not differ between the two groups (P = .17).

Mean fasting glucose was significantly lower with metformin vs. placebo at gestational week 32 (4.9 vs. 5.0 mmol/L; P = .03) and at gestational week 38 (4.5 vs 4.7 mmol/L; P < .001).

On average, those in the metformin group gained less weight between randomization and delivery (0.8 kg vs. 2.0 kg; P = .003).

Gestational week at delivery didn’t differ between the groups, both 39.1 weeks, nor did preterm births prior to 37 weeks’ gestation (9.2% metformin vs. 6.5% placebo; P = .33) or any other pregnancy-related complications.

More participants in the metformin group said that they would choose the drug compared with placebo (76.2% vs. 67.1%, P = .04).

Mean birth weight was lower in the metformin group compared with placebo, 3,393 g vs. 3,506 g (P = .005), with fewer weighing > 4,000 g (7.6% vs. 14.8%; P = .02) or being large for gestational age, i.e., above the 90th percentile (6.5% vs. 14.9%; P = .003).

Proportions of offspring that were SGA (less than 10th percentile) were 5.7% in the metformin group vs. 2.7% with placebo (P = .13).

There were no other significant differences in neonatal variables.

Dr. Dunne told this news organization that her group has recently received funding for long-term follow-up of the SGA offspring. “As other papers have pointed out, if there’s any hint of SGA that’s really important to follow up. So we’re now beginning our longitudinal follow up of the mother and infants to see if the small number that were SGA will in fact turn out to have an increase in body mass index and weight in their childhood and adolescent years.”

The trial was funded by the Health Review Board (HRB) of Ireland, coordinated by the HRB-Clinical Research Facility Galway, and sponsored by the University of Galway, Ireland. Metformin and matched placebo were provided by Merck Healthcare KGaA, Darmstadt, Germany (operating as EMD Serono in the United States), and blood glucose monitoring strips were provided by Ascensia.

Dr. Dunne reported nonfinancial support from Merck and matched placebo and nonfinancial support from Ascensia during the conduct of the study. Dr. Benhalima receives research funds from Flemish Research Fund, study medication from Novo Nordisk, and devices and unrestricted grants from Medtronic and Dexcom.

A version of this article appeared on Medscape.com.

HAMBURG – Initiating metformin treatment at gestational diabetes diagnosis was associated with improved glycemic control and reduced gestational weight gain, according to the results of a randomized, placebo-controlled trial.

Overall, the trial’s primary outcome, a composite of insulin initiation or a fasting glucose level ≥ 5.1 mmol/L (92 mg/dL) at gestation weeks 32 or 38, did not differ between women with gestational diabetes randomly assigned to either placebo or metformin. However, women taking metformin were significantly less likely to require insulin and had significantly lower fasting blood glucose levels at weeks 32 and 38.

“With a composite outcome it’s more difficult to find a positive result ... So, although the primary composite outcome was not positive, the components of the primary outcome that are clinically meaningful were positive,” lead study author Fidelma Dunne, PhD, professor and endocrine consultant at the University of Galway, Ireland, said in an interview.

There were no differences in maternal or neonatal morbidities, but there was a nonsignificant increase in small for gestational age (SGA), a finding that has been seen in some but not all previous studies of metformin use in gestational diabetes.

Dr. Dunne presented the findings on Oct. 3 at the annual meeting of the European Association for the Study of Diabetes. The results were simultaneously published in JAMA.

Current recommendations from the United Kingdom’s National Institute for Health and Care Excellence say metformin is a suitable first-line therapy for gestational diabetes. However, both the American Diabetes Association and the Society of Maternal-Fetal Medicine do not, particularly for pregnancies with hypertension or preeclampsia or in those who are at risk for intrauterine growth restriction.

“Gestational diabetes is now reaching epidemic proportions. And of course, the vast majority of these women are in low- and middle-income countries where insulin might not be available, or the storage may not allow it to be used effectively. If you have a medication that in the majority of women is safe and effective it may actually help a lot of women in [those regions],” Dr. Dunne said.

Moreover, she noted, “women with gestational diabetes are testing their sugar with finger pricks four to seven times per day and we ask them to take insulin one to four times a day. So if you can relieve any of that pain related to treatment of their condition than that is a benefit for the women as well.”

Asked to comment, Katrien Benhalima, MD, PhD, of University Hospital Gasthuisberg, KU Leuven, Belgium, said, “I think it’s an interesting study because they investigated something novel, to initiate immediately metformin or placebo. Normally what we do with gestational diabetes is once we get the diagnosis, we treat them with lifestyle, and if that’s insufficient then we start with medical therapy. So this is a novel approach.”

She also agreed with Dr. Dunne that the lack of significance for the primary outcome “isn’t an issue of power but it is a composite outcome. If you look at the individual outcomes, as can be expected, the women taking metformin had less need for insulin treatment.”

But, Dr. Benhalima said, the study still leaves open the SGA issue. “It wasn’t significant, but it’s still something we are worried about in the sense that we feel we need more data, especially in the long-term for the offspring health ... You really need to follow them for 10 years or longer to see an effect.”

So for now, Dr. Benhalima said that she wouldn’t use metformin as a first-line treatment for gestational diabetes. “Normally if lifestyle isn’t enough we will still start insulin ... Another issue is why would you offer everybody medical treatment when pregnancy outcomes can be met with lifestyle alone?”

Then again, she added, “of course metformin is easier than an injection. Treatment satisfaction is improved, and the cost is less.”
 

Primary outcome didn’t differ, but study findings point toward metformin benefit

The double-blind, placebo-controlled trial was conducted at two sites in Ireland, with 510 individuals (535 gestational diabetes pregnancies) enrolled between June 2017 and September 2022. In addition to usual care, they were randomly assigned 1:1 to either placebo or metformin (maximum 2,500 mg) at the time of gestational diabetes diagnosis and continued until delivery.

The primary outcome, a composite of insulin initiation or a fasting glucose ≥ 5.1 mmol/L at gestation weeks 32 or 38, did not differ significantly between the two groups, with risk ratio 0.89 (P = 0.13).

Insulin initiation occurred in 38.4% of the metformin and 51.1% of the placebo groups (relative risk, 0.75, P = .004). The amount of insulin required at the last assessment prior to delivery did not differ between the two groups (P = .17).

Mean fasting glucose was significantly lower with metformin vs. placebo at gestational week 32 (4.9 vs. 5.0 mmol/L; P = .03) and at gestational week 38 (4.5 vs 4.7 mmol/L; P < .001).

On average, those in the metformin group gained less weight between randomization and delivery (0.8 kg vs. 2.0 kg; P = .003).

Gestational week at delivery didn’t differ between the groups, both 39.1 weeks, nor did preterm births prior to 37 weeks’ gestation (9.2% metformin vs. 6.5% placebo; P = .33) or any other pregnancy-related complications.

More participants in the metformin group said that they would choose the drug compared with placebo (76.2% vs. 67.1%, P = .04).

Mean birth weight was lower in the metformin group compared with placebo, 3,393 g vs. 3,506 g (P = .005), with fewer weighing > 4,000 g (7.6% vs. 14.8%; P = .02) or being large for gestational age, i.e., above the 90th percentile (6.5% vs. 14.9%; P = .003).

Proportions of offspring that were SGA (less than 10th percentile) were 5.7% in the metformin group vs. 2.7% with placebo (P = .13).

There were no other significant differences in neonatal variables.

Dr. Dunne told this news organization that her group has recently received funding for long-term follow-up of the SGA offspring. “As other papers have pointed out, if there’s any hint of SGA that’s really important to follow up. So we’re now beginning our longitudinal follow up of the mother and infants to see if the small number that were SGA will in fact turn out to have an increase in body mass index and weight in their childhood and adolescent years.”

The trial was funded by the Health Review Board (HRB) of Ireland, coordinated by the HRB-Clinical Research Facility Galway, and sponsored by the University of Galway, Ireland. Metformin and matched placebo were provided by Merck Healthcare KGaA, Darmstadt, Germany (operating as EMD Serono in the United States), and blood glucose monitoring strips were provided by Ascensia.

Dr. Dunne reported nonfinancial support from Merck and matched placebo and nonfinancial support from Ascensia during the conduct of the study. Dr. Benhalima receives research funds from Flemish Research Fund, study medication from Novo Nordisk, and devices and unrestricted grants from Medtronic and Dexcom.

A version of this article appeared on Medscape.com.

TOPLINE:

Women who use cocaine, cannabis, or other substances during pregnancy have increased risks of acute cardiovascular (CV) events while in the hospital for delivery, including more than double the risk of maternal mortality, a new study shows.

METHODOLOGY:

• Using the National Inpatient Sample database to identify hospital deliveries between 2004 and 2018 and diagnostic codes to identify maternal substance use, researchers compared 955,531 pregnancies with accompanying substance use – the most common substances being cannabis and opioids, followed by stimulants – to over 60 million pregnancies in which there was no substance use.
• The primary outcome was any CV event, including acute myocardial infarction, stroke, arrhythmia, endocarditis, any acute cardiomyopathy or heart failure, or cardiac arrest; other outcomes included maternal mortality and major adverse cardiac events (MACE).

TAKEAWAY:

• Deliveries complicated by substance use increased from 1,126 per 100,000 deliveries in 2004 to 1,547 per 100,000 in 2018, peaking at 2,187 per 100,000 in 2014.
• After the researchers controlled for patient demographics and CVD risk factors, results showed that pregnant women who used any substance (cannabis, opioids, methamphetamine, alcohol, tobacco, or cocaine) were more likely to experience a CVD event (adjusted odds ratio [aOR], 1.61; 95% confidence interval [CI], 1.53-1.70; P < .001), MACE (aOR, 1.53; 95% CI, 1.46-1.61; P < .001), or maternal mortality (aOR, 2.65; 95% CI, 2.15-3.25; P < .001) during hospitalization for delivery.
• Those using amphetamine/methamphetamine had ninefold higher odds of cardiomyopathy or heart failure and more than sevenfold higher odds of cardiac arrest.

IN PRACTICE:

“For the wellbeing of pregnant women and their children, substance use needs to be considered an independent risk factor for CV events in pregnancy,” the authors wrote. They called for prenatal assessments by a multidisciplinary cardio-obstetrics team to try to decrease cardiac complications.

In an accompanying editorial by Abha Khandelwal, MD, department of medicine, Stanford (Calif.) University, and others, the authors said the findings “highlight the critical support required during pregnancy and postpartum” for substance users, which should include comprehensive medical care and social services as well as access to addiction medicine and treatment of co-occurring mental health disorders.

SOURCE:

The study was carried out by Kari Evans, MD, division of maternal fetal medicine, department of obstetrics and gynecology, University of Arizona, Phoenix. It was published online in the Journal of the American College of Cardiology: Advances.

LIMITATIONS:

Use of administrative databases may have resulted in underreporting of diagnoses. The researchers could not assess the association of dose, duration, method, or timing of use for any substance with CV events. They also could not examine the effect of vaping on maternal CV events or differentiate hospitalizations for delivery that were complicated by CV events from hospitalizations for CV events that prompted delivery. The data did not reflect the postpartum period, during which a high rate of adverse CV events occurs.

DISCLOSURES:

The authors and editorial writers have no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Women who use cocaine, cannabis, or other substances during pregnancy have increased risks of acute cardiovascular (CV) events while in the hospital for delivery, including more than double the risk of maternal mortality, a new study shows.

METHODOLOGY:

• Using the National Inpatient Sample database to identify hospital deliveries between 2004 and 2018 and diagnostic codes to identify maternal substance use, researchers compared 955,531 pregnancies with accompanying substance use – the most common substances being cannabis and opioids, followed by stimulants – to over 60 million pregnancies in which there was no substance use.
• The primary outcome was any CV event, including acute myocardial infarction, stroke, arrhythmia, endocarditis, any acute cardiomyopathy or heart failure, or cardiac arrest; other outcomes included maternal mortality and major adverse cardiac events (MACE).

TAKEAWAY:

• Deliveries complicated by substance use increased from 1,126 per 100,000 deliveries in 2004 to 1,547 per 100,000 in 2018, peaking at 2,187 per 100,000 in 2014.
• After the researchers controlled for patient demographics and CVD risk factors, results showed that pregnant women who used any substance (cannabis, opioids, methamphetamine, alcohol, tobacco, or cocaine) were more likely to experience a CVD event (adjusted odds ratio [aOR], 1.61; 95% confidence interval [CI], 1.53-1.70; P < .001), MACE (aOR, 1.53; 95% CI, 1.46-1.61; P < .001), or maternal mortality (aOR, 2.65; 95% CI, 2.15-3.25; P < .001) during hospitalization for delivery.
• Those using amphetamine/methamphetamine had ninefold higher odds of cardiomyopathy or heart failure and more than sevenfold higher odds of cardiac arrest.

IN PRACTICE:

“For the wellbeing of pregnant women and their children, substance use needs to be considered an independent risk factor for CV events in pregnancy,” the authors wrote. They called for prenatal assessments by a multidisciplinary cardio-obstetrics team to try to decrease cardiac complications.

In an accompanying editorial by Abha Khandelwal, MD, department of medicine, Stanford (Calif.) University, and others, the authors said the findings “highlight the critical support required during pregnancy and postpartum” for substance users, which should include comprehensive medical care and social services as well as access to addiction medicine and treatment of co-occurring mental health disorders.

SOURCE:

The study was carried out by Kari Evans, MD, division of maternal fetal medicine, department of obstetrics and gynecology, University of Arizona, Phoenix. It was published online in the Journal of the American College of Cardiology: Advances.

LIMITATIONS:

Use of administrative databases may have resulted in underreporting of diagnoses. The researchers could not assess the association of dose, duration, method, or timing of use for any substance with CV events. They also could not examine the effect of vaping on maternal CV events or differentiate hospitalizations for delivery that were complicated by CV events from hospitalizations for CV events that prompted delivery. The data did not reflect the postpartum period, during which a high rate of adverse CV events occurs.

DISCLOSURES:

The authors and editorial writers have no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Women who use cocaine, cannabis, or other substances during pregnancy have increased risks of acute cardiovascular (CV) events while in the hospital for delivery, including more than double the risk of maternal mortality, a new study shows.

METHODOLOGY:

• Using the National Inpatient Sample database to identify hospital deliveries between 2004 and 2018 and diagnostic codes to identify maternal substance use, researchers compared 955,531 pregnancies with accompanying substance use – the most common substances being cannabis and opioids, followed by stimulants – to over 60 million pregnancies in which there was no substance use.
• The primary outcome was any CV event, including acute myocardial infarction, stroke, arrhythmia, endocarditis, any acute cardiomyopathy or heart failure, or cardiac arrest; other outcomes included maternal mortality and major adverse cardiac events (MACE).

TAKEAWAY:

• Deliveries complicated by substance use increased from 1,126 per 100,000 deliveries in 2004 to 1,547 per 100,000 in 2018, peaking at 2,187 per 100,000 in 2014.
• After the researchers controlled for patient demographics and CVD risk factors, results showed that pregnant women who used any substance (cannabis, opioids, methamphetamine, alcohol, tobacco, or cocaine) were more likely to experience a CVD event (adjusted odds ratio [aOR], 1.61; 95% confidence interval [CI], 1.53-1.70; P < .001), MACE (aOR, 1.53; 95% CI, 1.46-1.61; P < .001), or maternal mortality (aOR, 2.65; 95% CI, 2.15-3.25; P < .001) during hospitalization for delivery.
• Those using amphetamine/methamphetamine had ninefold higher odds of cardiomyopathy or heart failure and more than sevenfold higher odds of cardiac arrest.

IN PRACTICE:

“For the wellbeing of pregnant women and their children, substance use needs to be considered an independent risk factor for CV events in pregnancy,” the authors wrote. They called for prenatal assessments by a multidisciplinary cardio-obstetrics team to try to decrease cardiac complications.

In an accompanying editorial by Abha Khandelwal, MD, department of medicine, Stanford (Calif.) University, and others, the authors said the findings “highlight the critical support required during pregnancy and postpartum” for substance users, which should include comprehensive medical care and social services as well as access to addiction medicine and treatment of co-occurring mental health disorders.

SOURCE:

The study was carried out by Kari Evans, MD, division of maternal fetal medicine, department of obstetrics and gynecology, University of Arizona, Phoenix. It was published online in the Journal of the American College of Cardiology: Advances.

LIMITATIONS:

Use of administrative databases may have resulted in underreporting of diagnoses. The researchers could not assess the association of dose, duration, method, or timing of use for any substance with CV events. They also could not examine the effect of vaping on maternal CV events or differentiate hospitalizations for delivery that were complicated by CV events from hospitalizations for CV events that prompted delivery. The data did not reflect the postpartum period, during which a high rate of adverse CV events occurs.

DISCLOSURES:

The authors and editorial writers have no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Cerebral palsy (CP) affects 1-4 per 1,000 live births in the United States. A new cohort study found children conceived during the winter and spring months appear to have a slightly higher risk for developing CP than those conceived during the summer. Fall months carried about the same or only slightly higher risk of CP than summer months.

METHODOLOGY:

• Researchers examined data from nearly 4.5 million live births registered in California between 2007 and 2015, exploring if the season of conception could serve as an indicator of exposure to environmental risk factors.
• For instance, infants conceived in winter months may have higher exposure to viruses like influenza. In California, agricultural pesticides are most often applied in summer months, when pregnant people would be in their first or second trimester and receive their most exposure to the fine particulates, the authors hypothesize.
• Almost 4,700 babies in the study population were diagnosed with CP. Researchers also considered the role of preterm birth as a potential mediating factor, and adjusted for sociodemographic characteristics such as maternal age, race, education, smoking during pregnancy, and body mass index.

TAKEAWAY:

• The study found that children conceived in winter and spring had a 9% (95% confidence interval, 1.01-1.19) to 10% (95% CI, 1.02-1.20) higher risk of developing CP than those conceived in the summer.
• Children conceived in January, February, or May carried a 15% higher risk, compared with babies conceived in July.
• The risk was more pronounced among mothers with low education levels or living in neighborhoods where residents have high rates of unemployment, single-parent households, multiunit households, and lower rates of high school graduates.

IN PRACTICE:

The researchers noted that possible explanations for the seasonal link to CP risk may include the prevalence of maternal infections during pregnancy, variations in exposure to pesticides, and seasonal patterns for air pollution. “Investigating seasonal variations in disease occurrence can provide clues about etiologically relevant factors.”

SOURCE:

Lead author Haoran Zhou, MPH, Yale University, New Haven, Conn., and colleagues published their findings online in JAMA Network Open. The study was partly supported by a grant from the American Academy for Cerebral Palsy and Developmental Medicine.

LIMITATIONS:

The study may not have fully captured all children with CP in the cohort due to the possibility of misclassification. The findings may not be generalizable beyond California. The overall increased risk associated with the season of conception was relatively small, suggesting family planning strategies may not need to change based on these findings. The exact mechanisms involving potential environmental factors need further investigation.

DISCLOSURES:

The authors reported no relevant financial relationships.

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

TOPLINE:

Cerebral palsy (CP) affects 1-4 per 1,000 live births in the United States. A new cohort study found children conceived during the winter and spring months appear to have a slightly higher risk for developing CP than those conceived during the summer. Fall months carried about the same or only slightly higher risk of CP than summer months.

METHODOLOGY:

• Researchers examined data from nearly 4.5 million live births registered in California between 2007 and 2015, exploring if the season of conception could serve as an indicator of exposure to environmental risk factors.
• For instance, infants conceived in winter months may have higher exposure to viruses like influenza. In California, agricultural pesticides are most often applied in summer months, when pregnant people would be in their first or second trimester and receive their most exposure to the fine particulates, the authors hypothesize.
• Almost 4,700 babies in the study population were diagnosed with CP. Researchers also considered the role of preterm birth as a potential mediating factor, and adjusted for sociodemographic characteristics such as maternal age, race, education, smoking during pregnancy, and body mass index.

TAKEAWAY:

• The study found that children conceived in winter and spring had a 9% (95% confidence interval, 1.01-1.19) to 10% (95% CI, 1.02-1.20) higher risk of developing CP than those conceived in the summer.
• Children conceived in January, February, or May carried a 15% higher risk, compared with babies conceived in July.
• The risk was more pronounced among mothers with low education levels or living in neighborhoods where residents have high rates of unemployment, single-parent households, multiunit households, and lower rates of high school graduates.

IN PRACTICE:

The researchers noted that possible explanations for the seasonal link to CP risk may include the prevalence of maternal infections during pregnancy, variations in exposure to pesticides, and seasonal patterns for air pollution. “Investigating seasonal variations in disease occurrence can provide clues about etiologically relevant factors.”

SOURCE:

Lead author Haoran Zhou, MPH, Yale University, New Haven, Conn., and colleagues published their findings online in JAMA Network Open. The study was partly supported by a grant from the American Academy for Cerebral Palsy and Developmental Medicine.

LIMITATIONS:

The study may not have fully captured all children with CP in the cohort due to the possibility of misclassification. The findings may not be generalizable beyond California. The overall increased risk associated with the season of conception was relatively small, suggesting family planning strategies may not need to change based on these findings. The exact mechanisms involving potential environmental factors need further investigation.

DISCLOSURES:

The authors reported no relevant financial relationships.

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

TOPLINE:

Cerebral palsy (CP) affects 1-4 per 1,000 live births in the United States. A new cohort study found children conceived during the winter and spring months appear to have a slightly higher risk for developing CP than those conceived during the summer. Fall months carried about the same or only slightly higher risk of CP than summer months.

METHODOLOGY:

• Researchers examined data from nearly 4.5 million live births registered in California between 2007 and 2015, exploring if the season of conception could serve as an indicator of exposure to environmental risk factors.
• For instance, infants conceived in winter months may have higher exposure to viruses like influenza. In California, agricultural pesticides are most often applied in summer months, when pregnant people would be in their first or second trimester and receive their most exposure to the fine particulates, the authors hypothesize.
• Almost 4,700 babies in the study population were diagnosed with CP. Researchers also considered the role of preterm birth as a potential mediating factor, and adjusted for sociodemographic characteristics such as maternal age, race, education, smoking during pregnancy, and body mass index.

TAKEAWAY:

• The study found that children conceived in winter and spring had a 9% (95% confidence interval, 1.01-1.19) to 10% (95% CI, 1.02-1.20) higher risk of developing CP than those conceived in the summer.
• Children conceived in January, February, or May carried a 15% higher risk, compared with babies conceived in July.
• The risk was more pronounced among mothers with low education levels or living in neighborhoods where residents have high rates of unemployment, single-parent households, multiunit households, and lower rates of high school graduates.

IN PRACTICE:

The researchers noted that possible explanations for the seasonal link to CP risk may include the prevalence of maternal infections during pregnancy, variations in exposure to pesticides, and seasonal patterns for air pollution. “Investigating seasonal variations in disease occurrence can provide clues about etiologically relevant factors.”

SOURCE:

Lead author Haoran Zhou, MPH, Yale University, New Haven, Conn., and colleagues published their findings online in JAMA Network Open. The study was partly supported by a grant from the American Academy for Cerebral Palsy and Developmental Medicine.

LIMITATIONS:

The study may not have fully captured all children with CP in the cohort due to the possibility of misclassification. The findings may not be generalizable beyond California. The overall increased risk associated with the season of conception was relatively small, suggesting family planning strategies may not need to change based on these findings. The exact mechanisms involving potential environmental factors need further investigation.

DISCLOSURES:

The authors reported no relevant financial relationships.

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

All pregnant women should undergo screening for hypertensive disorders, with evidence-based management for those screening positive, according to a new recommendation from the U.S. Preventive Services Task Force.

Hypertensive disorders of pregnancy in the United States increased from approximately 500 cases per 10,000 deliveries to 1,021 cases per 10,000 deliveries from 1993 to 2016-2017, and remain a leading cause of maternal morbidity and mortality, wrote Task Force Chair Michael J. Barry, MD, of Massachusetts General Hospital, Boston, and colleagues in the final recommendation statement published in JAMA.

The USPSTF commissioned a systematic review to assess the risks and benefits of hypertensive screening for asymptomatic pregnant women. The resulting grade B recommendation indicates that screening for hypertensive disorders in pregnancy using blood pressure measurements yields a substantial net benefit.

The recommendation applies to “all pregnant women and pregnant persons of all genders without a known diagnosis of a hypertensive disorder of pregnancy or chronic hypertension,” the authors said.

The recommendation calls for the use of blood pressure measurements to evaluate hypertensive disorders, with measurements taken at each prenatal visit. A positive result for new-onset hypertension was defined as systolic blood pressure of 140 mm Hg or diastolic blood pressure 90 mm Hg in the absence of chronic hypertension, based on two measurements at least 4 hours apart. Regular review of blood pressure can help identify and manage potentially fatal conditions.

However, screening alone is insufficient to improve inequities in health outcomes associated with hypertensive disorders of pregnancy, the authors emphasized. Data from previous studies have shown that Black patients are at increased risk for hypertensive disorders of pregnancy and severe complications, and that Black and Hispanic patients have twice the risk of stroke with hypertensive disorders of pregnancy as White patients.

In the evidence report that supported the recommendation, Jillian T. Henderson, PhD, of Kaiser Permanente in Portland, Ore., and colleagues reviewed six studies including 10,165 individuals. The studies (five clinical trials and one nonrandomized study) compared changes in prenatal screening with usual care.

Overall, the review yielded no evidence that any other screening strategies were more useful than routine blood pressure measurement to identify hypertensive disorders of pregnancy in asymptomatic women.

The findings cited to support the recommendation were limited by several factors, including the lack of power to detect pregnancy health outcomes and potential harms of different screening programs, and the lack of power to evaluate outcomes for American Indian, Alaska Native, or Black individuals, who have disproportionately high rates of hypertensive disorders of pregnancy, the authors said.

More research is needed to identify which screening approaches may lead to improved disease detection and better health outcomes, but the results of the review support the grade B recommendation for hypertensive screening of all pregnant women, they concluded.
 

Early identification makes a difference

The new recommendation is important because it can help all moms and babies to be healthier, said Wanda Nicholson, MD, vice chair of the task force, in an interview.

“We are recommending that all pregnant persons have a blood pressure check at every visit throughout pregnancy,” said Dr. Nicholson, an ob.gyn. by training who also serves as professor of prevention and community health at George Washington University in Washington. “We know that there is a maternal health crisis in this country, and we know that hypertensive disorders of pregnancy are one of the key factors related to that,” she said.

Unfortunately, barriers to routine screening for hypertensive disorders of pregnancy persist, said Dr. Nicholson. The incidence of hypertensive disorders of pregnancy is higher in many of the same populations who also have challenges in accessing regular prenatal care, notably those who are Black, Native American, or Alaska Native, she noted.

The new recommendation also serves as an opportunity to call attention to the health care disparities for these populations, not only during pregnancy, but in general, she emphasized.

In clinical practice, the definition of hypertensive disorders of pregnancy involves three different diagnoses – gestational hypertension, preeclampsia, and eclampsia – that can be seen as points on a continuum, said Dr. Nicholson. The sooner patients are identified with hypertensive disorders of pregnancy, the sooner intervention and treatment can begin, she said. To that end, she added the clinical pearl of using a properly sized blood pressure cuff to obtain an accurate reading and avoid missed diagnoses.

The task force also outlined several key areas for additional research, said Dr. Nicholson. First, more research is needed on alternative screening strategies, such as at-home blood pressure monitoring for patients, as well as teleheath visits. Second, more studies are needed to address the disparities in prenatal care and include more diverse populations in clinical research. Third, future studies need to consider social determinants of health and other factors that might impact maternal health outcomes. “These steps will help achieve the larger goal of healthier mothers and babies,” Dr. Nicholson said.
 

Back to basics to improve women’s health

Some clinicians may be disappointed by the Evidence Report’s primary finding that no alternative screening strategies outperformed routine blood pressure measurement, wrote Anne E. Denoble, MD, and Christian M. Pettker, MD, both of Yale University, New Haven, Conn., in an accompanying editorial.

While potentially frustrating at first glance, the findings of the Evidence Report provide a foundation for improvement and reassurance that the best existing screening methods are basic and fundamental: regular prenatal visits with routine, in-office blood pressure measurements, and urine protein screening when clinically indicated, they said.

However, the USPSTF review also noted persistent research gaps that must be addressed to significantly improve maternal health outcomes, they said. Notable gaps include the disproportionately low numbers of Black patients in current studies, and the need for studies of alternate models of prenatal care, including the use of remote blood pressure monitoring, and the use of biomarkers to screen for and predict hypertensive disorders of pregnancy.

The most striking limitation may be the focus on prenatal care, with lack of attention to postpartum mortality risk, given that more than half of pregnancy-related deaths occur postpartum, the authors noted.

Although current screening tools may be used in practice “with skill and might,” more effort at multiple levels is needed to address the larger maternal health crisis in the United States, they said.
 

Expand screening, engage primary care for long-term benefits

Screening for hypertensive disorders of pregnancy “can and should be within the purview of internists,” wrote Srilakshmi Mitta, MD; Cary P. Gross, MD; Melissa A. Simon, MD, of Brown University, Yale University, and Northwestern University, respectively, in a separate editorial. The recommendation to extend screening beyond preeclampsia is timely, given the consistent increase in all hypertensive disorders of pregnancy since 1990, the authors said.

Pregnancy is not the only time for screening, counseling, and management of hypertensive disorders, they emphasized. “All persons who have reproductive capacity and/or are planning pregnancy, along with those who are post partum, should be screened for hypertensive disorders, aligning the USPSTF with guidelines from the American College of Obstetricians and Gynecologists, the American College of Cardiology, and the American Heart Association,” they said, and all clinicians should be on board to identify and treat hypertensive disorders of pregnancy, especially in underserved racial and ethnic minorities for whom primary care may be their only source of health care.

“Pregnancy is a window of opportunity to influence current and future life course, not just of the individual, but also of the fetus(es),other children, and family,” and timely intervention has the potential for great public health impact, they said.

Dr. Denoble disclosed grants from the HealthPartners Institute for Education and Research and from the Patient-Centered Outcomes Research Institute. Dr. Simon serves on the Advisory Committee for Research on Women’s Health for the National Institutes of Health Office of Research on Women’s Health and serves as a member of the Centers for Disease Control and Prevention Community Preventive Services Task Force; she was a member of the USPSTF from 2017 to 2020. Dr. Gross disclosed grants from Johnson and Johnson and the National Comprehensive Cancer Network (through a grant to the NCCN from AstraZeneca) and personal fees from Genentech.

All pregnant women should undergo screening for hypertensive disorders, with evidence-based management for those screening positive, according to a new recommendation from the U.S. Preventive Services Task Force.

Hypertensive disorders of pregnancy in the United States increased from approximately 500 cases per 10,000 deliveries to 1,021 cases per 10,000 deliveries from 1993 to 2016-2017, and remain a leading cause of maternal morbidity and mortality, wrote Task Force Chair Michael J. Barry, MD, of Massachusetts General Hospital, Boston, and colleagues in the final recommendation statement published in JAMA.

The USPSTF commissioned a systematic review to assess the risks and benefits of hypertensive screening for asymptomatic pregnant women. The resulting grade B recommendation indicates that screening for hypertensive disorders in pregnancy using blood pressure measurements yields a substantial net benefit.

The recommendation applies to “all pregnant women and pregnant persons of all genders without a known diagnosis of a hypertensive disorder of pregnancy or chronic hypertension,” the authors said.

The recommendation calls for the use of blood pressure measurements to evaluate hypertensive disorders, with measurements taken at each prenatal visit. A positive result for new-onset hypertension was defined as systolic blood pressure of 140 mm Hg or diastolic blood pressure 90 mm Hg in the absence of chronic hypertension, based on two measurements at least 4 hours apart. Regular review of blood pressure can help identify and manage potentially fatal conditions.

However, screening alone is insufficient to improve inequities in health outcomes associated with hypertensive disorders of pregnancy, the authors emphasized. Data from previous studies have shown that Black patients are at increased risk for hypertensive disorders of pregnancy and severe complications, and that Black and Hispanic patients have twice the risk of stroke with hypertensive disorders of pregnancy as White patients.

In the evidence report that supported the recommendation, Jillian T. Henderson, PhD, of Kaiser Permanente in Portland, Ore., and colleagues reviewed six studies including 10,165 individuals. The studies (five clinical trials and one nonrandomized study) compared changes in prenatal screening with usual care.

Overall, the review yielded no evidence that any other screening strategies were more useful than routine blood pressure measurement to identify hypertensive disorders of pregnancy in asymptomatic women.

The findings cited to support the recommendation were limited by several factors, including the lack of power to detect pregnancy health outcomes and potential harms of different screening programs, and the lack of power to evaluate outcomes for American Indian, Alaska Native, or Black individuals, who have disproportionately high rates of hypertensive disorders of pregnancy, the authors said.

More research is needed to identify which screening approaches may lead to improved disease detection and better health outcomes, but the results of the review support the grade B recommendation for hypertensive screening of all pregnant women, they concluded.
 

Early identification makes a difference

The new recommendation is important because it can help all moms and babies to be healthier, said Wanda Nicholson, MD, vice chair of the task force, in an interview.

“We are recommending that all pregnant persons have a blood pressure check at every visit throughout pregnancy,” said Dr. Nicholson, an ob.gyn. by training who also serves as professor of prevention and community health at George Washington University in Washington. “We know that there is a maternal health crisis in this country, and we know that hypertensive disorders of pregnancy are one of the key factors related to that,” she said.

Unfortunately, barriers to routine screening for hypertensive disorders of pregnancy persist, said Dr. Nicholson. The incidence of hypertensive disorders of pregnancy is higher in many of the same populations who also have challenges in accessing regular prenatal care, notably those who are Black, Native American, or Alaska Native, she noted.

The new recommendation also serves as an opportunity to call attention to the health care disparities for these populations, not only during pregnancy, but in general, she emphasized.

In clinical practice, the definition of hypertensive disorders of pregnancy involves three different diagnoses – gestational hypertension, preeclampsia, and eclampsia – that can be seen as points on a continuum, said Dr. Nicholson. The sooner patients are identified with hypertensive disorders of pregnancy, the sooner intervention and treatment can begin, she said. To that end, she added the clinical pearl of using a properly sized blood pressure cuff to obtain an accurate reading and avoid missed diagnoses.

The task force also outlined several key areas for additional research, said Dr. Nicholson. First, more research is needed on alternative screening strategies, such as at-home blood pressure monitoring for patients, as well as teleheath visits. Second, more studies are needed to address the disparities in prenatal care and include more diverse populations in clinical research. Third, future studies need to consider social determinants of health and other factors that might impact maternal health outcomes. “These steps will help achieve the larger goal of healthier mothers and babies,” Dr. Nicholson said.
 

Back to basics to improve women’s health

Some clinicians may be disappointed by the Evidence Report’s primary finding that no alternative screening strategies outperformed routine blood pressure measurement, wrote Anne E. Denoble, MD, and Christian M. Pettker, MD, both of Yale University, New Haven, Conn., in an accompanying editorial.

While potentially frustrating at first glance, the findings of the Evidence Report provide a foundation for improvement and reassurance that the best existing screening methods are basic and fundamental: regular prenatal visits with routine, in-office blood pressure measurements, and urine protein screening when clinically indicated, they said.

However, the USPSTF review also noted persistent research gaps that must be addressed to significantly improve maternal health outcomes, they said. Notable gaps include the disproportionately low numbers of Black patients in current studies, and the need for studies of alternate models of prenatal care, including the use of remote blood pressure monitoring, and the use of biomarkers to screen for and predict hypertensive disorders of pregnancy.

The most striking limitation may be the focus on prenatal care, with lack of attention to postpartum mortality risk, given that more than half of pregnancy-related deaths occur postpartum, the authors noted.

Although current screening tools may be used in practice “with skill and might,” more effort at multiple levels is needed to address the larger maternal health crisis in the United States, they said.
 

Expand screening, engage primary care for long-term benefits

Screening for hypertensive disorders of pregnancy “can and should be within the purview of internists,” wrote Srilakshmi Mitta, MD; Cary P. Gross, MD; Melissa A. Simon, MD, of Brown University, Yale University, and Northwestern University, respectively, in a separate editorial. The recommendation to extend screening beyond preeclampsia is timely, given the consistent increase in all hypertensive disorders of pregnancy since 1990, the authors said.

Pregnancy is not the only time for screening, counseling, and management of hypertensive disorders, they emphasized. “All persons who have reproductive capacity and/or are planning pregnancy, along with those who are post partum, should be screened for hypertensive disorders, aligning the USPSTF with guidelines from the American College of Obstetricians and Gynecologists, the American College of Cardiology, and the American Heart Association,” they said, and all clinicians should be on board to identify and treat hypertensive disorders of pregnancy, especially in underserved racial and ethnic minorities for whom primary care may be their only source of health care.

“Pregnancy is a window of opportunity to influence current and future life course, not just of the individual, but also of the fetus(es),other children, and family,” and timely intervention has the potential for great public health impact, they said.

Dr. Denoble disclosed grants from the HealthPartners Institute for Education and Research and from the Patient-Centered Outcomes Research Institute. Dr. Simon serves on the Advisory Committee for Research on Women’s Health for the National Institutes of Health Office of Research on Women’s Health and serves as a member of the Centers for Disease Control and Prevention Community Preventive Services Task Force; she was a member of the USPSTF from 2017 to 2020. Dr. Gross disclosed grants from Johnson and Johnson and the National Comprehensive Cancer Network (through a grant to the NCCN from AstraZeneca) and personal fees from Genentech.

All pregnant women should undergo screening for hypertensive disorders, with evidence-based management for those screening positive, according to a new recommendation from the U.S. Preventive Services Task Force.

Hypertensive disorders of pregnancy in the United States increased from approximately 500 cases per 10,000 deliveries to 1,021 cases per 10,000 deliveries from 1993 to 2016-2017, and remain a leading cause of maternal morbidity and mortality, wrote Task Force Chair Michael J. Barry, MD, of Massachusetts General Hospital, Boston, and colleagues in the final recommendation statement published in JAMA.

The USPSTF commissioned a systematic review to assess the risks and benefits of hypertensive screening for asymptomatic pregnant women. The resulting grade B recommendation indicates that screening for hypertensive disorders in pregnancy using blood pressure measurements yields a substantial net benefit.

The recommendation applies to “all pregnant women and pregnant persons of all genders without a known diagnosis of a hypertensive disorder of pregnancy or chronic hypertension,” the authors said.

The recommendation calls for the use of blood pressure measurements to evaluate hypertensive disorders, with measurements taken at each prenatal visit. A positive result for new-onset hypertension was defined as systolic blood pressure of 140 mm Hg or diastolic blood pressure 90 mm Hg in the absence of chronic hypertension, based on two measurements at least 4 hours apart. Regular review of blood pressure can help identify and manage potentially fatal conditions.

However, screening alone is insufficient to improve inequities in health outcomes associated with hypertensive disorders of pregnancy, the authors emphasized. Data from previous studies have shown that Black patients are at increased risk for hypertensive disorders of pregnancy and severe complications, and that Black and Hispanic patients have twice the risk of stroke with hypertensive disorders of pregnancy as White patients.

In the evidence report that supported the recommendation, Jillian T. Henderson, PhD, of Kaiser Permanente in Portland, Ore., and colleagues reviewed six studies including 10,165 individuals. The studies (five clinical trials and one nonrandomized study) compared changes in prenatal screening with usual care.

Overall, the review yielded no evidence that any other screening strategies were more useful than routine blood pressure measurement to identify hypertensive disorders of pregnancy in asymptomatic women.

The findings cited to support the recommendation were limited by several factors, including the lack of power to detect pregnancy health outcomes and potential harms of different screening programs, and the lack of power to evaluate outcomes for American Indian, Alaska Native, or Black individuals, who have disproportionately high rates of hypertensive disorders of pregnancy, the authors said.

More research is needed to identify which screening approaches may lead to improved disease detection and better health outcomes, but the results of the review support the grade B recommendation for hypertensive screening of all pregnant women, they concluded.
 

Early identification makes a difference

The new recommendation is important because it can help all moms and babies to be healthier, said Wanda Nicholson, MD, vice chair of the task force, in an interview.

“We are recommending that all pregnant persons have a blood pressure check at every visit throughout pregnancy,” said Dr. Nicholson, an ob.gyn. by training who also serves as professor of prevention and community health at George Washington University in Washington. “We know that there is a maternal health crisis in this country, and we know that hypertensive disorders of pregnancy are one of the key factors related to that,” she said.

Unfortunately, barriers to routine screening for hypertensive disorders of pregnancy persist, said Dr. Nicholson. The incidence of hypertensive disorders of pregnancy is higher in many of the same populations who also have challenges in accessing regular prenatal care, notably those who are Black, Native American, or Alaska Native, she noted.

The new recommendation also serves as an opportunity to call attention to the health care disparities for these populations, not only during pregnancy, but in general, she emphasized.

In clinical practice, the definition of hypertensive disorders of pregnancy involves three different diagnoses – gestational hypertension, preeclampsia, and eclampsia – that can be seen as points on a continuum, said Dr. Nicholson. The sooner patients are identified with hypertensive disorders of pregnancy, the sooner intervention and treatment can begin, she said. To that end, she added the clinical pearl of using a properly sized blood pressure cuff to obtain an accurate reading and avoid missed diagnoses.

The task force also outlined several key areas for additional research, said Dr. Nicholson. First, more research is needed on alternative screening strategies, such as at-home blood pressure monitoring for patients, as well as teleheath visits. Second, more studies are needed to address the disparities in prenatal care and include more diverse populations in clinical research. Third, future studies need to consider social determinants of health and other factors that might impact maternal health outcomes. “These steps will help achieve the larger goal of healthier mothers and babies,” Dr. Nicholson said.
 

Back to basics to improve women’s health

Some clinicians may be disappointed by the Evidence Report’s primary finding that no alternative screening strategies outperformed routine blood pressure measurement, wrote Anne E. Denoble, MD, and Christian M. Pettker, MD, both of Yale University, New Haven, Conn., in an accompanying editorial.

While potentially frustrating at first glance, the findings of the Evidence Report provide a foundation for improvement and reassurance that the best existing screening methods are basic and fundamental: regular prenatal visits with routine, in-office blood pressure measurements, and urine protein screening when clinically indicated, they said.

However, the USPSTF review also noted persistent research gaps that must be addressed to significantly improve maternal health outcomes, they said. Notable gaps include the disproportionately low numbers of Black patients in current studies, and the need for studies of alternate models of prenatal care, including the use of remote blood pressure monitoring, and the use of biomarkers to screen for and predict hypertensive disorders of pregnancy.

The most striking limitation may be the focus on prenatal care, with lack of attention to postpartum mortality risk, given that more than half of pregnancy-related deaths occur postpartum, the authors noted.

Although current screening tools may be used in practice “with skill and might,” more effort at multiple levels is needed to address the larger maternal health crisis in the United States, they said.
 

Expand screening, engage primary care for long-term benefits

Screening for hypertensive disorders of pregnancy “can and should be within the purview of internists,” wrote Srilakshmi Mitta, MD; Cary P. Gross, MD; Melissa A. Simon, MD, of Brown University, Yale University, and Northwestern University, respectively, in a separate editorial. The recommendation to extend screening beyond preeclampsia is timely, given the consistent increase in all hypertensive disorders of pregnancy since 1990, the authors said.

Pregnancy is not the only time for screening, counseling, and management of hypertensive disorders, they emphasized. “All persons who have reproductive capacity and/or are planning pregnancy, along with those who are post partum, should be screened for hypertensive disorders, aligning the USPSTF with guidelines from the American College of Obstetricians and Gynecologists, the American College of Cardiology, and the American Heart Association,” they said, and all clinicians should be on board to identify and treat hypertensive disorders of pregnancy, especially in underserved racial and ethnic minorities for whom primary care may be their only source of health care.

“Pregnancy is a window of opportunity to influence current and future life course, not just of the individual, but also of the fetus(es),other children, and family,” and timely intervention has the potential for great public health impact, they said.

Dr. Denoble disclosed grants from the HealthPartners Institute for Education and Research and from the Patient-Centered Outcomes Research Institute. Dr. Simon serves on the Advisory Committee for Research on Women’s Health for the National Institutes of Health Office of Research on Women’s Health and serves as a member of the Centers for Disease Control and Prevention Community Preventive Services Task Force; she was a member of the USPSTF from 2017 to 2020. Dr. Gross disclosed grants from Johnson and Johnson and the National Comprehensive Cancer Network (through a grant to the NCCN from AstraZeneca) and personal fees from Genentech.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●