key: cord-0851417-c2cpi31n
authors: Kotlyar, Alexander; Grechukhina, Olga; Chen, Alice; Popkhadze, Shota; Grimshaw, Alyssa; Tal, Oded; Taylor, Hugh S.; Tal, Reshef
title: Vertical Transmission of COVID-19: A Systematic Review and Meta-analysis
date: 2020-07-31
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.07.049
sha: 049fc4496eac2671760abdc3a2054325d7730ad7
doc_id: 851417
cord_uid: c2cpi31n

Abstract Objective We sought to conduct a systematic review of the current literature to determine estimates of vertical transmission of COVID-19 based upon early RNA detection of SARS-CoV-2 after birth from various neonatal/fetal sources and neonatal serology. Data sources Eligible studies published up to May 28, 2020 were retrieved from Pubmed, EMbase, MedRXiv, BioRXiv collection databases. Study eligibility criteria This systematic review included cohort studies, case series and case reports of pregnant women who had COVID-19 infection as confirmed by positive SARS-CoV-2 viral RNA testing, and had reported data regarding testing of neonates/fetuses for SARS-CoV-2 immediately after birth and up to within 48hrs of birth. In total, 30 eligible case reports describing 43 tested neonates, and 38 cohort/case series studies describing 936 tested neonates were included. Study appraisal and synthesis methods The methodological quality of all included studies was evaluated by a modified Newcastle-Ottawa scale. Quantitative synthesis was performed on cohort/case series studies according to neonatal biological specimen site to reach pooled proportions of vertical transmission. Results Our quantitative synthesis revealed that of 936 neonates from COVID-19 infected mothers, 27 neonates had SARS-CoV-2 viral RNA positive nasopharyngeal swab, indicating a pooled proportion of 3.2% (95% CI 2.2-4.3%) for vertical transmission. Notably, the pooled proportion of SARS-CoV-2 positivity in neonates by nasopharyngeal swab in studies from China was 2.0% (8/397) which was similar to pooled proportion of 2.7% (14/517) in studies from outside of China. SARS-CoV-2 viral RNA testing in neonatal cord blood was positive in 2.9% (1/34) of samples, 7.7% (2/26) of placenta samples, 0% (0/51) of amniotic fluid and 0% (0/17) of urine samples and 9.7% (3/31) of fecal/rectal swabs. Neonatal serology was positive in 3/82 (3.7%) (based upon the presence of IgM). Conclusion Vertical transmission of SARS-CoV-2 is possible and appears to occur in a minority of cases of maternal COVID-19 infection in third trimester. Rates of infection are similar to other pathogens that cause congenital infections. However, given the paucity of early trimester data, no assessment can yet be made regarding rates of vertical transmission in early pregnancy as well as potential risk for consequent fetal morbidity and mortality.

women are not at increased risk of spontaneous abortion or spontaneous preterm birth but have 128 higher rates of cesarean delivery (11, 12) . 129

Vertical transmission is defined as the transmission of the infectious pathogen from the 130 mother to the fetus/neonate during the antepartum, intrapartum or postpartum period via the 131 placenta in-utero, body fluid contact during childbirth and/or through direct contact of breast-132 feeding after birth. Although multiple infectious vectors have been shown to be capable of 133 vertical transmission, the possibility of vertical transmission of SARS-CoV-2 from the infected 134 mother to the fetus/neonate has been a point of a recent debate with prior systematic reviews, 135 albeit with a limited number of studies, concluding that there is no evidence of vertical 136 transmission (13-16). No known cases of vertical transmission have been noted with similar 137 coronaviruses such as SARS and Middle East Respiratory Syndrome (MERS), although the 138 number of cases has been limited (17, 18) . COVID-19 shares 50% and 79% sequence homology 139 with SARS and MERS, respectively; despite this homology, a similar lack of vertical 140 transmission cannot be assumed (6) . 141

Concern over vertical transmission in the case of COVID-19 exists for several reasons. 142

First is the known tissue tropism of COVID-19. The main receptor that COVID-19 binds to enter 143 a cell is the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is expressed in the 144 placenta (19) and is found in both the syncytiotrophoblast, cytotrophoblast, endothelium and 145 vascular smooth muscle from both primary and secondary villi (20). A recent systematic review 146 also found evidence that ACE2 is expressed in gynecologic organs such as the ovary, uterus, and 147 vagina (21). Overall, ACE2 expression is seen in numerous tissues which are in direct 148 communication with a developing pregnancy. These data were further bolstered by a recent 149 single cell RNA-seq analysis which found expression of ACE2 in stromal, perivascular, Answering the question of vertical transmission is crucial for guiding patient counseling 168 regarding COVID-19 related risks before and during pregnancy as well as obstetric care for 169 women infected with COVID-19. Therefore, we conducted this systematic review to summarize 170 the available evidence regarding the risk of vertical transmission. 171 172

A systematic search of the literature was conducted by a medical librarian in Pubmed, EMbase, 175 MedRXiv, BioRXiv collection databases to find relevant articles published from inception of 176 database to May 28, 2020 to identify cohort studies, case series and case reports of pregnant 177 women with COVID-19 infection which include information regarding fetal/neonatal COVID-19 178 testing. The study was conducted according to the Preferred Reporting Items for Systematic 179

Reviews and Meta-analysis (PRISMA) guidelines for the reporting of systematic reviews and 180 meta-analyses and was registered in PROSPERO (CRD42020190885). Databases were searched 181 using a combination of controlled vocabulary and free text terms for SARS-CoV-2, COVID-19, 182 coronavirus, coronaviridae, pregnancy, fetus, infant, mother-to-child, mother-to-infant, maternal-183 fetal, virus transmission, disease transmission, and vertical transmission (full search strategy is 184 provided in Supplemental Figure 1 ). Search results were limited to English language abstracts. 185

Foreign language articles were included only if a translation was available due to the time-186 sensitive nature of this review. Bibliographies were cross-referenced to identify additional 187 relevant studies. Studies were included if they were English-language articles that focused on the 188 development of COVID-19 infection in fetuses and neonates. Citations from all databases were 189 imported into an Endnote X9 library. Duplicates were removed in Endnote, reducing the initial 190 list of 4907 citations to 2904 citations. The database of 2904 citations was entered into 191

Covidence, a screening and data extraction tool. Two independent screeners (A.K. and O.G.) 192 performed a title abstract review and resolved conflicts by consensus between the two screeners. 193

The screeners selected a total of 81 records for full text review and included 68 studies which 194 fulfilled the eligibility criteria in the qualitative synthesis ( Figure 1) Each cohort or case series study selected for final inclusion in the quantitative synthesis was 215 scored by the researchers (A.C. and R.T.) using a modified Newcastle-Ottawa scale (NOS) as 216 previously described (Supplemental Figure 1 ) (32). Items that relate to comparability and 217 adjustment are not relevant and were removed while items that focused on selection and 218 representativeness of cases, and ascertainment of outcome and exposure were maintained. This has resulted in 5 items regarding study quality characteristics: (1) representativeness of exposed 220 cohort, (2) exposure assessment, (3) outcome assessment, (4) adequacy of length of time before 221 follow-up, and (5) adequacy of follow-up of cohorts. We considered the quality of the report 222 good (low risk of bias) when all 5 criteria are fulfilled, moderate when 4 are fulfilled, and poor 223 (high risk of bias) when 3 or less are fulfilled. Table 1 . A total of 39 additional studies were cohort/case series (defined as 5 or more patients) and were selected for quantitative synthesis. 243

The characteristics and test findings of these cohort/case series studies are summarized in Tables 244 2 and 3. They were divided into reports from China (Table 2 ) and reports from the rest of the 245 World (Table 3) The current systematic review included 30 eligible case reports describing a total of 44 SARS-255

CoV-2 positive pregnant women with outcomes available for 43 neonates (Table 1) (Table 2 ) and 17 studies from countries outside of China (Italy, Spain, UK and USA) 294 (Table 3) Other neonatal sites have been tested for SARS-CoV-2 RNA. A total of 8 cohort/case series 364 studies included in this systematic review had SARS-CoV-2 testing of amniotic fluid (6 from 365 China, one from UK and one from Italy). There were no positive cases out of 51 total amniotic 366 fluid specimens tested (0/51) ( Figure 2 ). However, we identified two case reports of positive 367 amniotic fluid testing (Table 1 ). In the first case report, sterilely collected amniotic fluid (via 368 syringe prior to rupturing the membranes) during a cesarean delivery performed on a critically ill 369 mother at 34 weeks of gestation, was subjected to RT-PCR and resulted positive for SARS-CoV-370 2 RNA. The infant was immediately separated from the mother, and initial testing was negative 371 for SARS-CoV-2 RNA in the NP samples, however the second neonatal NP swab was positive at Zika and Rubella, vertical transmission remains a concern with COVID-19. Compared to other 444 known viruses leading to congenital infections, the vertical transmission rates reported in this 445 review are consistent with numerous pathogens. The transmission rates for these pathogens range 446 from as low as 0.2-0.4% for cytomegalovirus and varicella-zoster virus to as high as 17-33% for Parvovirus B19 (98). While the vast majority of the infants delivered in these reports did not 448 experience significant morbidity and mortality, nearly all of them were born in the third trimester 449 (98). For the aforementioned pathogens, transplacental passage of infectious pathogens tends to 450 occur with increasing frequency as gestational age increases, while detrimental effects on the 451 fetus increase with decreasing gestational age. Therefore, we should assume that COVID-19 also 452 may have similar detrimental effects when maternal infection occurs early in gestation. 453

In addition to direct fetal infection and subsequent teratogenicity, indirect fetal affects are 454 also a major concern with COVID-19 infection. It has recently been proposed that COVID The standard for detecting COVID-19 infection is via detection of viral RNA using 474 reverse-transcription-polymerase chain reaction (RT-PCR). However, this diagnostic method 475 does exhibit variable performance. In one study assessing the performance capability of RT-PCR 476 test in patients with COVID-19 using numerous sources for viral RNA including nasal, broncho-477 alveolar lavage, feces, blood and urine specimens, sensitivities for COVID-19 detection were 478 63%, 93%, 29%, 1% and 0%, respectively (103). In our systematic review, blood similarly had 479 one of the lowest rates of SARS-CoV-2 detection (2.9%), along with urine (0%) and amniotic 480 fluid (0%). The lack of detection of SARS-CoV-2 in amniotic fluid is not surprising since its 481 source of production is fetal urine. Nevertheless, such substantial variation in SARS-CoV-2 482 positivity as a factor of testing site argues for specimens testing from multiple sites in order to 483 increase sensitivity and reduce false negative rates, and preferably utilizing complementary 484 testing methods such as serology. In this systematic review, the rate of IgM positivity in tested 485 neonates was 3.6% which is quite similar to positive rates by RT-PCR nasopharyngeal testing 486 

ACE2 expression and activity 599 are enhanced during pregnancy

Potential influence of COVID-19/ACE2 on the 605 female reproductive system

The SARS-CoV-2 receptor ACE2 expression of 608 maternal-fetal interface and fetal organs by single-cell transcriptome study

Mouse hepatitis virus and host determinants of 614 vertical transmission and maternally-derived passive immunity in mice

Possible Vertical Transmission of SARS-CoV-2 From an 617 Infected Mother to Her Newborn

Antibodies in Infants Born to 619 Mothers With COVID-19 Pneumonia

Vertical transmission of COVID-19: SARS-CoV-629 2 RNA on the fetal side of the placenta in pregnancies with COVID-19 positive mothers and 630 neonates at birth

Frequency and Prognosis of

Acute Pancreatitis Associated With Fulminant or Non-Fulminant Acute Hepatitis A: A 635 Systematic Review

Transformations Related to the Angular and the Square Root

Meta-analysis in Clinical Trials

Spike mutation pipeline reveals the 641 emergence of a more transmissible form of SARS-CoV-2. bioRXiv

Vaginal delivery report of a healthy neonate born to a 647 convalescent mother with COVID-19

A case report of neonatal 650 COVID-19 infection in China

Severe acute respiratory distress syndrome in 653 coronavirus disease

Unlikely SARS-CoV-2 vertical transmission from mother 656 to child: A case report

Asymptomatic COVID 19 infection in -658 late pregnancy indicated no vertical transmission

COVID 19 vaginal delivery --A case report

COVID-19) During 663 Pregnancy: A Case Series

Lack of Vertical Transmission of Severe Acute Respiratory 665 Syndrome Coronavirus 2

Impact of COVID-19 infection on pregnancy 667 outcomes and the risk of maternal-to-neonatal intrapartum transmission of COVID-19 during 668 natural birth

Lung ultrasound and computed tomographic 670 findings in pregnant woman with COVID 19 Ultrasound Obstet Gyne col

CoV-2 medRxiv

Pregnancy With New Coronavirus Infection: Clinical 674 Characteristics and Placental Pathological Analysis of Three Cases

Acute Respiratory Distress Syndrome in a 677 Preterm Pregnant Patient With Coronavirus Disease 2019 (COVID-19). Obstetrics & 678 Gynecology. 2020;Volume Publish Ahead of Print. 679 50

Severe Acute Respiratory Syndrome Coronavirus

CoV-2) Infection During Pregnancy In China: A Retrospective Cohort Study. medRxiv

Emergency cesarean section on severe acute respiratory 691 syndrome coronavirus 2 (SARS-CoV-2) confirmed patient

Dialectical behavior therapy-based psychological 696 intervention for woman in late pregnancy and early postpartum suffering from COVID-19: a 697 case report

COVID 19 in pregnancy with 699 comorbidities: More liberal testing strategy is needed

Clinical role of lung ultrasound for the 703 diagnosis and monitoring of COVID 19 pneumonia in pregnant women

Visualization of SARS-CoV-2 virus 707 invading the human placenta using electron microscopy

CoV-2 infection

Clinical features and obstetric and 711 neonatal outcomes of pregnant patients with COVID-19 in Wuhan, China: a retrospective, 712 single-centre, descriptive study

Clinical characteristics and risk 714 assessment of newborns born to mothers with COVID-19

Clinical features and outcomes of 716 pregnant women suspected of coronavirus disease 2019

Coronavirus disease 2019 among 718 pregnant Chinese women: case series data on the safety of vaginal birth and breastfeeding 719

Radiological findings and clinical characteristics of pregnant 721 women with COVID 19 pneumonia

Coronavirus disease 2019 in pregnancy

Clinical features and the maternal and neonatal outcomes 726 of pregnant women with coronavirus disease 2019. medRxiv

The immunologic status of 729 newborns born to SARS-CoV2-infected mothers in Wuhan

Neonatal Early-Onset Infection With SARS-CoV-2 in 33

Neonates Born to Mothers With COVID-19 in Wuhan, China

Analysis of vaginal delivery outcomes 734 among pregnant women in Wuhan, China during the COVID 19 pandemic

Association of COVID-19 infection with pregnancy 737 outcomes in healthcare workers and general women

CoV-2) Vertical Transmission in Neonates Born to Mothers With Coronavirus Disease

Clinical analysis of pregnant women with 743 2019 novel coronavirus pneumonia

Safety and efficacy of 746 different anesthetic regimens for parturients with COVID-19 undergoing Cesarean delivery: a 747 case series of 17 patients

Clinical analysis of ten pregnant women with COVID-19 in

China: A retrospective study

Effects of SARS-CoV-2 infection on 751 pregnant women and their infants: A retrospective study in Wuhan, China

Vaginal delivery in SARS CoV 2 infected 758 pregnant women in Northern Italy: a retrospective analysis

Clinical course of 764 Coronavirus Disease 2019 (COVID 19) in pregnancy. Acta Obstetricia et Gynecologica 765 Scandinavica

Analysis of complement 770 deposition and viral RNA in placentas of COVID-19 patients

Pregnancy affected by SARS-CoV-2 infection: a flash report from

Clinical Characteristics of 46 Pregnant Women 776 with a SARS-CoV-2 Infection in Washington State

Novel Coronavirus COVID-19 in late 779 pregnancy: Outcomes of first nine cases in an inner city London hospital

Coronavirus disease 2019 infection 788 among asymptomatic and symptomatic pregnant women: two weeks of confirmed presentations 789 to an affiliated pair of New York City hospitals

Screening all pregnant women admitted to labor and delivery for the virus responsible for 796 coronavirus disease 2019

Preterm delivery in pregnant woman with critical COVID-19 pneumonia and vertical 799 transmission

Persistent viral shedding of SARS

Colorectal disease : the official journal of the Association of 802 Coloproctology of Great Britain and Ireland. 2020. 803 94

Probable congenital SARS-CoV-2 infection in a neonate born to a woman with 808 active SARS-CoV-2 infection

Hypertension, 818 Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A 819 Comprehensive Evaluation of Clinical and Basic Evidence

Pathophysiological 822 characteristics and therapeutic approaches for pulmonary injury and cardiovascular 823 complications of coronavirus disease 2019. Cardiovascular pathology : the official journal of the 824 Society for Cardiovascular Pathology

Coagulopathy of Coronavirus Disease

A Systematic Review of Vascular Structure and 828 Function in Pre-eclampsia: Non-invasive Assessment and Mechanistic Links