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18 June 2020

COVID-19 in Pregnant Women and Neonates: A Systematic Review of the Literature with Quality Assessment of the Studies

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1
Post-Graduate School of Pediatrics, Anna Meyer Children’s University Hospital, Department of Health Sciences, University of Florence, 50100 Florence, Italy
2
Division of Pediatric Immunology, Department of Health Sciences, University of Florence and Meyer Children’s Hospital, 50100 Florence, Italy
3
Department of Neurosciences, Psychology, Drug Research and Children’s Health, University of Florence, 50100 Florence, Italy
4
Division of Pediatric Infectious Disease, Anna Meyer Children’s University Hospital, Department of Health Sciences, University of Florence, 50100 Florence, Italy
Pathogens2020, 9(6), 485;https://doi.org/10.3390/pathogens9060485
This article belongs to the Section Human Pathogens
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Abstract

The SARS-CoV-2 virus emerged in December 2019 and then spread globally. Little is still known about the impact of COVID-19 on pregnant women and neonates. A review of the literature was performed according to the PRISMA guideline recommendations, searching the MEDLINE and EMBASE databases. Studies’ quality assessments were performed using the JBI Critical Appraisal Checklist. A total of 37 studies were included, involving 275 pregnant women with COVID-19 and 248 neonates. The majority of pregnant women presented with mild to moderate symptoms, only 10 were admitted in the ICU, and one died. Two stillbirths were reported and the incidence of prematurity was 28%. Sixteen neonates were tested positive for SARS-CoV-2 by RT-PCR, and nine of them were born from mothers infected during pregnancy. Neonatal outcomes were generally good: all the affected neonates recovered. RT-PCR for SARS-CoV-2 yielded negative results on amniotic fluid, vaginal/cervical fluids, placenta tissue, and breast milk samples. SARS-CoV-2 infection in pregnant women appeared associated with mild or moderate disease in most cases, with a low morbidity and mortality rate. The outcomes of neonates born from infected women were mainly favorable, although neonates at risk should be closely monitored. Further studies are needed to investigate the possibility of vertical transmission.

1. Introduction

The first case of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was described in Wuhan, Hubei Province, China, in December 2019. Since then, COVID-19 has been rapidly spreading all over the world, which led the World Health Organization (WHO) to declare the outbreak of COVID-19 as a pandemic on 11 March 2020 [1].
SARS-CoV-2 is a positive-sense single-stranded RNA (+ssRNA) virus. Coronaviruses (order Nidovirales, family Coronaviridae, and subfamily Orthocoronavirinae) include four coronavirus genera (α,β,γ,δ): human coronaviruses (HCoVs) are classified under α-CoV and β-CoV. SARS-CoV-2 is a β-CoV. Seven coronaviruses are capable of infecting humans, four of them (HCoV-OC43, HCoV-HKU1, HCoV-229E, HCoV-NL63) causing mild respiratory infections, while three, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2, have been associated with severe respiratory diseases, with a high fatality rate [2]. Despite sharing a lot of characteristics with them, most of the information regarding transmission, immune system response, and susceptibility among subgroups of populations is still unclear. Indeed, potentially vulnerable groups deserve special consideration. Pregnant women and neonates are categories of major interest, as they represent a challenge for public health care. Pregnant women have a unique and dynamic immune state during the different stages of pregnancy. It is well known that the hormonal state and the reduced chest expansion increase pregnant women’s risk of respiratory infections [3]. Furthermore, data regarding the previous epidemic coronaviruses, SARS-CoV and MERS-CoV, as well as data regarding influenza viruses, showed that pregnant women and their neonates are exposed to a higher risk of poor outcomes [4]. Little is known about the impact of COVID-19 on pregnancies, perinatal, and neonatal outcomes. The possibility of vertical transmission is still unknown. Although studies on pregnant women and neonates are increasing, most of them are case reports or case series with small population samples and conflicting results.
We performed a systematic review of the literature to provide a comprehensive overview of all the available data regarding clinical features, outcomes, and management of pregnant women with COVID-19. Moreover, we collected data on neonates born from mothers with COVID-19 and neonates with a post-natal diagnosis of COVID-19, analyzing the likelihood of vertical transmission. Finally, we discussed the current management strategies across different countries regarding maternal and neonatal care, which appeared particularly heterogeneous, especially on the type of delivery, isolation, and feeding of neonates.

2. Materials and Methods

2.1. Study Design and Search Strategy

We performed a systematic review of the literature, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline recommendations [5]. We searched the MEDLINE and EMBASE databases from 1 December 2019 to 18 April 2020. We did not restrict the research for language.
Search terms for the MEDLINE database were: (“COVID-19”[All Fields] OR “severe acute respiratory syndrome coronavirus 2”[Supplementary Concept] OR “severe acute respiratory syndrome coronavirus 2”[All Fields] OR “2019-nCoV”[All Fields] OR “SARS-CoV-2”[All Fields] OR “2019nCoV”[All Fields] OR “2019 coronavirus disease” OR ((“Wuhan”[All Fields] AND (“coronavirus”[MeSH Terms] OR “coronavirus”[All Fields])) AND 2019/12[PDAT]: 2030[PDAT])) AND (child* OR pediatri* OR paediatri* OR infan* OR newborn* OR neonate* OR pregnan* OR breastfeed* OR fetal OR fetus OR obstetric* OR “transplacental transmission” OR “placental transmission” OR “vertical transmission” OR intrauterine OR perinatal).
Search terms for the EMBASE database were: (‘covid-19’ OR ‘severe acute respiratory syndrome coronavirus 2’/exp OR ‘severe acute respiratory syndrome coronavirus 2’ OR ‘2019-ncov’ OR ‘sars-cov-2’ OR ‘2019ncov’ OR ‘2019 coronavirus disease’ OR (‘Wuhan’ AND (‘coronavirus’/exp OR ‘coronavirus’))) AND [1-12-2019]/sd AND (child* OR pediatri* OR paediatri* OR infan* OR newborn* OR neonate* OR pregnan* OR breastfeed* OR fetal OR fetus OR obstetric* OR ‘transplacental transmission’ OR ‘placental transmission’ OR ‘vertical transmission’ OR intrauterine OR perinatal).
We performed the research also on Google Scholar and Medrxiv, and finally the references of important articles were crosschecked.

2.2. Study Eligibility and Quality Assessment

The articles included provide epidemiological, clinical, diagnostic, and/or therapeutic data about pregnant women or neonates with COVID-19. At first, we screened titles and abstracts to discover eligible studies, and then we analyzed all full texts for the final evaluation. Two investigators (MF, CB) independently reviewed and evaluated every study.
We considered a study eligible when the following criteria were met: (1) population were pregnant women and/or neonates; (2) a diagnosis of COVID-19 was made with specified diagnostic criteria; and (3) epidemiological, clinical, diagnostic and/or therapeutic data were reported.
Exclusion criteria were: (1) not relevant topic (not appropriate population or not appropriate outcome) (2) non-original studies (e.g., literature reviews, guidelines, duplicate articles, comments); and (3) studies not reporting useful clinical data about patients.
Considering the relevance of the topic, we decided to include as many studies, fitting the eligibility criteria and presenting original data, as possible, comprising non-peer-reviewed publications. Nevertheless, we carefully assessed and described the quality of every study and verified that there was no overlap in the population sample. Specifically, we crosschecked the settings, the population samples, and the period of admission of the patients, finding several studies performed in the same setting and the same period. We excluded all the articles with confirmed (by contacting the authors) or suspected dataset overlap.
The quality of the eligible studies was evaluated by two authors independently (MC, GT), using different methods according to the study design: The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports [6], and the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series [7]. We planned to use the Newcastle-Ottawa Quality Assessment Form [8] for the analytic observational studies, however, we did not identify articles that properly fitted this definition.

2.3. Data Extraction and Definitions

Data were collected and entered into an electronic database (Microsoft Corporation, 2018 Microsoft Excel, Redmond, WA, USA).
From each study, we selected information regarding study design, date of publication, country of origin, setting, characteristics of the population sample, objective of the study, and outcome measured. As a measured outcome, we considered any clinical data described and analyzed. For mothers, we collected data on age, comorbidities, symptoms, gestational age at symptom onset and delivery, imaging and laboratory testing results, administered therapy, and type of delivery. Regarding neonates, we collected data on birth weight, Apgar score (Appearance, Pulse, Grimace, Activity, Respiration), isolation, feeding, symptoms, imaging and laboratory testing results, and administered therapy. Maternal and perinatal outcomes were evaluated and the likelihood of vertical transmission of the virus was analyzed.
We considered articles following the diagnostic criteria for COVID-19 based on the New Coronavirus Pneumonia Prevention and Control Program (Trial Fifth Edition) issued by the National Health Commission of China [9]. The above-mentioned diagnostic criteria of COVID-19 include (1) typical chest CT imaging of patchy shadowing and ground-glass opacity, and (2) positive in reverse transcription-polymerase chain reaction (RT-PCR) tests for SARS-CoV-2.
Moreover, considering the risk of false-negative results of laboratory tests (possibly related to low virus titers, inappropriate swabbing sites, or variability on laboratory test performance) [10] and the limited test capacities during a period of overloaded healthcare systems, we decided to include also studies using extended diagnostic criteria. Indeed, some authors included patients with negative RT-PCR tests, but typical symptoms and chest CT imaging, in association with suggestive clinical data (blood tests showing leukopenia or lymphocytopenia, exclusion of other causes of respiratory infections).

2.4. Statistical Analysis

Statistical analysis was performed using Microsoft Excel (Microsoft Corporation, 2018). Categorical variables were expressed as the number of cases (N) and percentages (%). Continuous variables were expressed as the mean with standard deviation (SD).

3. Results

3.1. Included Studies

The selection process is shown in Figure 1.
Figure 1. Flow chart of the study selection.
Our search strategy identified 700 articles, after duplicate removal. The Google Scholar research and the articles’ references crosscheck identified five articles. The abstracts and titles screening found 88 studies that met the inclusion criteria. After the full-text analyses, 51 of these studies were excluded (Supplementary Materials). Thirty-seven studies were eligible according to our criteria and were included in the review: 19 case reports ([11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]) and 18 case series ([30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47]).
Characteristics of the included studies are reported in Table 1.
Table 1. Characteristics of the included studies.

3.2. Quality Assessment

Only five case reports ([12,13,20,24,26]) completely fulfilled the checklist criteria, scoring 7 out of 8 on the JBI Critical Appraisal Checklist for Case Reports; we considered not applicable the seventh question of the checklist. In the remaining 17 articles, we found missing information or unclear information. Specifically, in five articles, the setting was not specified, while some articles did not report data about the pregnancy/birth (n = six), about the pregnant woman (n = one), about the neonate (n = four), about the administered treatment (n = eight), or the outcome (n = three).
Out of 17 analyzed case series, only 3 ([30,40,44]) completely fulfilled the checklist criteria, scoring 9 out of 10 on the JBI Critical Appraisal Checklist for Case Series. The 10th question, about statistical analysis, was appropriate for only one study [33], in which authors performed a comparison between two groups. In the remaining 12 articles, we found missing information in one or more of the investigated aspects. In three studies, patients’ characteristics were not evaluated in a standard way (some tests were not performed on all the population sample), and in five studies, the condition was not identified with valid methods for all patients (some maternal diagnoses were not laboratory-confirmed). Four case series described patients from different hospitals, without specifying if the inclusion was consecutive. Demographic and clinical data of the participants were not reported or were missing in one and four studies, respectively. Maternal and/or neonatal outcomes or follow-up information were not reported in nine articles. Finally, demographic data were not reported in the four case series.
The quality assessment of the studies is reported in Figure 2.
Figure 2. Quality assessment of the included studies. (a) The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports; (b) The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series.

3.3. Maternal Characteristics and Outcomes

The included articles described 275 pregnant women affected with COVID-19, 181 from China, and 94 from other countries. RT-PCR for SARS-CoV-2 was positive for 260 women (95%) on pharyngeal/nasopharyngeal swab, while 15 women were diagnosed using extended diagnostic criteria, based on clinical and radiological features, and excluding other causes of symptoms.
Out of 275 pregnant women, 239 gave birth: 3 women voluntarily decided to terminate their pregnancy in the first trimester and 33 women were still pregnant when the articles were published. Gestational age at delivery was reported for 208 patients: 160 (77%) delivered at term (≥37 weeks of gestation) and 48 (23%) had a preterm delivery (<37 weeks of gestation).
In 179 (75%) cases, the type of delivery was a cesarean section, which was performed in an emergency in 27 cases (11%). Sixty (25%) women delivered vaginally. Considering the available data, indications for cesarean section were often obstetric reasons (e.g., placenta previa, repeat cesarean, the arrest of descending, the arrest of dilation, failed labor induction, fetal distress); however, in some cases, the diagnosis of COVID-19 was considered itself an indication to perform surgical delivery, especially when a worsening of maternal respiratory conditions occurred or when mothers needed antiviral treatment.
Some of the articles reported the presence of comorbidities, most likely not related to COVID-19, such as obesity (n = 27), gestational diabetes (n = 10), hypertension (n = 10), asthma (n = 8), pre-eclampsia (n = 5), anemia (n = 5), diabetes mellitus (n = 3), hypothyroidism (n = 3), placenta previa (n = 3), hepatitis B (n = 2), cholecystitis (n = 2), placental abruption (n = 1), cephalopelvic disproportion (n = 1), and thalassemia (n = 1).
Symptoms were clearly described in 269 women out of 275 (98%). The most frequent symptoms were fever (155, 58%) and cough (98, 36%); thirty-seven (14%) patients complained of myalgia, malaise, or fatigue, 28 (10%) patients developed dyspnea, and only 9 (3%) presented with mild respiratory symptoms (sore throat, nasal congestion); a small number of patients (9, 3%) presented with gastrointestinal symptoms, such as diarrhea or abdominal pain. Twenty-two women (8%) were asymptomatic. In most of the cases, symptoms began before delivery (1 to 38 days before, mean 9.26 days, SD 8.86).
Laboratory findings were reported for 108 women out of 275 (39%) and revealed elevated C-reactive protein (CRP) in 52 cases (48%), lymphopenia in 31 cases (29%), and elevated liver enzymes in 9 cases (8%). Serological tests for SARS-CoV-2 were performed in nine RT-PCR-positive patients: all of them had positive IgG and six out of nine had positive IgM for SARS-CoV-2.
As diagnostic imaging, 171 patients underwent chest CT, which showed a typical pattern of viral pneumonia in 162 cases (95%), while 9 (5%) were normal. Chest X-rays were reported for 48 women and were all consistent with the diagnosis of viral pneumonia.
Regarding medical treatments, reported data are extremely heterogeneous, depending on the patients’ clinical presentation. Furthermore, hospital protocols varied among different countries and changed rapidly over time according to the emergence of new evidence.
Overall, the majority of pregnant women developed a mild or moderate illness; twenty-two women did not develop symptoms. However, complications were reported. Considering the reported data, 36 patients required oxygen therapy and 10 patients required the intensive care unit (ICU). Five women required invasive ventilation and one woman needed extracorporeal membrane oxygenation (ECMO) and hemodialysis. The latter was a 31-year-old Chinese woman at 35 + 2 weeks’ gestation, admitted to hospital because of fever and dyspnea, who developed severe acute respiratory distress syndrome (ARDS), septic shock, and multiple organ dysfunction syndrome (MODS). Cesarean section was performed, but the newborn underwent intra-uterine asphyxia and died. The patient received invasive ventilation, continuous renal replacement therapy, and ECMO and was treated with antiviral therapy (lopinavir-ritonavir and ribavirin) and transfusion of convalescent plasma [47]. The follow-up of this patient is described by Zhang B et al. [48], who showed that she finally recovered and was discharged from the hospital. One of the patients who required intensive treatment had a fatal outcome. [14] She was a 27-year-old mother at 30 + 3 weeks’ gestation, admitted to hospital for progressive respiratory distress. The day after the admission, she spontaneously gave birth to a cyanotic neonate with an Apgar score of 0 (at first and fifth minute) not responding to neonatal cardiopulmonary resuscitation (CPR). After delivery, there was a clinical deterioration; she was treated with lopinavir-ritonavir, oseltamivir, hydroxychloroquine, meropenem, and vancomycin and received corticosteroid pulse therapy, emergency plasmapheresis, and invasive ventilation. Despite treatment, the patient died as a result of multiple organ failure (MOF).
Data regarding the included pregnant women are reported in Table 2.
Table 2. Characteristics of the included pregnant women.

3.4. Neonatal Characteristics and Outcomes

The articles analyzed in our review described 248 neonates. Data on the gestational age of the neonates were available for 196 neonates, 72% of whom were at term (≥37 weeks of gestation). The average birth weight was 2914 (±573) g. Apgar scores were reported over 7 at the first minute and/or at the fifth minute in 97% of cases, while five (3%) were under 7 at the fifth minute.
Among the 248 included neonates, 191 neonates born from mothers with COVID-19 were tested with RT-PCR for Sars-CoV-2 on throat/nasopharyngeal/anal swab; in 28 cases (15%), also specimens were analyzed (urine, blood, feces samples). Twenty-six patients underwent serological tests (IgM, IgG) for SARS-CoV-2.
Out of the 191 tested neonates, 175 (92%) were negative. However, among the negative neonates, some authors reported clinical symptoms. Symptoms most frequently described were: fever (n = 4), mild respiratory symptoms (rhinitis) (n = 1), respiratory distress (n = 16), and gastrointestinal symptoms (n = 8). Zhu et al. [45] reported a high incidence of complications on a population sample of 10 negative neonates: respiratory distress (n = 6), fever (n = 2), thrombocytopenia with liver failure (n = 2), tachycardia (n = 1), vomiting (n = 1), pneumothorax (n = 1), refractory shock with subsequent MOF, and disseminated intravascular coagulation (DIC) until death (n = 1). Nevertheless, this series included cases from five different hospitals (in unclear settings) and all the sick babies were preterm neonates (range of gestational age: 31–35 + 6 weeks of gestation). One case of neonatal asphyxia was reported by Zeng et al. [38] Two stillbirths were described by Karami et al. [14] and Liu et al. [47], both from mothers with severe SARS-CoV-2 pneumonia requiring intensive treatment; in one case, the mother had a fatal outcome (see above).
Sixteen of the tested neonates yielded SARS-CoV-2-positive results (Table 3).
Table 3. Characteristics of neonates with positive SARS-Cov-2 RT-PCR.
Fourteen of them were RT-PCR-positive on the nasopharyngeal swab, and two were RT-PCR-positive on the anal swab. Among them, nine were born from mothers with COVID-19 diagnosed during pregnancy or in the immediate post-delivery period (within 36 h). The other seven positive neonates were born from asymptomatic mothers, and not tested, during pregnancy, who were diagnosed during the first month of life (range 8–27 days after birth). Among the RT-PCR-positive neonates, symptoms were reported in 14 cases. Fever was the most frequent symptom (n = nine), followed by gastrointestinal symptoms (n = five), respiratory distress (n = five), and mild respiratory symptoms (cough, rhinitis) (n = three). One neonate required non-invasive respiratory support and two required mechanical ventilation. All neonates had a good outcome. No cases of death in SARS-CoV-2-positive neonates are described in the literature. Zeng et al. [38] reported a positive neonate born at 31 + 2 weeks’ gestation by C-section because of fetal distress, who required resuscitation at birth (Apgar score was reported as 3 at the first minute and 4 at the fifth), treatment with antibiotics, caffeine, and non-invasive respiratory support. On day 2, nasopharyngeal and anal swabs resulted in positive for SARS-CoV-2. However, he also suffered from Enterobacter sepsis with subsequent thrombocytopenia, leukocytosis, and coagulopathy which progressively improved after antibiotic treatment.
Regarding the laboratory findings, data were reported for seven positive neonates and showed: thrombocytopenia (n = two), elevated PCT (n = one), lymphocytosis (n = one), leukocytosis (n = two), and lymphocytopenia (n = one); five neonates had normal laboratory tests.
Imaging diagnostic tests were performed on 11 positive neonates: 5 neonates underwent chest CT, while 8 neonates underwent chest X-ray (2 underwent both chest CT and chest X-ray). All chest CTs showed anomalies (most frequently increased lung marking), six chest X-rays were consistent with pneumonia, two were negative.
The majority of neonates (125, 73%) were separated from the infected mothers immediately after delivery and were isolated for at least 14 days. Data about feeding were reported for 56 cases; 68% of neonates were fed with formula. However, all RT-PCR tests for SARS-CoV-2 (25 specimens) performed on breast milk yielded negative results.
To evaluate the possibility of vertical transmission, some authors tested SARS-CoV-2 RT-PCR in other samples. Amniotic fluid (n = 24), cord blood (n = 30), placenta samples (n = 6), and cervical/vaginal fluids (n = 7) were tested in 14% of the 248 included cases. All of these samples yielded negative results.
Data regarding the included neonates are reported in Table 4.
Table 4. Characteristics of the included neonates.

4. Discussion

4.1. SARS-CoV-2 Infection in Pregnant Women

Since December 2019, when the first cases of COVID-19 pneumonia were identified in Wuhan, few narrative reviews ([4,49,50]) and only one systematic review [51] were published, evaluating the clinical outcome, diagnostic, and therapeutic data in pregnant women and neonates with COVID-19.
This is the most comprehensive systematic review, with a quality assessment of the included studies, describing pregnant women and neonates with COVID-19. A total of 37 studies were retrieved, involving overall 275 pregnant women and 248 neonates.
Most cases in the literature showed that pregnant women with SARS-CoV-2 infection and their neonates had better outcomes than expected. Specifically, the reported outcomes were better than the previously reported for patients affected with SARS or MERS. Being affected with SARS and MERS during pregnancy has been associated with severe prognosis, both for mothers and neonates. [4]
However, no vertical transmission has been identified among pregnant women infected with SARS-CoV and MERS-CoV [52]. Therefore, it is possible to speculate that the worse neonatal outcome was related to the poor clinical conditions of the mother during pregnancy and delivery, rather than being caused by vertical transmission of the infection. Nevertheless, so far, data are still limited.
Our review demonstrated that pregnant women with COVID-19 generally presented with mild symptoms, mostly fever and cough, a significant number of patients remained asymptomatic, and only a few cases developed dyspnea requiring oxygen therapy or admission in ICU for intensive treatment. One patient needed intensive care because of ARDS and MODS requiring intubation, mechanical ventilation, and the support of ECMO, however, she fully recovered. [47,48] Only one patient, out of the 275 described, had a fatal outcome. [14]
According to Chen et al. [41] and Wu et al. [36], clinical symptoms and chest CT features of COVID-19 in pregnant women were similar to those of non-pregnant women. Laboratory findings, as well, appeared analogous to the ones described in non-pregnant SARS-CoV-2-infected patients: elevated levels of C-reactive protein (48%), mild lymphocytopenia (29%), and elevated levels of liver transaminase (8%) were the most frequently recorded abnormalities.
In our review, a high rate of pregnant women (62%) underwent a chest CT, which was positive for viral pneumonia in 95% of cases. Chest CT imaging has been reported as superior to RT-PCR in sensitivity for early diagnosis of COVID-19 [53] and it is essential even for a severity assessment and follow-up of SARS-CoV-2 pneumonia, with higher sensitivity than chest X-rays, especially in clinically diagnosed patients [54]. Hence, it is important to choose low-dose techniques for diagnostic imaging, which are safer for the fetus, and to protect the mother’s abdomen whenever possible, to minimize ionizing radiation exposition. [54]
The only Italian study included in this review reported a different approach to patients regarding diagnostic imaging: patients did not undergo any chest CT, they received, instead, a confirmative chest X-ray, which was consistent with the diagnosis of viral pneumonia in all of the 42 cases [39]. Further studies are needed to define the appropriate diagnostic techniques in pregnant women.
A high incidence rate of premature delivery is reported in some studies [23,26,47]. We confirmed these data, with a percentage of preterm delivery of 28% among the reported cases, although most cases were late-preterm. The global preterm birth rate (percentage of all births delivered <37 completed weeks of gestation) was reported to be approximately 10.6% [55] and 10% [56] in the USA in 2014 and 2018, respectively. Among included studies, causes of preterm delivery were not always clarified. The most frequently reported causes of preterm emergency cesarean section were: fetal distress, worsening of mother’s respiratory symptoms [26,28], or the need to start antiviral treatment [46]. Indeed, causes of preterm delivery might not always be directly related to SARS-CoV-2 infection and further studies are needed to explain the correlation between pre-term delivery and SARS-CoV-2 infection.
Regarding the type of delivery, C-section was performed in most cases (75%). However, data showed that spontaneous vaginal delivery, when feasible according to clinical mothers’ conditions, was not associated with poorer outcomes either for mothers or for neonates. It is possible to speculate that, as experienced in the management of pregnant women with COVID19 increases, the rate of cesarean section will decrease.

4.2. SARS-CoV-2 Infection in Neonates

Our review reported 248 neonates born from infected mothers. Most of the cases (92%) were healthy babies at birth with an Apgar score of 8–10 and RT-PCR-negative for SARS-CoV-2. No spontaneous abortion or congenital anomalies were reported. Even neonates who resulted positive for SARS-CoV-2 infection showed a mild clinical course of the disease, with a good outcome.
We identified nine cases of neonates, born from mothers with a diagnosis of COVID-19 during pregnancy or in the immediate post-partum period, who were tested positive for SARS-CoV-2. Seven of them were isolated from the mothers immediately after birth and breastfed with formula, and in two cases, they were breastfed without the surgical mask during the first hours of life because the mothers were found positive after delivery (within 36 h). In these cases, it is difficult to speculate on how the infection was acquired: even though these neonates had positive results of the RT-PCR testing for SARS-CoV-2, the tests were not performed immediately at birth, but mostly 36–48 h after birth. Hence, a hospital-acquired infection could not be ruled out. In one case, the first test for SARS-CoV-2 was doubtful a few hours after birth and yielded a positive result on the third day of life [39].
Furthermore, the possibility of false-positive results could not be excluded. Indeed, one of the authors reported a false-positive result of RT-PCR testing for SARS-CoV-2: one neonate had positive RT-PCR in the throat swab at first, but the second test on the same swab was negative. Moreover, even RT-PCR on amniotic fluid and umbilical cord blood yielded a negative result [34].
Additionally, among the included studies, all RT-PCR testing for SARS-CoV-2 performed on amniotic fluid, cord blood, placental sample, and cervical/vaginal fluid yielded a negative result.
The other seven positive reported neonates were born from mothers without a COVID-19 diagnosis during pregnancy and were admitted to hospital from 8 to 27 days after birth. In these cases, it is possible to hypothesize a horizontal transmission, probably due to droplet transmission from infected family members.
Dong et al. [22] and Zeng et al. [42] reported three neonates with negative RT-PCR for SARS-CoV-2, but elevated IgM antibody for SARS-CoV-2 after birth, supporting the hypothesis of vertical infection. However, as Kimberlin et al. [57] suggested, the diagnosis of congenital infection should not be confirmed only by IgM detection because of the possibility of cross-reactivity with subsequent false-negative and false-positive results.
To the best of our knowledge, vertical transmission is unlikely, although the few positive neonates from infected mothers described in the literature do not allow to rule it out definitively. Further studies, focusing also on the detection of the virus on a specimen such as amniotic fluid, cord blood, placental sample, and cervical/vaginal fluid would need to confirm that.

4.3. International Guidelines on the Management of Infected Pregnant Women and Neonates

In our review, most of the Chinese neonates from positive mothers were isolated until the mothers were negative at RT-PCR for SARS-CoV-2 and were fed with formula because of the risk of transmission through respiratory droplets and maternal contact. Thus, for neonates born to mothers suspected for or diagnosed with SARS-CoV-2 infection, the Chinese expert consensus on the perinatal and neonatal management for the prevention and control of the 2019 novel coronavirus infection does not recommend mother–baby contact and recommends to avoid feeds with breast milk until a negative result for SARS-CoV-2 on milk has been obtained. As the Chinese Paediatrics COVID-19 Working Group suggests, the indication is unbalanced without any analysis of the global risks and benefits of not breastfeeding compared with those of neonatal infection. Authors who collected and tested breast milk samples from mothers with COVID-19 before delivery showed that all samples tested were negative. [34,41] Moreover, the primary concern is not only the virus’s transmission through breast milk, but whether mothers’ respiratory droplets could infect the baby during breastfeeding.
The World Health Organization, as well as United Nations Children’s Fund (UNICEF), underline that breast milk is the best source of feed even in infants born from mothers with suspected or confirmed SARS-CoV-2 infection, as well as all infants. Therefore, considering also the generally mild course in infants and young children, WHO encouraged to touch and hold the baby, breastfeed safely with good respiratory hygiene, hold the baby skin-to-skin, and share a room with the child when the mother’s clinical condition permits it.
The American College of Obstetricians and Gynaecologists (ACOG) [58], The Royal College of Obstetricians and Gynecologists (RCOG) [59], and the Italian Society of Neonatology endorsed by the Union of European Neonatal and Perinatal Societies [60] suggest that in case of a paucisymptomatic or asymptomatic mother with identified or suspected SARS-CoV-2 infection at delivery, direct breastfeeding and room-sharing is possible, with rigorous measures of infection control such as mother’s hands’ disinfection before holding the neonates and wearing a face mask during breastfeeding.
Ferrazzi et al. [39] reported the largest case series of neonates breastfed from mothers with COVID 19 (n = 11). All neonates had a favorable outcome, however, there are no available data regarding long-term follow-up.
Currently, the paucity of the studies’ results makes it hard to define the best strategy for the management of infected mothers with their infants during the post-natal period. Study results pending, it is likely that the benefits of breastfeeding and early mother–child contact are greater than the neonatal risk of SARS-CoV-2 infection.

4.4. Limitations of the Study

This review has several limitations. EMBASE, Medline, and Google Scholar were the only databases searched, hence relevant publications reported in other databases might have been missed. The search methodology could have introduced selection bias. Results should be interpreted cautiously due to the high heterogeneity among the included studies, and the fact that not all included articles were peer-reviewed articles. Finally, it is important to stress that the COVID-19 pandemic is still in progress all over the world; the reviewed studies are mostly carried out in China, using patient management and guidelines sometimes different from the ones used in Europe and the USA.

5. Conclusions

To the best of our knowledge, this is the biggest review regarding the impact of COVID-19 in pregnant women and neonates reported in the literature. According to our data, pregnant women with COVID-19 mostly presented with mild or moderate symptoms, with a low incidence of serious complications and adverse outcomes. Even the outcome of neonates born from infected mothers appeared mostly favorable. However, despite having a big population sample (275 pregnant women and 248 neonates), the information often derived from low-quality studies, which are case reports or case series. No observational analytic studies or clinical trials are available in the literature. Hence, although the data are reassuring, they must be confirmed by larger and high-quality studies.
Vertical transmission of SARS-CoV-2 was not detected in the majority of the reported cases, however, few cases of neonates with positive RT-PCR after birth are described. Hence, it is still not possible to rule out the vertical transmission.
Finally, we addressed that the creation of international registers, with easily available and detailed patient data, would be a useful tool to guide management decisions in a moment of global emergency.

6. Key Issues

  • SARS-CoV-2 infection in pregnant women appeared associated with mild or moderate disease in the majority of cases, with a low incidence of severe complications and low mortality rates;
  • Outcomes of neonates born from infected women were mainly favorable, although neonates at risk should be closely monitored to carry out early intervention for patients with abnormal findings;
  • Further studies are needed to investigate the possibility of vertical transmission.

Supplementary Materials

The following are available online at https://www.mdpi.com/2076-0817/9/6/485/s1, File S1: PRISMA Checklist.

Author Contributions

E.C. conceptualized the study; G.T. and I.M. carried out the research; M.C., M.F., and C.B. retrieved the pertinent literature; G.T. and M.F. carried out the analyses; G.T., M.C., M.F., and C.B. drafted the initial manuscript; C.D. supervised the project and gave conceptual advice; C.D., L.G., C.A., and E.C. reviewed and revised the manuscript. All authors approved the final manuscript as submitted. G.T. and E.C. take responsibility for the paper as a whole. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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