Summary of Teratology Studies:
MAJOR CONGENITAL ANOMALIES
The rates of major congenital malformations overall, and of congenital heart defects in specific, were not different than expected among liveborn infants of 2134 mothers who were vaccinated with an mRNA COVID-19 vaccine in the first trimester of pregnancy compared to the outcome of 3584 unvaccinated pregnant women using data from a large cohort study conducted in Israel (Goldshtein et al., 2022).
PREGNANCY AND NEONATAL OUTCOMES
Two systematic reviews and meta-analyses of epidemiological studies reporting on more than 117,552 vaccinated pregnancies--almost exclusively with mRNA vaccines--showed no significant differences in the overall frequency of adverse pregnancy and neonatal outcomes (spontaneous abortion, preterm birth, low birth weight, small for gestational age, NICU admission, and low Apgar scores) between vaccinated and unvaccinated pregnancies (Ma et al., 2022; Prasad et al., 2022). In one meta-analysis, the incidence of stillbirths was slightly lower among the vaccinated pregnant group (odds ratio=0.85, 95% confidence interval 0.73-0.99) (Prasad et al., 2022). Some of the studies included in those meta-analyses and reviews are discussed below.
The cumulative risk of spontaneous abortion (14.1%, 95% confidence interval 12.1-16.1) reported among 2456 pregnant women in the v-safe pregnancy registry who had received at least one dose of an mRNA COVID-19 vaccine either before conception or before 20 weeks of gestation was similar to that expected in the general population, and remained in the expected range following a secondary analysis using direct maternal age-standardization to the reference population (12.8%, 95% confidence interval 10.8-14.8) (Zauche et al., 2021). In two subsequent retrospective cohort studies, administration of an mRNA COVID-19 vaccine was not associated with a risk of early pregnancy loss among a total of 1149 vaccinated women compared to unvaccinated women (Aharon et al., 2022; Citu et al., 2022). No evidence of an increased rate of spontaneous abortion following first trimester COVID-19 mRNA vaccination was found in other reports (Magnus et al., 2021; Trostle et al., 2021).
In another preliminary stud of the v-safe pregnancy registry, no neonatal deaths were reported among 724 liveborn infants of mothers who received an mRNAy COVID-19 vaccine in the third trimester of pregnancy, and rates for preterm birth (9.4%), small for gestational age (3.2%), and stillbirth (0.1%) were similar to background population rates (Shimabukuro et al., 2021). Similarly, no significant differences in early infant morbidity or mortality were detected among 16,697 liveborn infants who were prenatally exposed to a mRNA vaccine compared to liveborn infants born to 7591 unvaccinated pregnant women in a large cohort study in Israel (Goldshtein et al., 2022). In other population-based studies conducted in Canada, Sweden and Norway, vaccination against SARS-CoV-2 during pregnancy was not significantly associated with an increased risk of adverse pregnancy and neonatal outcomes, including stillbirth, small for gestational age, preterm delivery, low Apgar scores, or NICU admission, compared to the outcome of unvaccinated pregnant women (Fell et al., 2022; Magnus et al., 2022). Most of the vaccinations in those studies were mRNA COVID-19 vaccines and were given during the second and third trimesters of pregnancy.
No evidence of increased adverse pregnancy or neonatal outcomes was found among the infants of 13 women who received an mRNA COVID-19 vaccine during pregnancy (Gray et al., 2021) or among the infants of 85 women who received an mRNA vaccine in the second or third trimester of pregnancy (Trostle et al., 2021). Pregnancy and neonatal outcomes of 127 women who received an mRNA vaccine were similar to those of a propensity score-matched cohort of 399 pregnant women who did not receive COVID-19 vaccines in pregnancy (Blakeway et al., 2022).
TRANSPLACENTAL PASSAGE OF SARS-CoV-2 ANTIBODIES
Several studies reported SARS-CoV-2 IgG antibodies being detectable in the cord blood of infants whose mothers were vaccinated with an mRNA vaccine in the second half of pregnancy (Gray et al., 2021; Mithal et al., 2021; Rottenstreich et al., 2021; Kassis et al., 2022). Evidence of transplacental passage following vaccination in early pregnancy has also been demonstrated in limited reports (Rottenstreich et al., 2022; Sourouni et al., 2022).
ANIMAL TERATOLOGY STUDIES
No teratogenic or other adverse fetal effects were observed among the offspring of mice injected with mRNA-1273 vaccine during early pregnancy with over 50 times greater doses than those used in humans (Lu-Culligan et al., 2022). In the same study, pregnant dams vaccinated prior to placental establishment and fetal circulation conferred fetal transfer of antibodies up to the time of birth.
Selected References:
(Each paper is classified as a review [R], human case report [C], human epidemiological study [E], human clinical series [S], animal study [A], or other [O].)
Aharon D, Lederman M, Ghofranian A, Hernandez-Nieto C, Canon C, Hanley W, Gounko D, Lee JA, Stein D, Buyuk E, Copperman AB: In vitro fertilization and early pregnancy outcomes after coronavirus disease 2019 (COVID-19) vaccination. Obstet Gynecol 139(4):490-497, 2022. [E]
akeway H, Prasad S, Kalafat E, Heath PT, Ladhani SN, Le Doare K, Magee LA, O'Brien P, Rezvani A, von Dadelszen P, Khalil A: COVID-19 vaccination during pregnancy: coverage and safety. Am J Obstet Gynecol 226(2):236.e1-236.e14, 2022. [E]
Citu IM, Citu C, Gorun F, Sas I, Bratosin F, Motoc A, Burlea B, Rosca O, Malita D, Gorun OM: The risk of spontaneous abortion does not increase following first trimester mRNA COVID-19 vaccination. J Clin Med 11(6):1698, 2022. [E]
Fell DB, Dhinsa T, Alton GD, Torok E, Dimanlig-Cruz S, Regan AK, Sprague AE, Buchan SA, Kwong JC, Wilson SE, Haberg SE, Gravel CA, Wilson K, El-Chaar D, Walker MC, Barrett J, MacDonald SE, Okun N, Shah PS, Dougan SD, Dunn S, Bisnaire L: Association of COVID-19 vaccination in pregnancy with adverse peripartum outcomes. JAMA 327(15):1478-1487, 2022. [E]
Goldshtein I, Steinberg DM, Kuint J, Chodick G, Segal Y, Shapiro Ben David S, Ben-Tov A: Association of BNT162b2 COVID-19 vaccination during pregnancy with neonatal and early infant outcomes. JAMA Pediatr 176(5):470-477, 2022. [E]
Gray KJ, Bordt EA, Atyeo C, Deriso E, Akinwunmi B, Young N, Baez AM, Shook LL, Cvrk D, James K, De Guzman R, Brigida S, Diouf K, Goldfarb I, Bebell LM, Yonker LM, Fasano A, Rabi SA, Elovitz MA, Alter G, Edlow AG: Coronavirus disease 2019 vaccine response in pregnant and lactating women: a cohort study. Am J Obstet Gynecol 225(3):303.e1-303.e17, 2021. [E]
Kassis NE, Abdallah W, Chakra RA, Arab W, Sassine S, Atallah D: COVID-19 mRNA vaccine in pregnancy and newborn passive immunization: a case report. Future Sci OA 8(1):FSO761, 2022. [C]
Lu-Culligan A, Tabachnikova A, Perez-Then E, Tokuyama M, Lee HJ, Lucas C, Silva Monteiro V, Miric M, Brache V, Cochon L, Muenker MC, Mohanty S, Huang J, Kang I, Dela Cruz C, Farhadian S, Campbell M, Yildirim I, Shaw AC, Ma S, Vermund SH, Ko AI, Omer SB, Iwasaki A: No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination. PLoS Biol 20(5):e3001506, 2022. [A]
Ma Y, Deng J, Liu Q, Du M, Liu M, Liu J: Effectiveness and safety of COVID-19 vaccine among pregnant women in real-world studies: a systematic review and meta-analysis. Vaccines 10(2):246, 2022. [R]
Magnus MC, Gjessing HK, Eide HN, Wilcox AJ, Fell DB, Haberg SE: Covid-19 vaccination during pregnancy and first-trimester miscarriage. N Engl J Med 385(21):2008-2010, 2021. [E]
Magnus MC, Ortqvist AK, Dahlqwist E, Ljung R, Skar F, Oakley L, Macsali F, Pasternak B, Gjessing HK, Haberg SE, Stephansson O: Association of SARS-CoV-2 vaccination during pregnancy with pregnancy outcomes. JAMA 327(15):1469-1477, 2022. [E]
Mithal LB, Otero S, Shanes ED, Goldstein JA, Miller ES: Cord blood antibodies following maternal coronavirus disease 2019 vaccination during pregnancy. Am J Obstet Gynecol 225(2):192-194, 2021. [S]
Prasad S, Kalafat E, Blakeway H, Townsend R, O'Brien P, Morris E, Draycott T, Thangaratinam S, Le Doare K, Ladhani S, von Dadelszen P, Magee LA, Heath P, Khalil A: Systematic review and meta-analysis of the effectiveness and perinatal outcomes of COVID-19 vaccination in pregnancy. Nat Commun 13(1):2414, 2022. [R]
Rottenstreich A, Zarbiv G, Oiknine-Djian E, Zigron R, Wolf DG, Porat S: Efficient maternofetal transplacental transfer of anti- SARS-CoV-2 spike antibodies after antenatal SARS-CoV-2 BNT162b2 mRNA vaccination. Clin Infect Dis 73(10):1909-1912, 2021. [S]
Rottenstreich A, Zarbiv G, Oiknine-Djian E, Vorontsov O, Zigron R, Kleinstern G, Wolf DG, Porat S: The effect of gestational age at BNT162b2 mRNA vaccination on maternal and neonatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels. Clin Infect Dis 75(1):e603-e610. [S]
Shimabukuro TT, Kim SY, Myers TR, Moro PL, Oduyebo T, Panagiotakopoulos L, Marquez PL, Olson CK, Liu R, Chang KT, Ellington SR, Burkel VK, Smoots AN, Green CJ, Licata C, Zhang BC, Alimchandani M, Mba-Jonas A, Martin SW, Gee JM, Meaney-Delman DM: Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons. N Engl J Med 384(24):2273-2282, 2021. [E]
Sourouni M, Braun J, Oelmeier K, Mollers M, Willy D, Hennies MT, Koster HA, Pecks U, Klockenbusch W, Schmitz R: Assessment of neonatal cord blood SARS-CoV-2 antibodies after COVID-19 vaccination in pregnancy: a prospective cohort study. Geburtshilfe Frauenheilkd 82(5):510-516, 2022. [S]
Trostle ME, Limaye MA, Avtushka V, Lighter JL, Penfield CA, Roman AS: COVID-19 vaccination in pregnancy: early experience from a single institution. Am J Obstet Gynecol MFM 3(6):100464, 2021. [E]
Zauche LH, Wallace B, Smoots AN, Olson CK, Oduyebo T, Kim SY, Petersen EE, Ju J, Beauregard J, Wilcox AJ, Rose CE, Meaney-Delman DM, Ellington SR; CDC v-safe Covid-19 Pregnancy Registry Team: Receipt of mRNA Covid-19 vaccines and risk of spontaneous abortion. N Engl J Med 385(16):1533-1535, 2021. [E]
COVID-19 VACCINE PREGNANCY REGISTRIES
Healthcare providers are encouraged to suggest their patients enroll in the following registries:
V-SAFE
A registry collecting health information from people who received COVID-19 vaccinations in the periconception period or during pregnancy is being maintained by the Centers for Disease Control and Prevention. The registry attempts to assist individuals and healthcare providers to make informed decisions about COVID-19 vaccination.
Pregnant vaccinated people who would like to participate must complete a registration in v-safe (a smartphone-based tool that uses text messaging and web surveys to provide personalized health check-ins after you receive a COVID-19 vaccine: www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html). People who meet the conditions of the study will be contacted by the registry staff for additional details for enrollment in v-safe.
COVID-PRICE (COVID-19 Pregnancy Related Immunological, Clinical, and Epidemiological Factors and Perinatal Outcomes)
A registry collecting health and exposure information from women who were diagnosed with COVID-19 or have received vaccinations against COVID-19 during pregnancy or while breastfeeding. The registry is maintained by Thomas Jefferson University in Philadelphia, Penn. It is a prospective cohort study of pregnant patients followed up to six weeks postpartum.
Healthcare providers may find more information about this registry at: https://www.clinicaltrials.gov/ct2/show/study/NCT04659759.
C-VIPER (COVID-19 Vaccines International Pregnancy Exposure Registry)
A registry collecting information from pregnant women who were vaccinated against COVID-19 during pregnancy and is maintained by Pregistry in Los Angeles, Calif. This registry evaluates obstetric, neonatal, and infant outcomes among women vaccinated during pregnancy to prevent COVID-19.
Healthcare providers may find additional information about this study at: https://www.clinicaltrials.gov/ct2/show/NCT04705116.
CANADIAN COVID-19 VACCINE REGISTRY FOR PREGNANT AND LACTATING INDIVIDUALS
A registry collecting information from women who are currently pregnant or breastfeeding regardless of vaccination status is maintained by the University of British Columbia in Vancouver, B.C., CANADA and in partnership with other Canadian vaccine surveillance networks. The registry is a longitudinal survey monitoring the safety, effectiveness, and opinions related to the COVID-19 vaccine.
Healthcare providers may find more information about this registry at: https://covered.med.ubc.ca/
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