COVID-19 increases the risk of pregnancy complications

Pregnant women with COVID-19 appear to be at greater risk for common pregnancy complications — in addition to health risks from the virus — than pregnant women without COVID-19, suggests a study funded by the National Institutes of Health.

Pregnant women with COVID-19 appear to be at greater risk for common pregnancy complications

The study, which included nearly 2,400 pregnant women infected with SARS-CoV-2, found that those with moderate to severe infection were more likely to have a cesarean delivery, to deliver preterm, to die around the time of birth, or to experience serious illness from hypertensive disorders of pregnancy, postpartum hemorrhage, or from infection other than SARS-CoV-2. They were also more likely to lose the pregnancy or to have an infant die during the newborn period. Mild or asymptomatic infection was not associated with increased pregnancy risks.

“The findings underscore the need for women of child-bearing age and pregnant individuals to be vaccinated and to take other precautions against becoming infected with SARS-CoV-2,” said Diana Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), which funded the study. “This is the best way to protect pregnant women and their babies.”

The study was conducted by Torri D. Metz, M.D., of the University of Utah, Salt Lake City, and colleagues in the NICHD Maternal-Fetal Medicine Units Network. It appears in the Journal of the American Medical Association. Additional funding was provided by NIH’s National Center for Advancing Translational Sciences.

The study included more than 13,000 pregnant individuals from 17 U.S. hospitals, approximately 2,400 of whom were infected with SARS-CoV-2. Participants delivered between March 1 and December 31, 2020, before SARS-CoV-2 vaccination was available. The researchers compared outcomes among those with COVID-19 to those from uninfected patients and tabulated the study results as a primary outcome — whether the patient had died from any cause or had a serious illness or condition related to common obstetric complications. They also evaluated the results in terms of several secondary outcomes, including cesarean delivery, preterm birth, and fetal and newborn death.

Moderate daily caffeine intake during pregnancy may lead to smaller birth size

The researchers found corresponding reductions in size and lean body mass for infants whose mothers consumed below the 200 milligrams of caffeine per day(link is external) — about two cups of coffee — believed to increase risks to the fetus. Smaller birth size can place infants at higher risk of obesity, heart disease and diabetes later in life.

The researchers were led by Katherine L. Grantz, M.D., M.S., of the Division of Intramural Population Health Research at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development. The study appears in JAMA Network Open.

“Until we learn more, our results suggest it might be prudent to limit or forego caffeine-containing beverages during pregnancy,” Dr. Grantz said. “It’s also a good idea for women to consult their physicians about caffeine consumption during pregnancy.”

Previous studies have linked high caffeine consumption (more than 200 milligrams of caffeine per day) during pregnancy to infants being small for their gestational age (stage of pregnancy) or at risk for intrauterine growth restriction—being in the lowest 10th percentile for infants of the same gestational age. However, studies on moderate daily caffeine consumption (200 milligrams or less) during pregnancy have produced mixed results. Some have found similar elevated risks  for low birth weight and other poor birth outcomes, while others have found no such links. The current study authors noted that many of the earlier studies did not account for other factors that could influence infant birth size, such as variation in caffeine content of different beverages and maternal smoking during pregnancy.

For their study, the authors analyzed data on more than 2,000 racially and ethnically diverse women at 12 clinical sites who were enrolled from 8 to 13 weeks of pregnancy. The women were non-smokers and did not have any health problems before pregnancy. From weeks 10 to 13 of pregnancy, the women provided a blood sample that was later analyzed for caffeine and paraxanthine, a compound produced when caffeine is broken down in the body. The women also reported their daily consumption of caffeinated beverages (coffee, tea, soda and energy drinks) for the past week—once when they enrolled and periodically throughout their pregnancies.

Compared to infants born to women with no or minimal blood levels of caffeine, infants born to women who had the highest blood levels of caffeine at enrollment were an average of 84 grams lighter at birth (about 3 ounces), were .44 centimeters shorter (about .17 inches), and had head circumferences .28 centimeters smaller (about .11 inches).

Based on the women’s own estimates of the beverages they drank, women who consumed about 50 milligrams of caffeine a day (equivalent to a half cup of coffee) had infants 66 grams (about 2.3 ounces) lighter than infants born to non-caffeine consumers. Similarly, infants born to the caffeine consumers also had thigh circumferences .32 centimeters smaller (about .13 inches).

The researchers noted that caffeine is believed to cause blood vessels in the uterus and placenta to constrict, which could reduce the blood supply to the fetus and inhibit growth. Similarly, researchers believe caffeine could potentially disrupt fetal stress hormones, putting infants at risk for rapid weight gain after birth and for later life obesity, heart disease and diabetes.

The authors concluded that their findings suggest that even moderate caffeine consumption may be associated with decreased growth of the fetus.

Preterm birth, prolonged labor influenced by progesterone balance

New research by the National Institutes of Health found that unbalanced progesterone signals may cause some pregnant women to experience preterm labor or prolonged labor. The study in mice — published online in the Proceedings of the National Academy of Sciences — provides novel insights for developing treatments.

During pregnancy, the hormone progesterone helps to prevent the uterus from contracting and going into labor prematurely. This occurs through molecular signaling involving progesterone receptor types A and B, referred to as PGR-A and PGR-B. In this first-of-its-kind study, the scientists showed how unbalanced PGR-A and PGR-B signaling can affect pregnancy duration.

“We used genetically engineered mouse models to alter the ratio of PGR-A and PGR-B in the muscle compartment of the uterus, called the myometrium,” said senior author Francesco DeMayo, Ph.D., head of the National Institute of Environmental Health Sciences Reproductive and Developmental Biology Laboratory. “Our team found that PGR-A promotes muscle contraction and PGR-B prevents such contraction, and we identified the biological pathways influenced by both forms.”

Previous research showed that PGR-A regulates processes involved in initiating childbirth and that PGR-B affects molecular pathways related to maintaining the normal course of pregnancy. This study builds on those findings, revealing that the relative abundance of PGR-A and PGR-B may be critical in promoting healthy pregnancy. The public health implications are significant.

Preterm birth affects 10% of all pregnancies and is the primary cause of neonatal morbidity and mortality worldwide, while prolonged labor increases the risks of infection, uterine rupture, and neonatal distress, according to the researchers.

The scientists pointed out that care for preterm deliveries can result in high social and economic costs, with infants born preterm at greater risk for experiencing disorders ranging from blindness to cerebral palsy. Prolonged labor can harm both mother and infant and lead to cesarean delivery.

Progesterone treatment aimed at preventing premature labor can help a subset of patients, but for other individuals, confounding factors may reduce effectiveness, noted Steve Wu, Ph.D., first author on the study and a staff scientist in DeMayo’s lab. Wu said that the research team found novel molecules that control uterine muscle contraction, and they could serve as future therapeutic targets. He added that the current study also may help to advance treatment for labor dystocia — the clinical name for abnormally slow or protracted labor.

“Although labor stimulation by oxytocin infusion is an approved measure to mitigate labor dystocia, serious side effects have been associated with this treatment,” said Wu. “Novel proteins that we identified as being part of progesterone signaling could serve as a key molecular switch of uterine contraction, through drug-dependent regulation of their activities,” he explained.

“Hormone signaling in pregnancy is complicated and involves both the hormone levels and the types of receptors in the uterus that sense the hormones,” said co-first author Mary Peavey, M.D., from the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill. “This publication sheds light on how hormones influence labor and can thus be used to help women when the uterus goes into labor too soon or for a prolonged period.”

NIH funds study to evaluate remdesivir for COVID-19 in pregnancy

A new study funded by the National Institutes of Health will evaluate the effects of remdesivir in pregnant women who have been prescribed the drug to treat COVID-19. The study, which will be conducted at 17 sites in the continental United States and Puerto Rico, aims to determine how pregnant women metabolize the drug and whether there are any potential side effects.

“Pregnant women with COVID-19 are at high risk for hospitalization, for intensive care admission and for needing ventilator support,” said Diana W. Bianchi, M.D., director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). “There is an urgent need to identify effective treatments for this population and to determine whether drugs prescribed for other adults are appropriate for use in pregnancy.”

The study is funded by NICHD, the National Institute of Allergy and Infectious Diseases (NIAID), and the National Institute of Mental Health, all part of NIH. Called IMPAACT 2032, the study will be conducted by the NIH-funded International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network.

Originally developed to treat Ebola and Marburg virus infections, remdesivir was shown in a NIAID-funded clinical trial to accelerate recovery in patients with advanced COVID-19 disease. Remdesivir has since been approved by the U.S. Food and Drug Administration for the treatment(link is external) of COVID-19 in adults and children over age 12 years.

Although it has not been approved specifically for use in pregnancy, remdesivir can be prescribed to pregnant women if their physicians believe the drug may benefit them. However, physicians currently lack scientific evidence for the safety and efficacy of remdesivir for treating pregnant women with COVID-19. Because pregnancy may influence a drug’s effects, IMPAACT 2032 will compare remdesivir use in pregnant and non-pregnant women of reproductive age who are hospitalized with COVID-19.

The study will evaluate remdesivir’s pharmacokinetics—how a drug is absorbed, moves through the body and is broken down and eliminated in pregnant women and nonpregnant women of childbearing potential who receive it as part of clinical care. For women who received the drug within five days of delivery, samples from the plasma and umbilical cord will be analyzed for insight into remdesivir’s pharmacokinetics in the placenta. Breast milk will also be tested for remdesivir among women who are lactating. Researchers will also document potential side effects and adverse events that could occur with use of the drug.

NIH calls for greater inclusion of pregnant and lactating people in COVID-19 vaccine research

Longstanding obstacles to include pregnant and lactating people in clinical research have led to this population now deciding whether or not to receive a SARS-CoV-2 vaccine without the benefit of scientific evidence, writes Diana W. Bianchi, M.D., director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), part of the National Institutes of Health, and colleagues. Their viewpoint article appears online in JAMA(link is external).

The manufacturers of currently available vaccines excluded pregnant and lactating people from the clinical trials needed to obtain Emergency Use Authorizations from the U.S. Food and Drug Administration. Now that the vaccines have been distributed, the U.S. Centers for Disease Control and Prevention and the FDA will obtain information from those who receive them on their potential impact during pregnancy, as well as information on infant outcomes. While these data will prove useful, pregnant people and their clinicians must make real-time decisions now about the vaccine based on little or no scientific evidence that applies specifically to them.

In 2016, the 21^st Century Cures Act established the Task Force on Research Specific to Pregnant Women and Lactating Women, representing multiple federal agencies, academia, industry and non-profit organizations. The Task Force developed recommendations on how to safely and ethically include pregnant and lactating people in clinical research. These recommendations must now be implemented to ensure pregnant people receive the same evidence that non-pregnant adults receive to make informed decisions about their medical care.

Recent findings from a National Institutes of Health study suggest COVID-19 during pregnancy can carry a higher risk for complications. Pregnant people need to be protected through research rather than from research, the authors contend.

Severe COVID-19 in pregnancy associated with preterm birth, other complications

Pregnant women who experienced severe symptoms of COVID-19 had a higher risk of complications during and after pregnancy, according to preliminary findings from a National Institutes of Health study.

Compared to COVID-19 patients without symptoms, those with severe symptoms were at higher risk for cesarean delivery, postpartum hemorrhage, hypertensive disorders of pregnancy and preterm birth.

The study was led by Torri Metz, M.D., of University of Utah Health, Salt Lake City, and Rebecca Clifton, Ph.D., of the Milken Institute School of Public Health at the George Washington University, Washington, D.C. An abstract of the study will be presented today at the Society for Maternal-Fetal Medicine’s(link is external) virtual annual meeting.

The findings come from the Gestational Research Assessments for COVID-19 (GRAVID) study conducted by investigators in the Maternal-Fetal Medicine Units (MFMU) Network, a group of  U.S. clinical centers funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Researchers evaluated more than 1,200 pregnant women with COVID-19 who delivered at 33 U.S. hospitals between March 1 and July 30, 2020. Roughly half of the women (47%) were asymptomatic, 27% had mild symptoms, 14% had moderate symptoms, 8% had severe symptoms and 4% were critically ill. Those with more severe symptoms tended to be older, with a higher than average body mass index and underlying health issues, such as asthma, diabetes, hypertension, liver disease and seizure disorder.

Researchers attributed four maternal deaths to COVID-19. Transmission of SARS-CoV-2, the virus that causes COVID-19, from mother to child was rare, with 1% of newborns testing positive for the virus before discharge from the hospital.

Low-dose aspirin may improve pregnancy chances for women with one or two prior miscarriages

Contrary to previous findings, low-dose aspirin therapy before conception and during early pregnancy may increase pregnancy chances and live births among women who have experienced one or two prior miscarriages, suggests a study by researchers at the National Institutes of Health.

Rather than looking solely at the difference in pregnancy rates between women who were given aspirin and those receiving a placebo, the study also accounted for differences in total aspirin use between women who deviated from the daily regimen and those who adhered to it.

The research team was led by Enrique Schisterman, Ph.D., of the Epidemiology Branch at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and colleagues. It appears in the Annals of Internal Medicine.

Published in 2014, the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial included more than 1,000 women between 18 and 40 years old with one or two previous miscarriages. The women received either daily low-dose aspirin (81 milligrams) or a placebo while trying to conceive. If they did conceive, they would continue to receive this regimen through the 36^th week of pregnancy. Although the study found no overall difference in pregnancy loss rates between the two groups, there was a higher birthrate for the subgroup of women who had experienced only one previous miscarriage before the 20th week of pregnancy.

Unlike the original analysis, the current reanalysis considered whether a participant adhered to the treatment or skipped days or discontinued it entirely for side effects such as bleeding, nausea or vomiting. Compared to the placebo group, for every 100 women, adhering to the aspirin regimen for five to seven days a week led to eight more positive pregnancy tests, six fewer pregnancy losses, and culminated in 15 more live births. Women who adhered to the therapy four days per week experienced similar results. The researchers concluded that taking low-dose aspirin at least four days per week could improve the odds for pregnancy and live birth in this group of women.