key: cord-0707648-aakdfrho
authors: Della Gatta, Anna Nunzia; Rizzo, Roberta; Pilu, Gianluigi; Simonazzi, Giuliana
title: COVID19 during pregnancy: a systematic review of reported cases.
date: 2020-04-18
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.04.013
sha: f7a410a3df8d0a6aa490ded799f11613c4e23406
doc_id: 707648
cord_uid: aakdfrho

Abstract Objective to conduct a systematic review of the outcomes reported for pregnant patients with COVID 19. Data sources we searched electronically Pubmed, Cinahl, Scopus using combination of keywords “Coronavirus and/ or pregnancy”; “COVID and/or pregnancy”; “COVID disease and/or pregnancy”; “COVID pneumonia and/or pregnancy. There were no restriction of languages in order to collect as much cases as possible. Study eligibility criteria all pregnant women, with a COVID19 diagnosed with acid nucleic test, with reported data about pregnancy and, in case of delivery, reported outcomes. Study appraisal and synthesis methods all the studies included have been evaluated according the tool for evaluating the methodological quality of case reports and case series described by Murad et al. Results 6 studies including 51 women were eligible for the systematic review. Three pregnancies were ongoing at the time of the report; of the remaining 48, 46 were delivered with a cesarean section and 2 vaginally; there was 1 stillbirth and 1 neonatal death. Conclusions although vertical transmission of SARS-Cov2 has been excluded thus far and the outcome for mothers and fetuses has been generally good, the high rate of preterm cesarean delivery is a reason for concern. These interventions were typically elective, and it is reasonable to question whether they were warranted or not. COVID-19 associated with respiratory insufficiency in late pregnancies certainly creates a complex clinical scenario.

The following electronic databases were screened from 14th March until 16th March 2020 in order 96 to detect eligible papers: PubMed, Scopus and Cinahl. The search terms for retrieving articles 97 related with the theme of interest were: "Coronavirus and/ or pregnancy"; "COVID and/or 98 pregnancy"; "COVID disease and/or pregnancy"; "COVID pneumonia and/or pregnancy. Criteria for study selection 101

Reports included in the present review consisted of case series, case reports and retrospective 102 studies. No randomized controlled trials (RCT) were found. Only reports describing management 103 of pregnancies complicated by COVID-19 infection were included in this systematic review. We 104 registered this review on PROSPERO. We did not provide contacts with the corresponding authors 105 because the time constraints and the importance to have immediate results. The selection process followed the PRISMA workflow. We excluded 180 papers for these reasons: 132 animal studies (165), the abstract was not available (3), the contents were not related to the topic of 133 our review, or not provided any significant information (12) . To collect as much cases as possible, 134 no restriction on language (Chinese and English) was applied in the selection of articles. We 135 included only studies in which the diagnosis was based on the criteria provided by the New 136

Coronavirus Pneumonia Prevention and Control Program (4th edition and subsequent) published by 137 the National Health Commission of China. 5 After deletion of duplicates, thus, a total of 12 138 references were selected; 6 full text articles were excluded because data were not comparable. We 139 subsequently reviewed the 6 articles describing clinical presentation, pathogenesis, macroscopic and 140 histopathological aspects, natural history, diagnosis and treatment. Therefore, we selected all 141 reported cases aged up to 20 years and analyzed the following aspects: clinical features, symptoms, 142 associated diseases, fetal characteristics, time of delivery, type of delivery and follow-up. Two 143 study investigators (ANDG and RR) independently reviewed the data collection forms to verify 144 data accuracy. after delivery and one study included 3 ongoing pregnancies. 10 We found a total of 51 cases of 152 pregnancies with COVID-19 illness. In 50 patients the diagnosis of COVID-19 was confirmed by 153 quantitative Reverse transcriptase-polymerase chain reaction (qRT-PCR) on samples from the 154 respiratory tract. In one patient 16 IQR 1-4). Symptoms appeared after delivery in 3 cases. 16 We found no cases of infection during the first trimester of pregnancy; 2 cases of infection in the 178 second trimester and 49 cases in the third trimester. The two second trimester and one third 179 trimester (33weeks) cases were reported as ongoing. 10 Of the remaining 48 women, 2 had a 180 spontaneous vaginal delivery: one at 34 weeks and 2 days (in this case, diagnosis of COVID-19 181 was done only after delivery) and at 31 weeks (this was a case of twin pregnancy). 16 within 72 hours after birth and were negative with the exception of one infant that however was 204 only tested 36 hours after birth. One neonate was delivered by cesarean section at 34 weeks and 5 205 days, adequate for gestational age (AGA), admitted to intensive neonate care unit (NICU) 30 206 minutes after delivery due to shortness of breath and moaning, developed thrombocytopenia, liver 207 dysfunction, multiple organ failure and died 9 days after delivery. The authors stated that, although 208 a throat swab in this neonate was negative for COVID 19 disease, a perinatal infection cannot be 209 excluded. 16 Admission to the intensive neonate care unit in the remaining infants was not clearly 210 described. 211 212 Comment 213

Thus far, pregnant patients with COVID-19 illness have been almost invariably delivered by 215 cesarean section, and frequently before term gestation. This is a reason for concern, as the COVID-216 19 pandemia is spreading around the world and most likely many pregnant women will be 217 affected. 17 However, one may question whether the choices made by the obstetricians thus far were 218 modified. In most cases, the indication for the operation was not clearly stated, and it is certainly 219 possible that the decision was influenced by the understandable anxiety towards the potential 220 consequences of a new viral infection. 18-20 Indeed, in our analysis of the available literature, the 221 outcome has been generally favorable for both mothers and fetuses, although a word of caution is 222 necessary. Of 51 cases we have analyzed, at least one mother was severely compromised, and in 223 general follow-up data were scanty. We confirm that there is no evidence of vertical transmission, 224 but previous experience with infections, caused by similar pathogens, such as SARS and 225 MERS, 21, 22 indicates that vertical transmission is not the exclusive cause of fetal morbidity and 226 mortality. Out of 48 fetuses that were delivered, there was one stillbirth in a severely compromised 227 mother, and there was also one neonatal death that may not be independent from the infection. At 228 present, the available evidence does not provide insight as to these patients require or not a different 229 approach from a standard one. It would be important that in the near future studies around the 230 implications of COVID-19 in pregnancy contain thorough information about both the maternal and 231 fetal conditions at the time of delivery, as well as the rational behind obstetric interventions. 232 233 234

The main strength of our analysis is that we have provided thus far the largest series on pregnancies 236 with COVID-19 illness. The main weakness is that the available literature around the obstetric 237 implications of COVD-19 is limited, both in numbers and quality. The justification behind our 238 study is that the spread of the disease dictates the need to rapidly evaluate and discuss the evidence 239 that has been generated. favorable results that were observed seems unlikely, but cannot be excluded with certainty. In non-249 pregnant patients COVID-19 illness spans along a wide spectrum of severity. The majority of 250 patients, particularly those of young age, are asymptomatic or anyhow have no respiratory 251 compromise. In these cases, standard obstetric care seems sufficient, with the only caveat, that fetal 252 distress was described in almost 20% of cases. Whether this was related to maternal compromise or 253 not is not known, but it seems reasonable to provide continuous fetal monitoring in labor. In a 254 minority of patients (1 case in our series of 51) severe compromise will be present. In such a cases, 255 after fetal viability, cesarean delivery may be life -saving for both the mother and neonate. The 256 most difficult scenario is certainly the intermediate case, a patient with compensated respiratory 257 insufficiency, that may deteriorate in the following days. In preterm pregnancies, balancing the pros 258 and cons of a conservative management versus expediting the delivery is difficult, as well as 259 deciding the optimal mode to deliver a mother on the presence of hypoxia. The issue of obstetric 260 complications is also relevant. The high rate of premature delivery in our review appears to be 261 mostly the consequence of elective interventions. However, COVID-19 illness seems to be 262 associated with spontaneous preterm birth as well, as in our review preterm labour was reported in 263 at least 6/48 cases and premature rupture of the membranes in 9/34. 264

The available data on COVID-19 illness in pregnant patients do not provide a clear conclusion into 266 the clinical implications for mother and fetus. The outcome thus far described is favorable, but fetal 267 and maternal risks should be underestimated. Although preterm delivery was mostly the 268 consequence of elective interventions, a trend towards spontaneous prematurity is present. It is 269 essential that future studies provide more detailed information on maternal and fetal conditions, as 270 well as the rationale for obstetric interventions. Experience, thus far, is limited to patients that 271 developed the disease in late gestation and were delivered shortly after the diagnosis. Search strategy flow chart

World Health Organization. Coronavirus disease (COVID-19) outbreak 2020

The outbreak of COVID-19: An overview

Outcome of Coronavirus Spectrum Infections (SARS, MERS, COVID-19) 293 during Pregnancy: A Systematic Review and Meta-Analysis

COVID-19)Infection in Pregnancy. Information for Healthcare 296

Zhonghua bing li xue za

Lack of Vertical Transmission of Severe Acute Respiratory 310 Syndrome Coronavirus 2, China

Novel corona virus disease (COVID-19) in pregnancy: What clinical 313 recommendations to follow? Acta Obstet Gynecol Scand

Clinical manifestations and outcome of SARS-CoV-2 316 infection during pregnancy

Preferred Reporting Items for 318

Systematic Reviews and Meta-Analyses: The PRISMA Statement. www.annals.org

Methodological quality and synthesis of case 322 series and case reports

Novel coronavirus infection and pregnancy

Delivery of pregnancies with

Clinical analysis of 10 neonates born to mothers with 2019-330 nCoV pneumonia

Reflections on pandemics, past and present

Infant outcomes among women with Zika virus 334 infection during pregnancy: results of a large prenatal Zika screening program

Point-of-care HIV viral load in pregnant 337 women without prenatal care: a cost-effectiveness analysis

Additional Considerations Regarding Point-340 of-care HIV Viral Load in Pregnant Women Without Prenatal Care

Potential Maternal and Infant Outcomes from

Coronavirus 2019-nCoV Infecting Pregnant Women: Lessons from SARS, MERS, and Other

COVID-19) and Pregnancy: What obstetricians need to know

 Table 3 . Reported symptoms at diagnosis