Summary of Teratology Studies:
MAJOR CONGENITAL ANOMALIES
Epidemiological studies of infants of women who had SARS-CoV-2 infection during early pregnancy have not been reported.
OTHER ADVERSE PERINATAL OUTCOMES
Rates of stillbirth (3/266) and neonatal death (3/266) were both approximately 1% in a national population study of pregnancy outcomes in women with confirmed cases of SARS-CoV-2 (Knight et al., 2020). This study, using data from the United Kingdom Obstetric Surveillance System, also found a preterm birth rate of 25% (66/262). One infant born to a SARS-CoV-2 positive woman at 34 weeks gestation developed multiple organ failure and died but complications of prematurity likely contributed to this outcome (Zhu et al., 2020). There is currently no direct evidence linking maternal COVID-19 with an increased frequency of neonatal death (Chen et al., 2020c).
In women with severe or critical COVID-19, 10/32 delivered preterm infants before 34 weeks gestation and 19/32 delivered preterm infants before 37 weeks gestation in a multi-center cohort study (Pierce-Williams et al., 2020). When the analysis was restricted to cases of critical disease only, 15/17 births were preterm. No cases of stillbirth or neonatal death were reported in this study. In a smaller retrospective cohort study of women infected with SARS-CoV-2, 6/13 births were preterm (Liu et al., 2020b) and in a meta-analysis of data from 41 identified cases of maternal infection, 17/42 births were preterm (Di Mascio et al., 2020). Higher rates of neonatal complications were also reported in a review of data on pregnancy outcomes in 55 women infected with SARS-CoV-2; 39% (21/55) of births were preterm and 10% (6/55) were diagnosed with intrauterine growth retardation (Dashraath et al., 2020). This review used pooled data and likely included cases that have already been cited but the degree of overlap is unknown.
Some studies have found no increase in the risk of adverse perinatal outcomes. The frequency of preterm birth was not increased in an epidemiology study of 16 women infected with SARS-CoV-2 and 45 uninfected controls (Zhang et al., 2020) and in a clinical records review of 116 pregnancy outcomes in infected women (Yan et al., 2020). Similarly, no increased risk of preterm birth was found in a systematic review of 252 published cases (likely including previously cited data) of infants born to women with COVID-19 (Elshafeey et al., 2020).
Most studies of pregnancy and SARS-CoV-2 have been conducted during the third trimester in which the risk of transplacental transmission appears to be low. This is consistent with data on vertical transition from other coronaviruses (MERS and SARS) that suggest intrauterine transmission can occur but is rare (Schwartz & Dhaliwal, 2020).
SARS-CoV-2 was found in three of 11 placental and membrane samples collected from women with moderate to severe illness at the time of delivery (Penfield et al., 2020). All infants in the study were asymptomatic and tested negative with nasopharyngeal swabs for the first five days of life despite the presence of viral RNA in the placental and membrane samples. Amniotic fluid samples and the second round of neonatal nasal and throat swabs tested positive for SARS-CoV-2 in a healthy preterm infant born to a mother with severe COVID-19 (Zamaniyan et al., 2020). In a separate case report, a woman infected with SARS-CoV-2 delivered a full-term asymptomatic infant by C-section who had elevated IgM antibody levels and abnormal cytokine test results just two hours after birth (Dong et al., 2020). Although repeated nasopharyngeal swabs were negative in this neonate and infection during delivery could not be ruled out, elevated IgM in neonatal blood collected so close to delivery suggests intrauterine infection. The virus has also been identified in placental samples from a woman with COVID-19 who miscarried during her second trimester of pregnancy (Baud et al., 2020).
Positive test results were found in nasal swabs collected immediately after C-section delivery from two infants in a retrospective cohort study of 17 pregnant women with confirmed or suspected SARS-CoV-2 infections (Khan et al., 2020a). One of the two infants with positive nasal swabs developed neonatal pneumonia. In a case report, neonatal nasopharyngeal swabs collected at birth (before contact with the mother) and on days four and seven tested positive for SARS-CoV-2 in an infant born by C-section at 36 weeks gestation to a woman with confirmed COVID-19 (Kirtsman et al., 2020). This infant was vigorous at birth but admitted to the NICU at 37 hours for repeated episodes of hypoglycemia and difficulties with feeding. Similarly, a full-term infant with a positive nasopharyngeal swab collected close to the time of delivery developed fever and exhibited signs of pneumonia on postnatal day six (Govind et al., 2020) and an infant born at 34 weeks gestation with a positive nasopharyngeal swab collected approximately 16 hours after birth required respiratory support for six days (Alzamora et al., 2020). Supportive but less compelling evidence of possible vertical transmission has been found in studies where sample collection was more remote from delivery (Ferrazzi et al., 2020; Wang et al., 2020a; Yu et al., 2020; Zeng et al., 2020a).
The absence of vertical virus transmission has been widely reported. Repeated throat swabs were negative in three infants born to mothers with confirmed or suspected SARS-CoV-2 infections in a case-control study (Li et al., 2020b). Similarly, nasal swabs were negative in seven vaginally-delivered newborns in an epidemiological study of pregnant women with a clinical diagnosis of COVID-19 (Liao et al., 2020). No cases of vertical transmission were reported in 32 infants born to women with confirmed COVID-19 in a multi-site cohort study (Pierce-Williams et al., 2020).
No evidence of intrauterine SARS-CoV-2 transmission was found in record-linkage studies and clinical series that identified approximately 192 infants born to women with confirmed or suspected clinical cases of SARS-CoV-2 during pregnancy (Chen et al., 2020a, b, c, d; Liu et al., 2020a, b; Xu et al., 2020; Yan et al., 2020; Yang et al., 2020; Zeng et al., 2020b; Zhu et al., 2020). A variety of biological mediums were used in these studies to measure transmission of the virus, including amniotic fluid, cord blood and neonatal nasopharyngeal swabs, urine, feces, and blood and all tested negative.
Maternal vaginal secretion samples and neonatal throat and anal swabs collected on postnatal day one and three were negative in a records review study of five infants born to women with confirmed third trimester SARS-CoV-2 infections (Wu et al., 2020). These results suggest that vaginal delivery may be a relatively safe option for women with COVID-19. In multiple case reports, SARS-CoV-2 was not detected in samples collected from 17 infants born to women with confirmed or suspected COVID-19 (Buonsenso et al., 2020; Fan et al., 2020; Iqbal et al., 2020; Khan et al., 2020b; Kuhrt et al., 2020; Li et al., 2020a; Lu et al., 2020; Peng et al., 2020; Wang et al., 2020b; Xiong et al., 2020; Zambrano et al., 2020).
ANIMAL TERATOLOGY STUDIES
Studies of neonatal outcomes in the offspring of pregnant animals infected with SARS-CoV-2 have not been published in the peer-reviewed literature.
(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].)
Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, La Rosa M: Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol 37(8):861-865, 2020. [C]
Baud D, Greub G, Favre G, Gengler C, Jaton K, Dubruc E, Pomar L: Second-trimester miscarriage in a pregnant woman with SARS-CoV-2 infection. JAMA 323(21):2198-2200, 2020. [C]
Buonsenso D, Costa S, Sanguinetti M, Cattani P, Posteraro B, Marchetti S, Carducci B, Lanzone A, Tamburrini E, Vento G, Valentini P: Neonatal late onset infection with severe acute respiratory syndrome coronavirus 2. Am J Perinatol 37(8):869-872, 2020. [C]
Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, Li J, Zhao D, Xu D, Gong Q, Liao J, Yang H, Hou W, Zhang Y: Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 395(10226):809-815, 2020a. [S]
Chen L, Li Q, Zheng D, Jiang H, Wei Y, Zou L, Feng L, Xiong G, Sun G, Wang H, Zhao Y, Qiao J: Clinical characteristics of pregnant women with Covid-19 in Wuhan, China. N Engl J Med 382(25):e100, 2020c. [S]
Chen S, Liao E, Cao D, Gao Y, Sun G, Shao Y: Clinical analysis of pregnant women with 2019 novel coronavirus pneumonia. J Med Virol 2020b Mar 28 (published online ahead of print). [S]
Chen Y, Peng H, Wang L, Zhao Y, Zeng L, Gao H, Liu Y: Infants born to mothers with a new coronavirus (COVID-19). Front Pediatr 8:104, 2020d. [C]
Dashraath P, Wong JLJ, Lim MXK, Lim LM, Li S, Biswas A, Choolani M, Mattar C, Su LL: Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol 222(6):521-531, 2020. [R]
Di Mascio D, Khalil A, Saccone G, Rizzo G, Buca D, Liberati M, Vecchiet J, Nappi L, Scambia G, Berghella V, D'Antonio F: Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis. Am J Obstet Gynecol MFM 2(2 Suppl):100107, 2020. [R]
Dong L, Tian J, He S, Zhu C, Wang J, Liu C, Yang J: Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn. JAMA 323(18):1846-1848, 2020. [C]
Ellington S, Strid P, Tong VT, Woodworth K, Galang RR, Zambrano LD, Nahabedian J, Anderson K, Gilboa SM: Characteristics of women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status--United States, January 22-June 7, 2020. MMWR 69(25):769-775, 2020. [S]
Elshafeey F, Magdi R, Hindi N, Elshebiny M, Farrag N, Mahdy S, Sabbour M, Gebril S, Nasser M, Kamel M, Amir A, Emara MM, Nabhan A: A systematic scoping review of COVID-19 during pregnancy and childbirth. Int J Gynaecol Obstet 150(1):47-52, 2020. [R]
Fan C, Lei D, Fang C, Li C, Wang M, Liu Y, Bao Y, Sun Y, Huang J, Guo Y, Yu Y, Wang S: Perinatal transmission of COVID-19 associated SARS-CoV-2: should we worry? Clin Infect Dis 2020 Mar 17 (published online ahead of print). [C]
Ferrazzi E, Frigerio L, Savasi V, Vergani P, Prefumo F, Barresi S, Bianchi S, Ciriello E, Facchinetti F, Gervasi MT, Iurlaro E, Kustermann A, Mangili G, Mosca F, Patane L, Spazzini D, Spinillo A, Trojano G, Vignali M, Villa A, Zuccotti G, Parazzini F, Cetin I: Vaginal delivery in SARS-CoV-2 infected pregnant women in Northern Italy: a retrospective analysis. BJOG 2020 Apr 27 (published online ahead of print). [E]
Govind A, Essien S, Kartikeyan A, Fakokunde A, Janga D, Yoong W, Nakhosteen A: Re: Novel coronavirus COVID-19 in late pregnancy: outcomes of first nine cases in an inner city London hospital. Eur J Obstet Gynecol Reprod Biol 251:272-274, 2020. [S]
Hantoushzadeh S, Shamshirsaz AA, Aleyasin A, Seferovic MD, Aski SK, Arian SE, Pooransari P, Ghotbizadeh F, Aalipour S, Soleimani Z, Naemi M, Molaei B, Ahangari R, Salehi M, Oskoei AD, Pirozan P, Darkhaneh RF, Laki MG, Farani AK, Atrak S, Miri MM, Kouchek M, Shojaei S, Hadavand F, Keikha F, Hosseini MS, Borna S, Ariana S, Shariat M, Fatemi A, Nouri B, Nekooghadam SM, Aagaard K: Maternal death due to COVID-19. Am J Obstet Gynecol 223(1):109.e1-109.e16, 2020. [S]
Iqbal SN, Overcash R, Mokhtari N, Saeed H, Gold S, Auguste T, Mirza M-U, Ruiz M-E, Chahine JJ, Waga M, Wortmann G: An uncomplicated delivery in a patient with Covid-19 in the United States. N Engl J Med 382(16):e34, 2020. [C]
Khan S, Jun L, Nawsherwan, Siddique R, Li Y, Han G, Xue M, Nabi G, Liu J: Association of COVID-19 with pregnancy outcomes in health-care workers and general women. Clin Microbiol Infect 26(6):788-790, 2020a. [S]
Khan S, Peng L, Siddique R, Nabi G, Nawsherwan, Xue M, Liu J, Han G: Impact of COVID-19 infection on pregnancy outcomes and the risk of maternal-to-neonatal intrapartum transmission of COVID-19 during natural birth. Infect Control Hosp Epidemiol 41(6):748-750, 2020b. [C]
Kirtsman M, Diambomba Y, Poutanen SM, Malinowski AK, Vlachodimitropoulou E, Parks WT, Erdman L, Morris SK, Shah PS: Probable congenital SARS-CoV-2 infection in a neonate born to a woman with active SARS-CoV-2 infection. CMAJ 192(24):E647-E650, 2020. [C]
Knight M, Bunch K, Vousden N, Morris E, Simpson N, Gale C, O'Brien P, Quigley M, Brocklehurst P, Kurinczuk JJ: Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-CoV-2 infection in UK: national population based cohort study. BMJ 369:m2107, 2020. [E]
Kuhrt K, McMicking J, Nanda S, Nelson-Piercy C, Shennan A: Placental abruption in a twin pregnancy at 32 weeks' gestation complicated by coronavirus disease 2019 without vertical transmission to the babies. Am J Obstet Gynecol MFM 2020 May 8 (published online ahead of print). [C]
Li N, Han L, Peng M, Lv Y, Ouyang Y, Liu K, Yue L, Li Q, Sun G, Chen L, Yang L: Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study. Clin Infect Dis 2020b Mar 30 (published online ahead of print). [E]
Li Y, Zhao R, Zheng S, Chen X, Wang J, Sheng X, Zhou J, Cai H, Fang Q, Yu F, Fan J, Xu K, Chen Y, Sheng J: Lack of vertical transmission of severe acute respiratory syndrome coronavirus 2, China. Emerg Infect Dis 26(6):1335-1336, 2020a. [C]
Liao J, He X, Gong Q, Yang L, Zhou C, Li J: Analysis of vaginal delivery outcomes among pregnant women in Wuhan, China during the COVID-19 pandemic. Int J Gynaecol Obstet 150(1):53-57, 2020. [S]
Liu W, Wang J, Li W, Zhou Z, Liu S, Rong Z: Clinical characteristics of 19 neonates born to mothers with COVID-19. Front Med 14(2):193-198, 2020a. [E]
Liu Y, Chen H, Tang K, Guo Y: Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy. J Infect 2020b Mar 4 (published online ahead of print). [E]
Lu D, Sang L, Du S, Li T, Chang Y, Yang X-A: Asymptomatic COVID-19 infection in late pregnancy indicated no vertical transmission. J Med Virol. 2020 Apr 24 (published online ahead of print). [C]
Penfield CA, Brubaker SG, Limaye MA, Lighter J, Ratner AJ, Thomas KM, Meyer J, Roman AS: Detection of severe acute respiratory syndrome coronavirus 2 in placental and fetal membrane samples. Am J Obstet Gynecol MFM 2020 May 8 (published online ahead of print). [E]
Peng Z, Wang J, Mo Y, Duan W, Xiang G, Yi M, Bao L, Shi Y: Unlikely SARS-CoV-2 vertical transmission from mother to child: a case report. J Infect Public Health 13(5):818-820, 2020. [C]
Pierce-Williams RAM, Burd J, Felder L, Khoury R, Bernstein PS, Avila K, Penfield CA, Roman AS, DeBolt CA, Stone JL, Bianco A, Kern-Goldberger AR, Hirshberg A, Srinivas SK, Jayakumaran JS, Brandt JS, Anastasio H, Birsner M, O'Brien DS, Sedev HM, Dolin CD, Schnettler WT, Suhag A, Ahluwalia S, Navathe RS, Khalifeh A, Anderson K, Berghella V: Clinical course of severe and critical COVID-19 in hospitalized pregnancies: a US cohort study. Am J Obstet Gynecol MFM 2020 May 8 (published online ahead of print). [E]
Schwartz DA, Dhaliwal A: Infections in pregnancy with COVID-19 and other respiratory RNA virus diseases are rarely, if ever, transmitted to the fetus: experiences with coronaviruses, HPIV, hMPV RSV, and influenza. Arch Pathol Lab Med 2020 Apr 27 (published online ahead of print). [R]
Shanes ED, Mithal LB, Otero S, Azad HA, Miller ES, Goldstein JA: Placental pathology in COVID-19. Am J Clin Pathol 154:23-32, 2020. [O]
Stumpfe FM, Titzmann A, Schneider MO, Stelzl P, Kehl S, Fasching PA, Beckmann MW, Ensser A: SARS-CoV-2 infection in pregnancy--a review of the current literature and possible impact on maternal and neonatal outcome. Geburtshilfe Frauenheilkd 80(4):380-390, 2020. [R]
Wang S, Guo L, Chen L, Liu W, Cao Y, Zhang J, Feng L: A case report of neonatal COVID-19 infection in China. Clin Infect Dis 2020a Mar 12 (published online ahead of print). [C]
Wang X, Zhou Z, Zhang J, Zhu F, Tang Y, Shen X: A case of 2019 novel coronavirus in a pregnant woman with preterm delivery. Clin Infect Dis 2020b Feb 28 (published online ahead of print). [C]
Wu Y, Liu C, Dong L, Zhang C, Chen Y, Liu J, Zhang C, Duan C, Zhang H, Mol BW, Dennis C-L, Yin T, Yang J, Huang H: Coronavirus disease 2019 among pregnant Chinese women: Case series data on the safety of vaginal birth and breastfeeding. BJOG 2020 May 5 (published online ahead of print). [S]
Xiong X, Wei H, Zhang Z, Chang J, Ma X, Gao X, Chen Q, Pang Q: Vaginal delivery report of a healthy neonate born to a convalescent mother with COVID-19. J Med Virol 2020 Apr 10 (published online ahead of print). [C]
Xu L, Yang Q, Shi H, Lei S, Liu X, Zhu Y, Wu Q, Ding X, Tian Y, Hu Q, Chen F, Geng Z, Zeng X, Lin L, Cai X, Wu M, Wang Z, Wang Z, Xia G, Wang L: Clinical presentations and outcomes of SARS-CoV-2 infected pneumonia in pregnant women and health status of their neonates. Sci Bull 2020 Apr 28 (published online ahead of print). [S]
Yan J, Guo J, Fan C, Juan J, Yu X, Li J, Feng L, Li C, Chen H, Qiao Y, Lei D, Wang C, Xiong G, Xiao F, He W, Pang Q, Hu X, Wang S, Chen D, Zhang Y, Poon LC, Yang H: Coronavirus disease 2019 in pregnant women: a report based on 116 cases. Am J Obstet Gynecol 223(1):111.e1-111.e14, 2020. [E]
Yang P, Wang X, Liu P, Wei C, He B, Zheng J, Zhao D: Clinical characteristics and risk assessment of newborns born to mothers with COVID-19. J Clin Virol 127:104356, 2020. [S]
Yu N, Li W, Kang Q, Xiong Z, Wang S, Lin X, Liu Y, Xiao J, Liu H, Deng D, Chen S, Zeng W, Feng L, Wu J: Clinical features and obstetric and neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, single-centre, descriptive study. Lancet Infect Dis 20(5):559-564, 2020. [S]
Zaigham M, Andersson O: Maternal and perinatal outcomes with COVID-19: a systematic review of 108 pregnancies. Acta Obstet Gynecol Scand 99(7):823-829, 2020. [R]
Zamaniyan M, Ebadi A, Aghajanpoor Mir S, Rahmani Z, Haghshenas M, Azizi S: Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical transmission. Prenat Diagn 2020 Apr 17 (published online ahead of print). [C]
Zambrano LI, Fuentes-Barahona IC, Bejarano-Torres DA, Bustillo C, Gonzales G, Vallecillo-Chinchilla G, Sanchez-Martinez FE, Valle-Reconco JA, Sierra M, Bonilla-Aldana DK, Cardona-Ospina JA, Rodriguez-Morales AJ: A pregnant woman with COVID-19 in Central America. Travel Med Infect Dis 2020 Mar 25 (published online ahead of print). [C]
Zeng H, Xu C, Fan J, Tang Y, Deng Q, Zhang W, Long X: Antibodies in infants born to mothers with COVID-19 pneumonia. JAMA 323(18):1848-1849, 2020b. [S]
Zeng L, Xia S, Yuan W, Yan K, Xiao F, Shao J, Zhou W: Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China. JAMA Pediatr 174(7):722-725, 2020a. [E]
Zhang L, Jiang Y, Wei M, Cheng BH, Zhou XC, Li J, Tian JH, Dong L, Hu RH: [Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei Province.] Zhonghua Fu Chan Ke Za Zhi 55(3):166-171, 2020. [E]
Zhu H, Wang L, Fang C, Peng S, Zhang L, Chang G, Xia S, Zhou W: Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia. Transl Pediatr 9(1):51-60. 2020. [S]
COVID-19 PREGNANCY STUDIES
Pregnancy studies have been established for women infected with, or exposed to, the SARS-CoV-2 coronavirus (which causes COVID-19) during pregnancy.
Healthcare providers are encouraged to enroll such patients in the MotherToBaby Pregnancy Study by calling 877-311-8972 (https://mothertobaby.org/join-study/) or in the PRIORITY (Pregnancy CoRonavIrus Outcomes RegIsTrY) Study by calling 415-754-3729 (https://priority.ucsf.edu/).