mRNA COVID-19 vaccination early in pregnancy and the risk of spontaneous abortion in an international pregnancy registry.

PURPOSE: mRNA COVID-19 vaccines are used in pregnant populations whether advertently or inadvertently. However, evidence on the safety of these vaccines during pregnancy is limited. The objective of this study is to evaluate the effect of BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccination during the first 20 weeks of gestation on the risk of spontaneous abortion (SAB). METHODS: All pregnant women who received at least one dose of BNT162b2 or mRNA-1273 and enrolled in the COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER) were prospectively followed from enrollment until 20 weeks of gestation, SAB, or loss to follow-up. Baseline demographics, vaccination information, and pregnancy outcomes were collected via monthly online self-administered questionnaires, vaccination certificates, and medical records. Life tables were used to calculate the cumulative risk of SAB. Cox regression was used to estimate the hazard ratio (HR) comparing the two vaccines groups stratified by country of residence and gestational age at enrollment. RESULTS: Among 6840 participants who received at least one dose of BNT162b2 or mRNA-1273 at any time in pregnancy between Jan-Sep, 2021, 2129 met the inclusion criteria (1576 received BNT162b2 and 553 mRNA-1273). The two groups were balanced in terms of baseline characteristics. There were 37 SABs, with an overall 13.4% estimated cumulative risk by 20 weeks of gestation, which is similar to the expected risk in the population. The HR of SAB comparing mRNA-1273 to BNT162b2 was 1.46 (95% CI: 0.66, 3.22). CONCLUSION: The C-VIPER data show no evidence that mRNA COVID-19 vaccines increase the risk of SAB.

The COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER): Protocol and Methodological Considerations.

INTRODUCTION: The advent of the coronavirus disease 2019 (COVID-19) pandemic has led to the development of vaccines against severe acute respiratory syndrome coronavirus 2. Prospective evidence regarding safety for pregnant people and their developing fetuses is lacking. The aim of the COVID-19 Vaccines International Pregnancy Exposure Registry (C-VIPER) is to estimate the relative risk of obstetric, neonatal, and infant outcomes by comparing participants vaccinated against COVID-19 during pregnancy to a reference group of people enrolled in the Pregistry International Pregnancy Exposure Registry (PIPER) who remained unvaccinated during pregnancy. METHODS: The C-VIPER and the PIPER are international, non-interventional, real-world cohort studies. Participants receiving a COVID-19 vaccine during pregnancy will be matched in the analyses by country and gestational age at enrollment to unvaccinated individuals. Self-enrolled and self-consented participants complete online questionnaires at enrollment, during pregnancy, and for 12 months after the delivery of a live infant. Where possible, outcomes are verified by medical records. The study aims to recruit at least 500 pregnancies for each approved or authorized vaccine and will last for 5 years for each product. CONCLUSIONS: By collecting data for each vaccine brand, the C-VIPER will be able to determine individual safety profiles. The study design allows for analysis of the effects of exposure to COVID-19 vaccines during specific etiologically relevant periods of gestation. Although the sample size may be too small to detect associations with rare outcomes, the study will be used to generate hypotheses for future research. Ultimately, the C-VIPER should provide data that will allow pregnant people and their healthcare providers to make informed decisions about COVID-19 vaccination. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04705116. Registered on 12 January, 2021. EU PAS EUPAS39096. Registered on 20 January, 2021.

Social determinants of health associated with COVID-19 severity during pregnancy: a multinational cohort study (in the International Registry of Coronavirus Exposure in Pregnancy).

BACKGROUND: The COVID-19 pandemic has caused morbidity and mortality, particularly among vulnerable populations. We aimed to assess social and demographic characteristics associated with COVID-19 severity among symptomatic participants during pregnancy. METHODS: The International Registry of Coronavirus Exposure in Pregnancy is a multinational, longitudinal observational cohort study of adult participants tested for SARS-CoV-2 or who received clinical diagnosis of COVID-19 during pregnancy (NCT04366986). Disease severity status of mild, moderate, or severe was determined based on symptoms and healthcare utilization. Stratified by current versus recent pregnancy at enrollment, univariate mixed-effects logistic regression modeling was used to characterize association between social and demographic characteristics with COVID-19 severity, using a cumulative mixed effect model with country as a random effect. RESULTS: The odds of developing more severe COVID-19 (odds ratio [95% confidence interval]) were higher among participants with lower socioeconomic status (poor: 2.72 [2.01,3.69]; lower-middle class: 2.07 [1.62,2.65] vs wealthy), among participants with lower educational attainment (high school: 1.68 [1.39,2.03]; < high school (1.77 [1.25,2.51] vs graduate education). Participants over 25 years of age had lower odds of severe COVID-19 versus participants < 25 years (25-34: 0.69 [0.56,0.85]; 35-50: 0.62 [0.48,0.80]). Employment in food services was also associated with increased odds of more severe COVID-19, whereas employment in healthcare and within home, and primiparity were associated with lower severity. CONCLUSIONS: Findings suggest that employment setting and economic status have strong associations with COVID-19 severity, which warrants considering social determinants of health in the context of assessing risk factors of more severe COVID-19 during pregnancy. TRIAL REGISTRATION: IRCEP was registered with the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) [EUPAS37360] and clinicaltrials.gov [NCT04366986].

Timing and severity of COVID-19 during pregnancy and risk of preterm birth in the International Registry of Coronavirus Exposure in Pregnancy.

BACKGROUND: Studies of preterm delivery after COVID-19 are often subject to selection bias and do not distinguish between early vs. late infection in pregnancy, nor between spontaneous vs. medically indicated preterm delivery. This study aimed to estimate the risk of preterm birth (overall, spontaneous, and indicated) after COVID-19 during pregnancy, while considering different levels of disease severity and timing. METHODS: Pregnant and recently pregnant people who were tested for or clinically diagnosed with COVID-19 during pregnancy enrolled in an international internet-based cohort study between June 2020 and July 2021. We used several analytic approaches to minimize confounding and immortal time bias, including multivariable regression, time-to-delivery models, and a case-time-control design. RESULTS: Among 14,264 eligible participants from 70 countries who did not report a pregnancy loss before 20 gestational weeks, 5893 had completed their pregnancies and reported delivery information; others were censored at time of their last follow-up. Participants with symptomatic COVID-19 before 20 weeks' gestation had no increased risk of preterm delivery compared to those testing negative, with adjusted risks of 10.0% (95% CI 7.8, 12.0) vs. 9.8% (9.1, 10.5). Mild COVID-19 later in pregnancy was not clearly associated with preterm delivery. In contrast, severe COVID-19 after 20 weeks' gestation led to an increase in preterm delivery compared to milder disease. For example, the risk ratio for preterm delivery comparing severe to mild/moderate COVID-19 at 35 weeks was 2.8 (2.0, 4.0); corresponding risk ratios for indicated and spontaneous preterm delivery were 3.7 (2.0, 7.0) and 2.3 (1.2, 3.9), respectively. CONCLUSIONS: Severe COVID-19 late in pregnancy sharply increased the risk of preterm delivery compared to no COVID-19. This elevated risk was primarily due to an increase in medically indicated preterm deliveries, included preterm cesarean sections, although an increase in spontaneous preterm delivery was also observed. In contrast, mild or moderate COVID-19 conferred minimal risk, as did severe disease early in pregnancy.

First trimester COVID-19 and the risk of major congenital malformations-International Registry of Coronavirus Exposure in Pregnancy.

There is limited information about the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first trimester of pregnancy on the risk of major congenital malformations (MCMs). The International Registry of Coronavirus Exposure in Pregnancy (IRCEP) was designed to estimate the relative risk of adverse perinatal outcomes among women with Coronavirus Disease 2019 (COVID-19) at specific times during gestation. Adult women were eligible to enroll if they had a SARS-CoV-2 test, regardless of the results, or clinically confirmed COVID-19 during pregnancy. Self-administered questionnaires collected data on SARS-CoV-2 infection, pregnancy outcomes (including detailed questions on MCMs), and potential confounders. The analysis of MCMs includes women with either a positive SARS-CoV-2 PCR test or a clinical diagnosis of COVID-19 during the first trimester (exposed group) or a negative SARS-CoV-2 test (reference) that enrolled while pregnant. Sensitivity analyses were restricted to participants who enrolled before the availability of informative prenatal screening tests and extended to those enrolled after end of pregnancy. Generalized linear models were used to estimate relative risks (RR) and 95% confidence intervals (CI). Of 17,163 participants enrolled between June 2020 and July 2021, 1727 had a SARS-CoV-2 infection during the first trimester, of whom 1,675 enrolled during pregnancy. Of 10,235 controls with a negative test during pregnancy, 4,172 enrolled during pregnancy. Restriction to participants with complete follow-up reduced the sample size to 92 exposed and 292 unexposed reference pregnancies. MCMs were reported in 3 (3.3%) exposed and 8 (2.7%) unexposed (RR 1.2; 95% CI 0.32-4.2) newborns. The RR was 2.5 (95%CI 0.23-27) among those enrolled before prenatal screening, and 2.2 (95%CI 0.89-5.3) in the overall study population including those enrolled post-pregnancy. No specific pattern of malformations was observed. Although results are compatible with no major teratogenic effects associated with maternal SARS-CoV-2 infection, RR estimates were imprecise and larger studies are warranted.

COVID-19 pharmacotherapy utilization patterns during pregnancy: International Registry of Coronavirus Exposure in Pregnancy.

PURPOSE: Women infected with SARS-CoV-2 during pregnancy are at increased risk of developing severe illness and experience a higher rate of preterm births than pregnant women who are not infected. The use of innovative or repurposed therapies to treat COVID-19 patients is widespread; however, there are very limited data regarding the patterns of use and safety profile of most of these therapeutics in pregnant women. We assessed the patterns of use of COVID-19 therapeutics during pregnancy using data from the International Registry of Coronavirus in Pregnancy (IRCEP). METHODS: The IRCEP is an international observational cohort study intended to assess the risk of major obstetric and neonatal outcomes among pregnant women with COVID-19. Women enrolled while pregnant or within 6 months after end of pregnancy. Follow-up for women enrolled while pregnant includes monthly online questionnaires throughout the pregnancy and, for live births, through the infant's first 90 days of life. Participants provide information on demographic characteristics, health history, COVID-19 tests and symptoms, medications, and obstetric and neonatal outcomes. RESULTS: A total of 5780 women with COVID-19 during pregnancy were identified from the IRCEP. Severity of COVID-19 was classified in 372 of them as severe, 3053 moderate, and 2355 mild. The most frequently reported COVID-19 therapies, other than analgesics, included azithromycin (12.8%), steroids (3.5%), interferon (2.4%), oseltamivir (2.1%), chloroquine/hydroxychloroquine (1.7%), anticoagulants (2.0%), antibodies (0.9%), and remdesivir (0.3%). Most drugs were preferentially used for severe cases. Patterns of use varied by country. CONCLUSIONS: IRCEP participants reported use of therapeutics for COVID-19 during pregnancy for which there is little safety information. Findings on COVID-19 pharmacotherapy utilization patterns can guide future studies examining the safety of COVID-19 therapies during pregnancy.

International Registry of Coronavirus Exposure in Pregnancy (IRCEP): Cohort Description and Methodological Considerations.

Limited data are available about the potential health effects of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pregnant women and their developing offspring. We established the International Registry of Coronavirus Exposure in Pregnancy (IRCEP) to provide data on the risk of major adverse obstetric and neonatal outcomes among women with varying degrees of severity and timing of coronavirus disease 2019 (COVID-19) during pregnancy. We describe here the cohort and share the lessons learned. The IRCEP enrolls women tested for SARS-CoV-2 or with a clinical diagnosis of COVID-19 during pregnancy and obtains information using an online data collection system. By March 2021, 17,532 participants from 77 countries had enrolled; 54% enrolled during pregnancy and 46% afterward. Among women with symptomatic COVID-19 with a positive SARS-CoV-2 test (n = 4,934), symptoms were mild in 41%, moderate in 52%, and severe in 7%; 7.7% were hospitalized for COVID-19 and 1.7% were admitted to an intensive care unit. The biggest challenges were retention of participants enrolled during pregnancy and the potential bias introduced when participants enroll after pregnancy outcomes are known. Multiple biases need to be considered and addressed when estimating and interpreting the effects of COVID-19 in pregnancy in these types of cohorts.

Frequency and source of worries in an International sample of pregnant and postpartum women during the Covid-19 pandemic.

BACKGROUND: Pregnant and postpartum women face unique challenges and concerns during the COVID-19 pandemic. Thus far, no studies have explored the factors associated with increased levels of worry in this population globally. The current study sought to assess the frequency and sources of worry during the COVID-19 pandemic in an international sample of pregnant and postpartum women. METHODS: We conducted an anonymous, online, cross-sectional survey in 64 countries between May and June 2020. The survey was available in 12 languages and hosted on the Pregistry platform for COVID-19 studies. Participants were sought mainly on social media platforms and online parenting forums. The survey included questions related to demographics, level of worry, support, stress, COVID-19 exposure, frequency of media usage, and mental health indicators. RESULTS: The study included 7561 participants. Eighty-three percent of all participants indicated that they were either 'somewhat' or 'very' worried. Women 13-28 weeks pregnant were significantly more likely to indicate that they were 'very worried' compared to those who were postpartum or at other stages of pregnancy. When compared with women living in Europe, those in Africa, Asia and Pacific, North America and South/Latin America were more likely to have increased levels of worry, as were those who more frequently interacted with social media. Different forms of support and stress also had an impact upon level of worry, while indicators of stress and anxiety were positively associated with worry level. CONCLUSION: Pregnant and postpartum women are vulnerable to the changes in societal norms brought about by the COVID-19 pandemic. Understanding the factors associated with levels of worry within this population will enable society to address potential unmet needs and improve the current and future mental health of parents and children.

Stress levels among an international sample of pregnant and postpartum women during the COVID-19 pandemic.

BACKGROUND: Stress is a complex condition that can have a profound effect on an individual's sense of wellbeing and their ability to live a happy and healthy life. COVID-19 and its associated stressors have the potential to disrupt numerous facets of our everyday lives. Pregnant and postpartum women are especially vulnerable to changes in the availability of routine health and social care services and of their support networks. The current study sought to explore stress levels and their influencers among an international cohort of pregnant and postpartum women during the COVID-19 pandemic. METHODS: We conducted an anonymous, online, cross-sectional survey in 64 countries between May and June 2020. The survey was hosted on the Pregistry platform and made available in 12 languages, with respondents sought through a variety of social media platforms and parenting forums. In addition to levels of stress, we collected data related to demographics, COVID-19 exposure and worries, lifestyle changes, traditional and social media use, precautionary measures related to COVID-19, and mental health. RESULTS: In total, 7185 women were included in our sample. We found statistically significant (p-value <0.05) reductions in stress score among older women (≥35 years of age), those either living with a partner or married, those who had graduated from college, and those with medical coverage. Higher stress scores were found among women who resided in Africa, Asia and the Pacific, the Middle East, and North America compared with those in Europe. When race and ethnicity were included in the model, black women were found to have higher stress compared to white women. Level of family and community support was inversely associated with level of stress. CONCLUSION: Our study is one of the first to explore stress levels among pregnant and postpartum women during the COVID-19 pandemic. We found statistically significant differences in stress levels by age, education, marital status, region of residence, race/ethnicity and level of support. Understanding stress during the COVID-19 pandemic, and exploring ways to address it, will be key to contributing to the mental and physical health of expectant and new mothers, as well as their children, in both the short and long term.

A cross-national study of factors associated with women's perinatal mental health and wellbeing during the COVID-19 pandemic.

Pregnant and postpartum women face unique challenges during the COVID-19 pandemic that may put them at elevated risk of mental health problems. However, few large-scale and no cross-national studies have been conducted to date that investigate modifiable pandemic-related behavioral or cognitive factors that may influence mental health in this vulnerable group. This international study sought to identify and measure the associations between pandemic-related information seeking, worries, and prevention behaviors on perinatal mental health during the COVID-19 pandemic. An anonymous, online, cross-sectional survey of pregnant and postpartum women was conducted in 64 countries between May 26, 2020 and June 13, 2020. The survey, available in twelve languages, was hosted on the Pregistry platform for COVID-19 studies (https://corona.pregistry.com) and advertised in social media channels and online parenting forums. Participants completed measures on demographics, COVID-19 exposure and worries, information seeking, COVID-19 prevention behaviors, and mental health symptoms including posttraumatic stress via the IES-6, anxiety/depression via the PHQ-4, and loneliness via the UCLA-3. Of the 6,894 participants, substantial proportions of women scored at or above the cut-offs for elevated posttraumatic stress (2,979 [43%]), anxiety/depression (2,138 [31%], and loneliness (3,691 [53%]). Information seeking from any source (e.g., social media, news, talking to others) five or more times per day was associated with more than twice the odds of elevated posttraumatic stress and anxiety/depression, in adjusted models. A majority of women (86%) reported being somewhat or very worried about COVID-19. The most commonly reported worries were related to pregnancy and delivery, including family being unable to visit after delivery (59%), the baby contracting COVID-19 (59%), lack of a support person during delivery (55%), and COVID-19 causing changes to the delivery plan (41%). Greater worries related to children (i.e., inadequate childcare, their infection risk) and missing medical appointments were associated with significantly higher odds of posttraumatic stress, anxiety/depression and loneliness. Engaging in hygiene-related COVID-19 prevention behaviors (face mask-wearing, washing hands, disinfecting surfaces) were not related to mental health symptoms or loneliness. Elevated posttraumatic stress, anxiety/depression, and loneliness are highly prevalent in pregnant and postpartum women across 64 countries during the COVID-19 pandemic. Excessive information seeking and worries related to children and medical care are associated with elevated symptoms, whereas engaging in hygiene-related preventive measures were not. In addition to screening and monitoring mental health symptoms, addressing excessive information seeking and women's worries about access to medical care and their children's well-being, and developing strategies to target loneliness (e.g., online support groups) should be part of intervention efforts for perinatal women. Public health campaigns and medical care systems need to explicitly address the impact of COVID-19 related stressors on mental health in perinatal women, as prevention of viral exposure itself does not mitigate the pandemic's mental health impact.

COVID-19 vaccine acceptance among pregnant women and mothers of young children: results of a survey in 16 countries.

With the development of multiple effective vaccines, reducing the global morbidity and mortality of COVID-19 will depend on the distribution and acceptance of COVID-19 vaccination. Estimates of global vaccine acceptance among pregnant women and mothers of young children are yet unknown. An understanding of the challenges and correlates to vaccine acceptance will aid the acceleration of vaccine administration within these populations. Acceptance of COVID-19 vaccination among pregnant women and mothers of children younger than 18-years-old, as well as potential predictors, were assessed through an online survey, administered by Pregistry between October 28 and November 18, 2020. 17,871 total survey responses from 16 countries were obtained. Given a 90% COVID-19 vaccine efficacy, 52.0% of pregnant women (n = 2747/5282) and 73.4% of non-pregnant women (n = 9214/12,562) indicated an intention to receive the vaccine. 69.2% of women (n = 11,800/17,054), both pregnant and non-pregnant, indicated an intention to vaccinate their children. Vaccine acceptance was generally highest in India, the Philippines, and all sampled countries in Latin America; it was lowest in Russia, the United States and Australia. The strongest predictors of vaccine acceptance included confidence in vaccine safety or effectiveness, worrying about COVID-19, belief in the importance of vaccines to their own country, compliance to mask guidelines, trust of public health agencies/health science, as well as attitudes towards routine vaccines. COVID-19 vaccine acceptance and its predictors among women vary globally. Vaccination campaigns for women and children should be specific for each country in order to attain the largest impact.