The authors reply: Sun appropriately raises questions about the proportion of women reporting spontaneous abortion in our recent article. We agree that the denominator used in that proportion — 827 completed pregnancies — is not an appropriate denominator for the calculation of a risk estimate or rate. | | The number of spontaneous abortions (104) reflects data reported by the participants as of March 30, 2021, during telephone follow-up. In this preliminary report, follow-up information was missing for the majority of pregnancies in which exposure to vaccination occurred in early pregnancy. Among the 1224 women who had been vaccinated before conception or in the first trimester, follow-up through 20 weeks of gestation had been completed for only 204 pregnancies that were known to be ongoing and for 1 pregnancy that resulted in stillbirth. Among the pregnancies that had not yet reached 20 weeks of gestation, there were 10 pregnancies with other outcomes before 20 weeks of gestation, including 8 ectopic pregnancies and 2 induced abortions. For the other 905 pregnancies, follow-up had not occurred to establish whether these pregnancies were ongoing past 20 weeks of gestation. We have amended Table 4 in our earlier publication and have clarified the text. | | Subsequently, we completed telephone follow-up for the 905 pregnancies and enrolled additional persons in the v-safe pregnancy registry. To determine the cumulative risk of spontaneous abortion from 6 to less than 20 weeks of gestation, we used life-table methods to perform an updated analysis, now reported in the Journal, involving 2456 women who received at least one dose of an mRNA Covid-19 vaccine before conception or before 20 weeks of gestation.1 The estimated risks (14.1% overall and 12.8% in age-standardized analyses) are consistent with the risks of spontaneous abortion reported in the general population.1

BACKGROUND: Pregnant women less frequently receive Coronavirus Disease 2019 (COVID-19) vaccination and are at increased risk for adverse pregnancy outcomes from COVID-19. OBJECTIVES: First, describe the vaccination status, treatment, and outcomes of hospitalized, symptomatic pregnant women with COVID-19 and second, estimate whether treatment differs by pregnancy status among treatment-eligible (i.e., requiring supplemental oxygen per National Institutes of Health guidelines at the time of the study) women. STUDY DESIGN: During January-November 2021, the COVID-19-Associated Hospitalization Surveillance Network completed medical chart abstraction for a probability sample of 2,715 hospitalized women aged 15-49 years with laboratory-confirmed SARS-CoV-2 infection. Of these, 1,950 women had symptoms of COVID-19 upon admission; 336 were pregnant. We calculated weighted prevalence estimates of demographic and clinical characteristics, vaccination status, and outcomes among pregnant women with symptoms of COVID-19 upon admission. We used propensity score matching to estimate prevalence ratios (PR), and 95% confidence intervals (CI) of treatment-eligible patients who received remdesivir or systemic steroids by pregnancy status. RESULTS: Among 336 hospitalized pregnant women with symptomatic COVID-19, 39.6% were non-Hispanic Black, 24.8% were Hispanic or Latino, and 61.9% were aged 25-34 years. Among those with known COVID-19 vaccination status, 92.9% were unvaccinated. One-third (32.7%) were treatment-eligible. Among treatment-eligible pregnant women, 74.1% received systemic steroids and 61.4% received remdesivir. Among those that were no longer pregnant at discharge (n=180), 5.4% had spontaneous abortions and 3.5% had stillbirths. Of the 159 live births, 29.0% were pre-term. Among a propensity score-matched cohort of treatment-eligible hospitalized women of reproductive age, pregnant women were less likely than non-pregnant women to receive remdesivir (PR: 0.82, 95% CI 0.69-0.97) and systemic steroids (PR: 0.80, 95% CI 0.73-0.87). CONCLUSION: Most hospitalized pregnant patients with symptomatic COVID-19 were unvaccinated. Hospitalized pregnant patients were less likely to receive recommended remdesivir and systemic steroids compared to similar hospitalized non-pregnant women. Our results underscore the need to identify opportunities for improving COVID-19 vaccination, implementation of treatment of pregnant women, and the inclusion of pregnant women in clinical trials.

Pregnant persons are at risk for severe coronavirus disease 2019 (Covid-19), and infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy is associated with increased risks of preterm birth and other adverse maternal and neonatal outcomes.1 Although spontaneous abortion (pregnancy loss occurring at less than 20 weeks of gestation) is a common pregnancy outcome affecting 11 to 22% of recognized pregnancies (see Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org),2-4 data to inform estimates of the risk of spontaneous abortion after receipt of an mRNA Covid-19 vaccine either before conception (30 days before the first day of the last menstrual period through 14 days after) or during pregnancy are limited.

BACKGROUND: Many pregnant persons in the United States are receiving messenger RNA (mRNA) coronavirus disease 2019 (Covid-19) vaccines, but data are limited on their safety in pregnancy. METHODS: From December 14, 2020, to February 28, 2021, we used data from the "v-safe after vaccination health checker" surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) to characterize the initial safety of mRNA Covid-19 vaccines in pregnant persons. RESULTS: A total of 35,691 v-safe participants 16 to 54 years of age identified as pregnant. Injection-site pain was reported more frequently among pregnant persons than among nonpregnant women, whereas headache, myalgia, chills, and fever were reported less frequently. Among 3958 participants enrolled in the v-safe pregnancy registry, 827 had a completed pregnancy, of which 115 (13.9%) resulted in a pregnancy loss and 712 (86.1%) resulted in a live birth (mostly among participants with vaccination in the third trimester). Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported. Although not directly comparable, calculated proportions of adverse pregnancy and neonatal outcomes in persons vaccinated against Covid-19 who had a completed pregnancy were similar to incidences reported in studies involving pregnant women that were conducted before the Covid-19 pandemic. Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases). CONCLUSIONS: Preliminary findings did not show obvious safety signals among pregnant persons who received mRNA Covid-19 vaccines. However, more longitudinal follow-up, including follow-up of large numbers of women vaccinated earlier in pregnancy, is necessary to inform maternal, pregnancy, and infant outcomes.

Intentional release of infectious agents and biological weapons to cause illness and death has the potential to greatly impact pregnant women and their fetuses. We review what is known about the maternal and fetal effects of seven biological threats: Bacillus anthracis (anthrax); variola virus (smallpox); Clostridium botulinum toxin (botulism); Burkholderia mallei (glanders) and Burkholderia pseudomallei (melioidosis); Yersinia pestis (plague); Francisella tularensis (tularemia); and Rickettsia prowazekii (typhus). Evaluating the potential maternal, fetal, and infant consequences of an intentional release of an infectious agent requires an assessment of several key issues: (1) are pregnant women more susceptible to infection or illness compared to the general population?; (2) are pregnant women at increased risk for severe illness, morbidity, and mortality compared to the general population?; (3) does infection or illness during pregnancy place women, the fetus, or the infant at increased risk for adverse outcomes and how does this affect clinical management?; and (4) are the medical countermeasures recommended for the general population safe and effective during pregnancy? These issues help frame national guidance for the care of pregnant women during an intentional release of a biological threat.

Emerging infections have the potential to produce adverse effects on the pregnant woman or her fetus; however, studying these effects is often challenging. We review our experiences with investigating the prenatal effects of two mosquito-borne infections that emerged in the past 2 decades, West Nile virus (WNV) and Zika virus. Concerns regarding teratogenicity were raised about both viruses; Zika virus has been confirmed to be teratogenic, while WNV appears not to increase the risk for adverse outcomes, although teratogenicity has not been excluded. Study designs used to examine the effects of both viruses include case reports and series, pregnancy registries, and cohort studies. Case-control studies and birth defects surveillance systems are being used to study the effects during pregnancy of Zika virus, but not the effects of WNV, because a specific phenotype was observed among infants with congenital Zika infection, but not among infants with congenital WNV infection. Experimental data that demonstrated that Zika virus was neurotropic have also been useful because they provided biologic plausibility for Zika virus's teratogenic effects: these findings were consistent with observations in congenitally infected infants. Challenges encountered with studies to evaluate the effects of these infections include the broad range of possible adverse outcomes, the inability to include all infected pregnant women in studies because many infections are asymptomatic, and the difficulty with interpretation of diagnostic testing of infants (WNV and Zika) and pregnant women (Zika). This review might be helpful to guide future studies of the effects of emerging infections during pregnancy.

Background: Zika virus is a newly recognized human teratogen; monitoring its impact on the birth prevalence of microcephaly and other adverse pregnancy outcomes will continue to be an urgent need in the United States and worldwide. Methods: When the Centers for Disease Control and Prevention (CDC) activated the Emergency Operations Center for the Zika virus outbreak response in January of 2016, public health leadership recognized that a joint, coordinated effort was required between activities focused on the effects of the infection among pregnant women and those focused on birth defects in fetuses and infants. Before the introduction of Zika virus in the Americas, population-based birth defects surveillance occurred independently of pregnancy surveillance activities. Results: The coordination of pregnancy surveillance and birth defects surveillance implemented through the CDC Zika virus response represents a paradigm shift. Conclusion: Coordination of these surveillance systems provides an opportunity to capture information from both a prospective and retrospective approach. This relatively modest investment in the public health infrastructure can continue to protect pregnant women and their infants during the ongoing response to Zika virus and in the next emergent threat to maternal and child health. Birth Defects Research 109:372–378, 2017.

Zika virus infection during pregnancy can cause serious brain abnormalities, but the full range of adverse outcomes is unknown (1). To better understand the impact of birth defects resulting from Zika virus infection, the CDC surveillance case definition established in 2016 for birth defects potentially related to Zika virus infection* (2) was retrospectively applied to population-based birth defects surveillance data collected during 2013-2014 in three areas before the introduction of Zika virus (the pre-Zika years) into the World Health Organization's Region of the Americas (Americas) (3). These data, from Massachusetts (2013), North Carolina (2013), and Atlanta, Georgia (2013-2014), included 747 infants and fetuses with one or more of the birth defects meeting the case definition (pre-Zika prevalence = 2.86 per 1,000 live births). Brain abnormalities or microcephaly were the most frequently recorded (1.50 per 1,000), followed by neural tube defects and other early brain malformationsdagger (0.88), eye abnormalities without mention of a brain abnormality (0.31), and other consequences of central nervous system (CNS) dysfunction without mention of brain or eye abnormalities (0.17). During January 15-September 22, 2016, the U.S. Zika Pregnancy Registry (USZPR) reported 26 infants and fetuses with these same defects among 442 completed pregnancies (58.8 per 1,000) born to mothers with laboratory evidence of possible Zika virus infection during pregnancy (2). Although the ascertainment methods differed, this finding was approximately 20 times higher than the proportion of one or more of the same birth defects among pregnancies during the pre-Zika years. These data demonstrate the importance of population-based surveillance for interpreting data about birth defects potentially related to Zika virus infection.