The impact of COVID-19 on pregnancy and neonatal health: a systematic review

Background: In December 2019, a novel coronavirus disease (COVID-19) emerged in Wuhan, China. With an incredible rate of contagion, it has reached all over the world, with more than 2 million confirmed cases at the mid of April. However, the vertical transmission of COVID-19 is uncertain. This is a systematic review of published studies concerning pregnant women with confirmed COVID-19 and their neonates. Methods: We performed a systematic search in Pubmed, Web of Sciences, Google Scholar, Scopus, and World Health Organization (WHO) COVID-19 database to find articles reporting clinical data of COVID-19-positive pregnant women and their neonates. Results: 37 articles, involving 364 pregnant women with COVID-19 and 302 neonates, were included. The vast majority of pregnant patients were in their third trimester of pregnancy, and only 45 cases were in the first or second trimester (12.4%). Most mothers described mild to moderate manifestations of COVID-19. Of 364 pregnant women, 25 were asymptomatic at the time of admission. The most common symptoms were fever (62.4%) and cough (45.3%). Two maternal deaths occurred. Some pregnant patients (12.1%) had a negative SARS‐CoV‐2 test but displayed clinical manifestations and abnormalities in computed tomography (CT) scan related to COVID‐19. Twenty‐two (6.0%) pregnant patients developed severe pneumonia. Two maternal deaths occurred from severe pneumonia and multiple organ dysfunction. Studies included a total of 302 neonates from mothers with COVID‐19. Of the studies that provided data on the timing of birth, there were 65 (23.6%) preterm neonates. One baby was born dead from a mother who also died from COVID-19. Of the babies born alive from mothers with COVID‐19, five newborns faced critical conditions, and two of which later died. A total of 219 neonates underwent nasopharyngeal specimen collection for SARS‐ CoV‐2, of which 11 tested positive (5%). Seventeen studies examined samples of the placenta, breast milk, umbilical cord, and amniotic fluid, and all tested negative except one amniotic fluid sample.


Selection criteria
We sought studies that investigated the potential effect of COVID-19 on pregnancy and neonatal health. Original articles published in English were eligible if they included pregnant patients infected with COVID-19 and their newborns. The outcomes of interest consisted of clinical manifestations of COVID-19 in pregnant patients with COVID-19 and also, the effect of COVID-19 on neonatal and pregnancy outcomes.

Data extraction
For pregnant women infected with COVID-19, we extracted the following data: article title, author, study type, country, number of pregnant women with COVID-19, clinical manifestations of disease in pregnant women, the trimester of pregnancy, diagnostic technique, potential complications related to COVID-19, delivery, and the maternal outcome(s) of COVID-19. For neonates born from mothers with COVID-19, data on the article title, author, study type, country, number of neonates, neonatal maturity, clinical presentation, neonatal complications, a diagnostic test for COVID-19, Apgar score, and neonatal outcome were extracted. Finally, for pregnancy outcomes, we collected data on the article title, author, study type, country, placental test for viral nucleic acid, and pregnancy complications.

Literature search
The systematic search yielded a total of 1068 search results, of which 785 discrete records remained for screening after removing duplicates. During title and abstract screening, we selected 48 articles for detailed review. In the detailed review process, we excluded thirteen articles with the following reasons for exclusion: seven articles not provided data on pregnant patients or neonatal outcomes [4][5][6][7][8][9][10], three studies lacked data on neonates or vertical transmission [11][12][13], one study reported a 17day neonate who had exposure to parents complaining of fever and cough [14], one study was not original research [15], and the full-text was not available for one article [16]. Also, we carried out an additional search through reviewing reference lists of 35 included articles from systematic search and related review articles and found two additional articles [17,18]. Finally, a total number of 37 studies, including case reports and case series, were eligible to be included in this systematic review . Tables 1 -3 provide an overview of the characteristics of the included studies. Below is a narrative synthesis of studies that included pregnant women with confirmed COVID-19 and their neonates.

Clinical presentation of COVID-2019 in pregnant women
Of 37 studies, two provided no data on clinical symptoms of pregnant patients [18,19]. A total of 364 pregnant women was, thus, included in the data synthesis of clinical manifestations of COVID-19 in pregnant women.
Of 364 pregnant women, 25 were asymptomatic at the time of admission. The most common symptoms were fever (62.4%) and cough (45.3%). The other common symptoms included myalgia, diarrhea, dyspnea, headache, and chest tightness. There were two women with specific presentations: one with Cholecystitis [26] and another with oil intolerance [44].
For nearly all pregnant women, the diagnosis was made based on a combination of clinical symptoms, nucleic acid testing for the novel coronavirus, and computed tomography (CT

Neonatal outcomes
Thirty-seven studies included a total of 302 neonates from mothers with COVID-19. Two studies have not indicated the timing of birth [18,33]. Of the studies that provided data, there were 210 full-term and 65 preterm neonates.
Karami et al. reported the death of a mother from COVID-19 and also her fetus [42]. The dead baby was born with an Apgar score of 0, did not respond to resuscitation, and was not considered for COVID-19 diagnostic tests. Of the babies born alive from mothers with COVID-19, five newborns faced critical conditions. One of them presented with a fast heart rate developed gastric bleeding and refractory shock later and died. The second complicated case was a premature newborn born from a mother, who had a diagnosis of severe COVID-19 pneumonia [26]. This neonate showed shortness of breath at presentation and developed disseminated intravascular coagulation (DIC). This case could be cured. The third neonate died due to the multiple organ dysfunction syndrome and could not survive [34]. The nasopharyngeal samples of these three babies were all negative for SARS-CoV-2 RNA detection. The fourth one suffered from pneumonia and needed intubation at birth. Sixteen hours after birth, the neonate tested positive for SARS-CoV-2 RNA with throat swab nucleic acid testing [51].
This neonate was later extubated and discharged without any complications. The fifth one was a premature baby with the gestational age of 31 weeks and two days. This neonate had an Apgar score of 3, 4, and 4 at the first, fifth, and tenth minute after delivery and required resuscitation [43]. This neonate was later confirmed as a definite case of COVID-19 and developed DIC. Vital signs were successfully stabilized on the day of 14. This neonate had close contact with the mother after delivery.
Except for the babies mentioned above, most babies born alive had a 5-minute Apgar score of 8 and 9 [

Pregnancy outcomes
In a case-control study by Zhang et al., there was no difference between 16 pregnant women with COVID-19 and 45 pregnant women without COVID-19 in terms of pregnancy complications, including eclampsia, fetal distress, and premature rupture of membrane (Table 3)  Nearly all mothers were healthy women without underlying severe diseases such as diabetes mellitus, cardiovascular disease, and autoimmune diseases. Therefore, further research is necessary to evaluate whether or not ethnicity/race, maternal comorbidities, and pregnancy stage would influence the course of COVID-19 in pregnancy, and how this, in turn, would affect delivery complications.
Finally, one crucial issue which remained unresolved is the psychosocial effects of the COVID-19 outbreak on mental health during pregnancy. Pregnant women frequently report psychosocial stress, depression, and panic disorder. In particular, there is a direct correlation between the level of antenatal psychosocial stress and the risk of poor pregnancy outcomes in the manner that the higher the antenatal psychosocial stress, the greater the risk of poor pregnancy outcomes. Therefore, pregnancy might be complicated during the COVID-19 outbreak, even if women do not get infected by the virus.

Conclusion
In conclusion, the current evidence suggests that clinical features, diagnosis, and prognosis of COVID-19 in pregnant women are not different from those of the disease reported in the society. Despite the high rate of contagion of COVID-19, vertical transmission of the novel coronavirus may remain a missing piece of the puzzle due to a lack of sufficient evidence.

Competing interests
The authors declare that they have co conflicts of interest.

Funding
There is no funding for the present study.      Figure 1 PRISMA flowchart of the literature search