
25.6-57.6) of cases, while the rate of perinatal death was 7.0% (95% CI 1.4-16.3). None of the 41 84 newborns assessed showed clinical signs of vertical transmission. 85
Conclusion:
In mothers infected with coronavirus infections, including COVID-19, >90% of whom 86 also had pneumonia, PTB is the most common adverse pregnancy outcome. Miscarriage, 87 preeclampsia, cesarean, and perinatal death (7-11%) were also more common than in the general 88 population. There have been no published cases of clinical evidence of vertical transmission. 89
Conclusion:
Evidence is accumulating rapidly, so these data may need to be updated soon. The findings from 90 this study can guide and enhance prenatal counseling of women with COVID-19 infection 91 occurring during pregnancy. 92
INTRODUCTION 98
Coronavirus (CoV) is an enveloped, positive-stranded ribonucleic acid (RNA) virus of the family of 99
INTRODUCTION 98
Coronaviridae and belonging to the Nidovirales order, 1 generally causing respiratory and 100 gastrointestinal infections that might range from mild, self-limiting conditions to more serious 101 disorders, such as viral pneumonia with systemic impairment. 2 
102
In the last two decades, CoV has been responsible for two large epidemics: the Severe Acute 103
102
Respiratory Syndrome (SARS) that infected 8098 people with a case-fatality rate of about 10.5%, 3 104 and the Middle East Respiratory Syndrome (MERS) with a total of 2519 laboratory-confirmed 105 cases and a case-fatality rate of 34.4%. 4 106 Towards the end of 2019, a novel mutation of CoV (labelled as SARS-COV-2) was identified as the 107 cause of a severe respiratory illness -called COVID-19 -that typically presents with fever and 108 cough. 5 Infected people show abnormal findings at diagnostic imaging, suggestive for pneumonia. 109
102
After beginning as an epidemic in China, COVID-19 infection has rapidly spread in many other 110 countries and the number of affected cases continues to increase significantly on a daily basis. The 111 overall mortality rate ranges from 3% to 4% according to the World Health Organization reports, 6 112 but a higher rate of patients require admission to the intensive care unit (ICU). 7 113
102
It is well known that physiologic maternal adaptations to pregnancy predispose pregnant women to 114 a more severe course of pneumonia, with subsequent higher maternal and fetal morbidity and 115 mortality, 1, 8 but there is a lack of data in the literature about the effect of CoV infections during 116 pregnancy, thus limiting both counseling and management of these patients. 117
102
Objective 118
102
The aim of this systematic review was to report pregnancy and perinatal outcomes of CoV spectrum 119 infections and particularly COVID-19 during pregnancy. 120
METHODS 123

Search strategy and selection criteria 124
This review was performed according to a priori designed protocol recommended for systematic 125 reviews and meta-analysis. 9-11 Medline, Embase, Cinahl and Clinicaltrials.gov databases were 126 searched electronically on 03/13/2020, utilizing combinations of the relevant medical subject 127 heading (MeSH) terms, key words, and word variants for "coronavirus" or "severe acute respiratory 128 syndrome" or "SARS" or "Middle East respiratory syndrome" or "MERS" or "COVID-19" and 129 "pregnancy". The search and selection criteria were restricted to English language. Reference lists 130 of relevant articles and reviews were hand searched for additional reports. PRISMA and MOOSE 131 guidelines were followed. 12-14 132
Search strategy and selection criteria 124
Inclusion criteria were pregnant women with a confirmed Coronavirus spectrum illness, defined as 133 either SARS, MERS or COVID-19 infection. 134
Search strategy and selection criteria 124
The pregnancy outcomes observed were: 135
Search strategy and selection criteria 124
• Preterm birth (PTB) (either before 37 or 34 weeks of gestation) 136
Search strategy and selection criteria 124
• Pre-eclampsia (PE) 137
Search strategy and selection criteria 124
• Preterm prelabor rupture of membranes (pPROM) 138
Search strategy and selection criteria 124
• Fetal growth restriction (FGR) 139
Search strategy and selection criteria 124
• Miscarriage, as defined by authors 140
Search strategy and selection criteria 124
• Cesarean mode of delivery 141
Search strategy and selection criteria 124
The perinatal outcomes observed were: 142
Search strategy and selection criteria 124
• Fetal distress (as defined by original authors) 143
Search strategy and selection criteria 124
• Apgar score < 7 at five minutes 144
Search strategy and selection criteria 124
• Neonatal asphyxia (as defined by original authors) 145
Search strategy and selection criteria 124
• Evidence of vertical transmission, defined as the presence of clinical signs of mother-to-148 child transmission in the antenatal or perinatal period 149 150 Furthermore, we aimed to perform a sub-group analysis according to the trimester of pregnancy at 151 infection and the type of Coronavirus. 152 Data from studies reporting the incidence of these outcomes in pregnancies with CoV spectrum 153 infections were considered eligible for analysis. For the purpose of the analysis, we included only 154 full-text articles with data of pregnant women who already delivered; we excluded data regarding 155 on-going pregnancies. Furthermore, as these are relatively rare infections occurring during 156 pregnancy with the majority of data coming from studies with small sample sizes, case reports and 157 case series were also included in the analysis. Studies reporting cases of infective pneumonia or 158 other respiratory disorders during pregnancy caused by other viral agents were excluded. We also 159 excluded studies pediatric series on newborns and children from which maternal and pregnancy 160 information could not be extrapolated. 161
Search strategy and selection criteria 124
Two authors (DDM, GS) reviewed all abstracts independently. Agreement regarding potential 162 relevance or inconsistencies was reached by consensus or resolved by discussion with a third 163 reviewer (FDA). Full text copies of applicable papers were obtained, and the same reviewers 164 independently extracted relevant data regarding study characteristics and pregnancy outcome. If 165 more than one study was published on the same cohort with identical endpoints, the report 166 containing the most comprehensive information on the population was included to avoid 167 overlapping populations. 168 169
Data analysis 170
We used meta-analyses of proportions to combine data and reported pooled proportions (PP). 171
Data analysis 170
Funnel plots (displaying the outcome rate from individual studies versus their precision (1 per SE)) 172 were carried out with an exploratory aim. Tests for funnel plot asymmetry were not used when the total number of publications included for each outcome was <10. In this case, the power of the tests 174 is too low to distinguish chance from real asymmetry. 175
Data analysis 170
Between-study heterogeneity was explored using the I 2 statistic, which represents the percentage of 176 between-study variation that is due to heterogeneity rather than chance. A value of 0% indicates no 177 observed heterogeneity, whereas I 2 values ≥50% indicate a substantial level of heterogeneity. A 178 random effect model was used to compute the pooled data analyses. All proportion meta-analyses 179 were carried out by using StatsDirect version 2.7.9 (StatsDirect, Ltd, Altrincham, Cheshire, United 180 Kingdom). 181 Quality assessment of the included studies was assessed using the methodological quality and 182 synthesis of case series and case reports described by Murad et al. 15 According to this tool, each 183 study is judged on four broad perspectives: the selection of the study groups, the ascertainment and 184 the causality of the outcome observed, and the reporting of the case. A study can be awarded a 185 maximum of one star for each numbered item within the Selection and Reporting categories, two 186 stars for Ascertainment and four stars for Comparability. 15 Table 2 ). The most common symptom was fever that affected 82.6% (64/76) of 200 women, followed by cough (57.1%, 44/77) and dyspnea (27%, 21/77). Lymphopenia and elevated 201 liver enzymes were found in 79.8% (40/48) and 36.6% (9/26) of cases, respectively. 34.1% (22/70) 202 of pregnant women affected by CoV infections were admitted to ICU and 26.3% (16/69) required 203 mechanical ventilation. Maternal death occurred in 12.3% (9/79) of all reported CoV-related 204 diseases cases. Of note, the rates of admission to ICU (9.3% vs 44.6% vs 53.3%), need for 205 mechanical ventilation (5.4% vs 40.9% vs 40%) and maternal death (0% vs 28.6% vs 25.8%) were 206 significantly lower in pregnancies affected by COVID-19, compared to MERS and SARS 207 respectively ( Supplementary Table 3 ). 208
Data analysis 170
The majority of women affected by CoV infections were usually treated first with broad spectrum 209 antibiotics in 89.3% of cases (49/52) and then with antiviral therapy and steroids in 67.7% (37/51) 210 and 29.8% (12/31) of cases (Table 3 ; Supplementary Table 4 ). 211
Data analysis 170
The results of the quality assessment of the included studies are presented in Supplementary 212 Table 5 . 213 214
Synthesis of the results 215
In the overall population of pregnancies infected with CoV, The rate of miscarriage for CoV 216 infections was 39.1% (8/21 -95% CI 20.2-59.8). The rates of PTB < 37 and 34 weeks of gestation 217 were 24.3% (14/56 -95% CI 12.5-38.6) and 21.8% (11/56 -95% CI 12.5-32.9), respectively; 218 pPROM occurred in 20.7% (6/34 -95% CI 9.5-34.9), while the rate of pregnancies experiencing 219 PE and FGR was 16.2% (2/19 -95% CI 4.2-34.1) and 11.7% (2/29 -95% CI 3.2-24.4), 220
Synthesis of the results 215
respectively. The rate of CD was 83.9% (50/58 -95% CI 73.8-91.9) ( Table 4 ; Table 5 ). The rate of 221 perinatal death was 11.1% (5/60 -95% CI 84.8-19.6) including three stillbirths and two neonatal 222 deaths (further details are provided in Supplementary Table 6 ). Thirty-four point six percent (15/44 223 -95% CI 20.3-49.5) of fetuses suffered from fetal distress and 57.2% (3/12 -95% CI 3.6-99.8) of 224 newborns was admitted to NICU. The rate of Apgar score < 7 at five minutes was 6.1% (1/48 -95% CI 1.3-13.9), but no case of neonatal asphyxia were reported. Finally, none of the newborns 226 showed signs of vertical transmission during the follow-up period (Table 6; Table 7) . 227
COVID-19 228
Six studies 16-21 reported information on COVID-19 infection during pregnancy. There was no data 229 on miscarriage for COVID-19 infection occurring during the first trimester. The rates of PTB < 37 230 and 34 weeks of gestation were 41.1% (14/32 -95% CI 25.6-57.6) and 15% (4/32 -95% CI 3.9-231 31.7), respectively. pPROM occurred in 18.8% (5/31 -95% CI 0.8-33.5), while the rate of 232 pregnancies experiencing PE was 13.6% (1/12 -95% CI 1.2-36.0), with no reported cases of FGR. 233
COVID-19 228
The rate of CD was 91% (38/41 -95% CI 81.0-97.6) ( and no case of neonatal asphyxia was reported. Finally, none of the newborns showed signs of 238 vertical transmission during the follow-up period (Table 7) . 239
240

MERS 241
Seven studies 22-28 reported information on MERS infection during pregnancy. There was no data on 242 miscarriage for MERS infection occurring during the first trimester. The rate of PTB was 32.1% 243
MERS 241
(3/11 -95% CI 10.0-59.8), all occurring before 34 weeks of gestation. Preeclampsia occurred in 244 19.1% (1/7 -95% CI 1.1-51.3) respectively, while no case of pPROM or FGR was reported in these 245 studies. The rate of CD was 61.8% (5/8 -95% CI 32.7-86.9) ( Table 5 ). The rate of perinatal death 246 was 33.2% (3/10 -95% CI 11.2-59.9) including two stillbirths and one neonatal death (four hours 247 after birth of an extremely preterm infant). No case of fetal distress, Apgar score < 7 at five 248 minutes, neonatal asphyxia, and admission to NICU was reported. Finally, none of the newborns 249 showed signs of vertical transmission during the follow-up period (Table 7) . 250
SARS 252
Six studies 29-34 reported information on SARS infection during pregnancy. The rate of miscarriage 253 for MERS infection was 39.1% (8/21 -95% CI 20.2-59.8). The rate of PTB < 37 and 34 weeks of 254 gestation was 15% (1/15 -95% CI 0.3-45.6) and 28.9% (4/15 -95% CI 10.7-51.6), respectively. 255 pPROM and FGR occurred in 50% (1/2 -95% CI 0.5-95.3) and 18.5% (2/15 -95% CI 4.4-39.5) 256 respectively, while no cases of preeclampsia were reported. The rate of CD was 72.2% (7/9 -95% 257 CI 44.1-93.1) ( Table 5 ). Fetal distress occurred in 35.9% (3/9 -95% CI 12.0-64.4) of pregnancies, 258 while no case of perinatal death, Apgar score < 7 at five minutes, and neonatal asphyxia was 259
SARS 252
reported. There were no data on rates of admission to the NICU of infants born to infected mothers. 260
SARS 252
Finally, none of the newborns showed signs of vertical transmission during the follow-up period 261 (Table 7) . 262 263 It was not possible to perform a comprehensive pooled data synthesis on the incidence of pregnancy 264 and perinatal outcomes according to the trimester of pregnancy at infection due to the very small 265 number of included studies for each trimester of pregnancy. 266
267
COMMENT 268
Main findings 269
The findings from this systematic review show that more than 90% of hospitalized pregnant women 270 affected by CoV infections present radiological signs suggestive for pneumonia, detected either at 271 chest x-ray or computerized tomography and the most common symptoms are fever, cough and 272 lymphopenia. Pregnancies affected by CoV infections have high rates of PTB before 37 and 34 273 weeks, and miscarriage when the infection is acquired earlier in pregnancy. Preeclampsia and 274 cesarean delivery are also more common than in the general population. The rate of perinatal 275 mortality is about 10%, while the most common adverse perinatal outcome is fetal distress, with 276 more than half of the newborns admitted in NICU. Importantly, clinical evidence of vertical 277 transmission was found in none of the newborns included. 278
279

Strengths and limitations 280
To the best of our knowledge, this is the first systematic review exploring pregnancy and perinatal 281 outcomes of CoV infections occurring during pregnancy. This comprehensive meta-analysis 282 included all series published so far on this topic. 283
Strengths and limitations 280
The small number of cases in some of the included studies, their retrospective non-randomized 284 design, and the lack of standardized criteria for the antenatal surveillance, management and timing 285 of delivery of pregnancies affected by CoV infections represent the major limitations of this 286 systematic review, thus making it difficult to draw any convincing evidence on this clinical 287 management strategies. Furthermore, there is a possibility that some patients were included in more 288 than one report, although two authors independently reviewed all the included studies, carefully 289 focusing on the different Institutions reporting outcomes. Moreover, when focusing on the 290 outcomes of COVID-19 infection, and particularly perinatal outcomes, reported data are intuitively 291 limited to a very short-term follow-up period and thus infectious that occurred proximate to the 292 underestimate more longitudinal risks such as FGR. Additionally, it was not possible to extrapolate 294 data about the rate of both spontaneous and iatrogenic PTB and indications for CD, that was 295 performed in the majority of cases; furthermore, few outcomes, i.e. "fetal distress", were not clearly 296 defined, thus leading to some discrepancies in the results, like the rate of PTB < 34 weeks (15%) 297 and the rate of newborns admitted to NICU (9%), particularly in COVID-19 infection. Another 298 limitation of the present review was the lack of stratification of the analysis according to the 299 gestational age at CoV infection due to the very small number of included studies for each trimester 300 of pregnancy. We cannot assume that the rate of miscarriage and PTB should be attributed solely to 301 the virus / infection, since there are no comparable control groups of uninfected women from the 302 same time. It may be that the stress of the situation in the community contributed to some of these 303 outcomes. Finally, we also included case reports and case series, thus facing a higher risk 304 publication bias and decreasing the level of the evidence of our findings. The lack of knowledge about COVID-19 infection has raised urgent questions among physicians 316 regarding clinical management and expected outcomes of the affected patients, and therefore, there 317 is currently a compelling need of data to guide clinical decisions.
Strengths and limitations 280
Regarding pregnancy, the findings from this study found that radiological features suggestive for 319 pneumonia can be found in almost all of the hospitalized pregnant women, usually presenting with 320 fever, cough and lymphopenia similar to the non-pregnant population. Of note, serious conditions 321 requiring admission to ICU and mechanical ventilation are significantly less common when 322 compared with the two previous CoV infections (MERS and SARS). Similarly, we found no case of 323 maternal death related to COVID-19 infection, while MERS and SARS infections caused a 324 mortality rate in pregnant women ranging from 25% to 30%. 325
Strengths and limitations 280
In this systematic review, women affected by COVID-19 disease had higher rates of miscarriage, 326 preterm birth, preeclampsia, while the babies had higher rates of perinatal mortality (7-11%) and of 327 admission to NICU. 328 Furthermore, as all the included studies reported data on hospitalized women, the reported rate of 329 infection-related adverse outcomes, including either pregnancy and perinatal outcomes, might not 330 reflect the overall population of pregnant when who got infected with SARS-COV-2, and there may 331 be a cohort of patients with no or mild symptoms whose pregnancy outcome is, as of yet, 332 unknown. 36 
333
More importantly, it should be emphasized that there are no known neonatal symptoms and 334 therefore no clinical evidence suggestive for vertical transmission, particularly when COVID-19 335 infection occurs later in pregnancy. Unfortunately, the lack of data of first and early second 336 trimester infection does not allow to determine whether in this case the infection may cause more 337 severe perinatal outcomes and how to monitor the pregnancy once the infection has passed. 1 
338
Based on the limited information from this study, COVID-19 cannot be considered as an indication 339 for delivery and therefore the timing and mode of delivery should be individualized according to 340 maternal clinical conditions or obstetric factors as usual (and not COVID-19 status alone), and the 341 decision should involve a multidisciplinary team including maternal fetal doctors, neonatologists, 342 anesthesiologists, and infective disease specialists. 343
Conclusions 345
In summary, with the limited data reported to date, mothers infected with coronavirus infections, 346
Conclusions 345
including COVID-19, >90% of whom also had pneumonia, are at increased risks of miscarriage, 347 preterm birth, preeclampsia, cesarean delivery, and their babies at higher risk of perinatal death and 348 admission to the NICU, compared to the general population. There have been no published cases of 349 clinical evidence of vertical transmission. Evidence is accumulating rapidly, so these data may need 350 to be updated soon. For more information, visit www.prisma-statement.org.
PRISMA 2009 Flow Diagram
Records identified through database searching (n = 533)
Screening

Included Eligibility

Identification
Additional records identified through other sources (n = 5)
Identification
Records after duplicates removed (n = 538)
Identification
Records screened (n = 538)
Identification
Records excluded (n = 511)
Identification
Full-text articles assessed for eligibility (n = 27)
Identification
Full-text articles excluded, with reasons (n = 713-515-3198 n/N, number of cases / total number of included pregnancies; CI, confidence interval; ICU, intensive care unit

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