key: cord-0977540-oiwvx1dd
authors: Zhang, Clark; Chu, Haitao; Pei, Y. Veronica; Zhang, Jason
title: Laboratory Effects of COVID-19 Infection in Pregnant Women and Their Newborns: A Systematic Review and Meta-Analysis
date: 2021-04-13
journal: Front Glob Womens Health
DOI: 10.3389/fgwh.2021.647072
sha: 8fdaa3e53abc57ca82bb9f4be4aef5262d1dd604
doc_id: 977540
cord_uid: oiwvx1dd

Amidst the COVID-19 pandemic, there is a need for further research on its manifestation in pregnant women, since they are particularly prone to respiratory pathogens, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), due to physiological changes during pregnancy. Its effects on infants born to mothers with COVID-19 are also not well-studied, and more evidence is needed on vertical transmission of the disease from mother to infant and on the transmission of IgG/IgM antibodies between mother and infant. We aim to systematically review and evaluate the effects of COVID-19 among SARS-CoV-2-positive pregnant women in late pregnancy and neonates with SARS-CoV-2-positive pregnant mothers using blood assays to find indicators of maternal and neonatal complications. We searched for original published articles in Google Scholar, Medline (PubMed), and Embase databases to identify articles in the English language from December 2019 to July 20, 2020. Duplicate entries were searched by their titles, authors, date of publication, and Digital Object Identifier. The selected studies were included based on patient pregnancy on admission, pregnant mothers with laboratory-confirmed COVID-19 virus, maternal/neonatal complications, and blood test results. We excluded duplicate studies, articles where full text was not available, other languages than English, opinions, and perspectives. The meta-analysis using the Generalized Linear Mixed model was conducted using the “meta” and “metaprop” packages in R code. Of the 1,642 studies assessed for eligibility, 29 studies (375 mothers and neonates) were included. Preterm birth rate was 34.2%, and cesarean section rate was 82.7%. Maternal laboratory findings found elevated neutrophils (71.4%; 95% CI: 38.5–90.9), elevated CRP (67.7%; 95%: 50.6–81.1), and low hemoglobin (57.3%; 95% CI: 26.0–87.8). We found platelet count, lactate dehydrogenase, and procalcitonin to be less strongly correlated with preterm birth than between high neutrophil counts (P = 0.0007), low hemoglobin (P = 0.0188), and risk of preterm birth. There is little evidence for vertical transmission. Elevated procalcitonin levels (23.2%; 95% CI: 8.4–49.8) are observed in infants born to mothers with COVID-19, which could indicate risk for neonatal sepsis. These infants may gain passive immunity to COVID-19 through antibody transfer via placenta. These results can guide current obstetrical care during the current SARS-CoV-2 pandemic.

A global pandemic due to the outbreak of a novel coronavirus was first reported in Wuhan, China in December 2019. This novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes the disease COVID-19. While the name of SARS-CoV-2 suggests that COVID-19 is primarily a respiratory illness presenting with symptoms including fever, cough, and shortness of breath, which may progress to respiratory failure, COVID-19 can present with a wide spectrum of symptoms including sore throat, headache, loss of taste or smell, nausea, vomiting, and diarrhea (1) .

Pregnant women are particularly prone to respiratory pathogens, like SARS-CoV-2, due to physiological changes during pregnancy; increased oxygen intake and diaphragm elevation make pregnant women susceptible to hypoxia (2, 3) . There is accumulating evidence on pregnant women with COVID-19. However, early data do not indicate that pregnant women are at increased risk of morbidity, but do indicate increased risk for ICU admission and ventilation (4) . Furthermore, because of increased concentration of ACE2 receptors in the placenta, there is concern about the possibility of vertical transmission from mother to infant (5) . In fact, case studies have shown that SARS-CoV-2 can infect the placenta (6, 7) ; this study investigated whether or not this risk of vertical transmission is significant.

Reported laboratory abnormalities seen in pregnant patients with COVID-19 include lower white blood cell counts (lymphopenia and thrombocytopenia) and increased C-reactive (CRP) protein levels, elevated lactate dehydrogenase, and prolonged prothrombin time (8, 9) . To investigate these abnormalities, we systematically reviewed the blood assays among SARS-CoV-2-positive pregnant women in late pregnancy and among neonates with SARS-CoV-2-positive pregnant mother to find indicators of maternal and neonatal complications. We compared these laboratory values to those of non-COVID-19-infected pregnant women and to those of non-pregnant women to provide more accurate diagnosis. By identifying laboratory indicators and trends in preterm birth, neonatal sepsis, and other complications, clinicians are better prepared for treating those complications before they manifest.

This systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reviews of analytical observational studies.

We searched for original published articles in Google Scholar, Medline (PubMed), and Embase databases to identify articles reporting maternal and neonatal complications in pregnant women with COVID-19 in accordance with the PRISMA guidelines (Figure 1) . The authors also searched through the references listed within those published articles. The search was conducted using combinations of the terms "Novel coronavirus, " "COVID-19, " "SARS-CoV-2, " "Maternal, " "Neonatal, " "Mother, " "Pregnancy, " "Newborn, " "Infant, " "Antibody, " and "Laboratory" in the English language on July 20, 2020. Duplicate entries were searched by their titles, authors, date of publication, and Digital Object Identifier.

Two authors (C.Z. and J.Z.) searched the literature, compiled all articles identified through the literature search, and extracted the data. The primary eligibility for inclusion of studies were published studies, with patient pregnancy on admission and COVID-19 infection confirmed by laboratory diagnosis, which investigated maternal/neonatal complications, and recorded blood assay results. The following information was extracted from each eligible study: authors, publication date, type of study, study size, maternal characteristics (age, gestation, preterm birth, vaginal/cesarean birth, symptom severity, and maternal death), infant characteristics (birth weight, Apgar score, and neonatal death), maternal and neonatal blood assays, and laboratory-confirmed vertical transmission of COVID-19. We excluded duplicate studies, articles where full text was not available, other languages than English, opinions, and perspectives. After assessment for duplicates, titles, and abstracts, and full texts of articles, the individual patient characteristics and summary estimates from each selected article were extracted to an Excel spreadsheet (see section Data Availability Statement).

The meta-analysis included all studies. Pooled means on age, gestational age, blood assay values, antibody levels, and pooled prevalence on preterm birth, C-section delivery, vertical transmission, abnormal blood assay values, and elevated antibody levels were assessed using the Generalized Linear Mixed model; the meta-analysis was performed using the "meta" (10) and "metaprop" (11) packages in the R statistical software (12) . The random effects model was applied to calculate the pooled prevalence and single means with a 95% confidence interval (95% CI). Heterogeneity was assessed using Cochran Q test and Higgins' I 2 statistic (represented as a percentage, using the Restricted Maximum Likelihood method). Begg's Test, Egger's test, and a new publication bias statistic, Lin and Chu (13) , which generally performs better than Egger's test (14) , were used for testing publication bias. Statistical significance was considered with a P < 0.05. For studies without reported standard deviations (SD), their SD was replaced with the average of the studies whose SD were calculated or reported (15) .

A total of 1,673 literatures were initially retrieved from searching online databases and citations. Among these, 695 duplicate literatures were identified and removed. Remaining literatures were screened according to their titles and abstracts. Twentynine articles were selected to be analyzed ( Table 1) . A total of 375 SARS-CoV-2-positive pregnant women in late pregnancy and neonates born to these infected mothers were evaluated in 4 cohort studies, 7 case series, 11 retrospectives, and 2 observational studies, which were all conducted between December 2019 and July 2020. Three studies provided antibody (IgG/IgM) test results.

The general characteristics of pregnant patients with COVID-19 are summarized in Table 2 , and the prevalence of maternal and neonatal abnormalities are summarized in Figure 2 , and their meta-regression results are summarized in Table 3 . The pooled mean maternal age was estimated at 30.86 years (95% CI: 30. 16-31.55) . The pooled mean of gestational age was estimated as 37.20 weeks (95% CI: 36.52-37.88) and was not significantly different from the normal gestational age of 37 weeks (45) . The global proportion of preterm birth was estimated at 11% before the pandemic (46). This study found the proportion to be 34.19% (95% CI: 28.29-40.61%), suggesting a trend for higher risk of preterm birth in pregnant patients with COVID-19. The results of the meta-regression did not show any correlation between the means of gestational age and maternal age (P = 0.1542). Frequency of severe symptoms/admission to intensive care units (ICUs) was estimated at 9.28% (95% CI: 2.83-26.44%), which is not significantly different from the normal. There were seven cases of maternal death in this review; the prevalence of maternal death was not significantly different from zero (95% CI: 0.0-100.0%) and had significant publication bias (Begg's Test P < 0.01; Egger's Test P = 0.01; Lin and Chu P < 0.01).

The maternal laboratory findings are summarized in Table 4 . The most common laboratory findings were high neutrophil Frontiers in Global Women's Health | www.frontiersin.org . The pooled mean of neutrophils was estimated as 7.08 10 9 /L (95% CI: 5.07-9.10), CRP was estimated as 24.88 mg/L (95% CI: 13.80-35.96), and hemoglobin was estimated as 112.41 g/L (95% CI: 13.70-121.13). The results of the meta-regression showed that neutrophil levels have a significant relationship with gestational age (coefficient: −1.18, P < 0.01, 95% CI: −1.84-0.49; intercept = 50.48) and that hemoglobin levels have a relationship with gestational age (coefficient: 3.25, P = 0.02, 95% CI: 0.54-5.97; intercept = −5.35). Less commonly encountered abnormalities were lymphopenia, which was found in 31.99% of patients (95% CI: 21.64-44.49%), thrombocytopenia [15.07% (95% CI: 3.95-43.37%)], and elevated procalcitonin (PCT). The pooled prevalence of elevated PCT was estimated at 3.76% (95% CI: 0.06-72.79%) and had significant publication bias (Lin and Chu P = 0.01).

The following outcomes were from a meta-analysis with <10 studies. The pooled mean of lactate dehydrogenase has been estimated as 236.91 U/L (95% CI: 148.28-325.54), which is not significantly different from the normal. The results of the metaregression showed that blood urea nitrogen (BUN) levels have a significant relationship with gestational age (coefficient: 0.26, P = 0.04, 95% CI: 0.01-0.51). The pooled mean of prothrombin time (PT) was estimated as 12.11 s (95% CI: 11.7175-12.4990), which is significantly higher from the normal (8.7-11.5). The pooled mean of D-dimer has been estimated as 2.2651 mg/L (95% CI: 1.2956-3.2346), which is significantly higher than the normal range (<0.5).

The general characteristics of infants born to mothers with COVID-19 are summarized in Table 2 , and their meta-regression results are summarized in Table 3 . The pooled mean of birth weight has been estimated as 3,040 g (95% CI: 2,910-3,170). The pooled prevalence of low birth weight has been estimated as 13.2% (95% CI: 5.92-27.31%), which is not significantly different from the estimated worldwide prevalence of low birth weight in 2015 of 14.5% (47) . The results of the meta-regression showed that the means of birth weight have a relationship with gestational age with a correlation of 111 g/week (P < 0.01, 95% CI: 56.04-166.48; intercept = −1,106.99). This is not significantly from previous studies (48) .

The neonatal laboratory findings are summarized in Table 5 . The most common laboratory findings were elevated IL-6, which was present in 91.1% of the neonates (95% CI: 32.38-99.97%), abnormal white blood cell count (WBC), elevated neutrophil count [66.67% (95% CI: 47.33-81.66%)], and elevated AST/ALT , which is also significantly higher than the normal. Frequency of high PCT was less common and has been estimated as 23.17% (95% CI: 8.4-49.785%). The results of the meta-regression showed that PCT levels have a relationship with birth weight (coefficient: −0.01, P < 0.01, 95% CI: −0.01 to 0.01; intercept = 16.66).

The pooled mean of 1-min Apgar has been estimated as 7.94 (95% CI: 7.26-8.62). The results of the meta-regression showed that 1-min Apgar scores have a relationship with birth weight (coefficient: 0.002, P = 0.04, 95% CI: 0.00-0.01; intercept = 1.26). The pooled mean of 5 min Apgar has been estimated as 8.97 (95% CI: 8.34-9.61). The results of the meta-regression showed that 5 min Apgar scores have a relationship with birth weight (coefficient: 0.002, P = 0.04, 95% CI: 0.00-0.004; intercept = 2.49).

The pooled prevalence of vertical transmission has been estimated as 0.18%, but it was not significantly different from zero (95% CI: 0.0%−8.95%; I 2 = 88.6%, P < 0.01), and had significant publication bias (Begg's Test P < 0.01; Lin and Chu P < 0.01).

High IgG in mothers was highly prevalent and has been estimated as 72 The results of the meta-regression showed that infant IgG levels have a relationship with their mother's IgG level (coefficient: 0.85, P < 0.01, 95% CI: 0.67-0.93) and that infant IgM levels have a relationship with their mother's IgM level (coefficient: 0.43, P = 0.03, 95% CI: 0.06-0.70).

The global proportion of cesarean section was ∼21.1% in 2017 (49) . The present study found the overall proportion of cesarean section to be 82.7%, much higher than the global prevalence. While the decision to undergo C-section can vary due to differences in clinical practice and accepted standards of care, reasons found in studies selected in this review suggest that COVID-19 patients are more likely to have a C-section because they had underlying disease and intolerance against respiratory dysfunction. Given this is a novel disease, there is a general tendency for clinicians to avoid more complicated deliveries by undergoing C-section.

Results from our study suggest that severe symptoms or the need for intensive care appeared to be higher than that that for non-pregnant women of similar age (30.56 years). We found the proportion to be 9.3%, which was higher than previous estimates of 4.2-7.0% (50, 51); however, severe symptom criteria and ICU admission criteria were not well defined and varied between studies. Furthermore, this study's prevalence of severe symptoms is not significantly different from previous estimates, or from the general prevalence of severe COVID-19. Therefore, there is not enough evidence to suggest pregnant women are at increased risk of ICU admission or more severe symptoms. Prevalence of maternal death was not significantly different from zero; all maternal deaths were from a single study (27) , so maternal death is much more likely due to the quality of birthing conditions than due to maternal complications caused by COVID-19. The most common abnormalities found in the pooled blood assay were high neutrophil count, increased C-reactive protein (CRP), and low hemoglobin (71.9, 67.7, and 57.3%, respectively). Compared to abnormalities found in previous reviews, the only abnormalities shared by our review was increased CRPs among mothers with COVID-19 (2, 8, 9, 50) . Furthermore, the pooled mean of CRP was significantly higher than the normal range (<10 mg/L) for healthy non-pregnant patients, indicating that elevated CRP is strongly correlated with infection. Our mean CRP level and elevated CRP prevalence is not significantly different from recent meta-analyses on nonpregnant COVID-19-positive patients (52) (53) (54) . This is expected since COVID-19 can cause an overactive immune response, and CRP is a marker of that increased inflammation throughout the body.

Thrombocytopenia was previously identified as a symptom of infection. In this current study, the prevalence of low platelet counts was estimated at 15.1%, and its pooled mean was not significantly different from the normal range (150-450 10 3 /L). Platelet counts generally decrease during pregnancy, particularly during the third trimester, termed "gestational thrombocytopenia." In order to adjust for this, we used a lower limit for platelet count of 115 10 3 /µl (55) . Using this new parameter, a loose interpretation could be that COVID-19 does not significantly worsen gestational thrombocytopenia since the mean platelet levels is not significantly lower than the normal for pregnant patients. Our platelet results also did not differ significantly from those of a recent meta-analysis on nonpregnant COVID-19-positive patients, so pregnant patients are at no greater risk. Similarly, while elevated lactate dehydrogenase was identified in COVID-19 patients in previous studies and is associated with worse clinical outcome (53), our results showed that its pooled mean was not significantly different from the normal range (<225 U/L). However, due to the low number of studies that included lactate dehydrogenase in their blood assay, it is not possible to refute if it could also be correlated with infection.

Interestingly, we did not find elevated PCT to be a prevalent symptom of infection. Its prevalence was estimated at 3.8%, and its pooled mean, 0.29 ng/ml, was not significantly different from the normal range (<0.15 ng/ml). Furthermore, there was significant publication bias (Lin and Chu P < 0.01) for the pooled prevalence, so it is likely that the true prevalence is lower than the one presented in this study due to the inflation of elevated PCT publications (56) . This provides more evidence that suggests that elevated PCT is not a prevalent symptom of COVID-19.

In this study, we present other noteworthy values from the blood assays: neutrophils count, D-dimer, hemoglobin, and BUN. The most prevalent abnormality was high neutrophil count, or neutrophilia, with 71.4% of the women having this condition. Neutrophilia is its associated increased risk of small-for-gestational-age (SGA) birth, which reflects a cycle of inflammation and placental insufficiency (57) . The mean neutrophil level was estimated at 7.08 × 10 9 /L, which is over twice as concentrated than in non-pregnant COVID-19-positive patients (53) , and the prevalence of neutrophilia is over 10 times greater (52) . The results of the meta-regression further show that there is a significant negative correlation (P < 0.01) between a mother's neutrophil count and the gestational age at birth, with a gestational age of 32 weeks corresponding to neutrophil count of 13.1 × 10 9 /L. Therefore, excessively high neutrophil counts during mid-to-late pregnancy could be a risk indicator for preterm delivery. This is further supported by the high mean neutrophil-lymphocyte ratio (NLR), which was found to be 5.60. High NLR has been associated with greater risk of preeclampsia (58) and preterm birth (59) .

The pooled mean of D-dimer was estimated as 2.27 mg/L, which is much greater than the normal range (<0.5 mg/L) for non-pregnant patients. D-dimer is generally elevated during pregnancy; therefore, using this upper limit of 0.5 mg/L would result in false positives if using an upper limit of 0.5 mg/L. Studies have suggested increasing this threshold to 1.0 or 2.0 mg/L (60, 61) . Still, the point estimate and confidence interval (1.30-3.23) are still above these elevated thresholds. Our pooled mean for D-dimer was over twice as concentrated than in non-pregnant COVID-19-positive patients (53) . D-dimer is a biomarker for disease severity and blood clotting, so these observations provide evidence that indicate risk of venous thromboembolism and/or pulmonary embolism in mothers with COVID-19.

Low hemoglobin levels were the second most prevalent abnormality in the present study, with 57.3% patients presenting this abnormality. In general, pregnancy-induced anemia is common, so the normal hemoglobin range for pregnant women in the third trimester is 95-150 g/L (62). However, even given this lower threshold, there were many studies that included pregnant women with very low hemoglobin levels. This is concerning since very low hemoglobin levels are associated with increased fetal risk (63) . Furthermore, the results from the meta-regression found a significant positive relationship (P = 0.02) between hemoglobin levels and gestational age, with the gestational age of 32 weeks corresponding to 98.7 g/L. Very low hemoglobin levels during mid-to-late pregnancy could be a risk indicator for preterm birth, and the infant should be prioritized in consideration for neonatal ICU.

The pooled mean of BUN was estimated as 3.22 mmol/L, which falls within the normal range (2.5-7.1). We found that BUN had a significant positive correlation (P = 0.04) with gestational age, with the gestational age of 32 weeks corresponding to 1.44 mmol/L. However, a previous study (whose sampling frame was all pregnant women, not just those infected with COVID-19) found a negative correlation between BUN and gestational age, with a gestational age of 32 weeks corresponding to 17.1 mmol/L (64) . Since preliminary studies found that elevated BUN levels increase risk of in-hospital death by 2.51 in COVID-19 patients (65), it is possible that both of these conclusions are true: when BUN levels are abnormally low (<1.5 mmol/L) and are increasing, risk of kidney damage decreases, but the risk increases after BUN levels exceed 4 mmol/L (which is the upper bound for our confidence interval).

The most common abnormality found in the pooled blood assay was elevated IL-6, abnormal white blood cell count (WBC), elevated neutrophil count, and elevated AST/ALT. The pooled mean of IL-6, 23.22 pg/ml, is significantly above the normal range for IL-6 (5-15 pg/ml) (66) . Furthermore, the pooled prevalence of elevated IL-6 is 91.1%, which is very frequent. Since elevated IL-6 has been deemed a valid marker for predicting neonatal sepsis (NS) (67), more blood assays for neonates should include IL-6 as a tool for early NS diagnosis. Abnormally elevated IL-6 levels without IL-10 regulation (elevated IL-10 levels) are an essential indicator for further neonatal complications such as necrotizing enterocolitis (NEC) (68) . However, only a single study selected for this meta-analysis reported IL-10, and the neonate had elevated IL-10 levels and no NEC, so this study cannot meaningfully comment on the regulation of IL-10. However, given that IL-6 is the main cytokine responsible in the COVID-19-induced cytokine storms, these cytokines could have been shared from the mother to the fetus via the placenta.

Abnormal WBC and elevated neutrophils are well recognized within neonates (69) . Hyperleukocytosis (WBC > 100 × 10 9 /L) would be cause for concern, but no cases of hyperleukocytosis were identified in the present study. Similarly, the high prevalence of elevated AST/ALT in neonates has been deemed a benign condition that usually resolves within a year (70) .

The pooled mean for PCT has been estimated at 0.23 ng/ml and is significantly higher than the normal value for children older than 72 h (0.15 ng/ml). The results of the meta-regression found a significant negative relationship (P < 0.01) between birth weight and PCT levels, corresponding to a birth weight of 2,500 g to 4.4 ng/ml. This is highly concerning because elevated PCT is a biomarker that is much more specific than any other proinflammatory marker in identifying sepsis. Using this relationship, infants with birth weights under 3,000 g could have PCT levels >2 ng/ml, indicating severe sepsis and high risk of developing organ dysfunction.

The pooled 1 and 5 min Apgar scores, 7.94 and 8.97, respectively, were not significantly different from the normal range (7-10). As expected, the 1 and 5 min Apgar scores had significant positive relationships (P = 0.04, P = 0.04, respectively) with birth weight.

The pooled prevalence of vertical transmission was estimated to be 0.18%, which is not significantly different from 0%. Therefore, we found that the risk of vertical transmission is very low. Due to the significant publication bias, this suggests that the prevalence of vertical transmission is even lower than 0.18%. Recent studies into vertical transmission of SARS-CoV-2 via the placenta have also concluded that the virus very rarely infects the placenta and can only do so with very high maternal viral loads (6) . Even after placental infection, the virus may still be blocked from vertically transmitting (7) . Furthermore, we found that vertical transmission does not have significant correlations with gestational age and birth weight, so positive vertical transmission is much more likely due to birthing conditions (such as cleanliness and ventilation) than due to maternal or neonatal characteristics.

High levels of IgM antibodies were indicated as the first line of defense to SARS-CoV-2 when the disease is still active, whereas detection of SARS-CoV-2 virus IgG indicates recovery or past exposure to the virus (71) . In this study, we used 10 AU/ml as the threshold for IgG/IgM detection (33) . As expected, elevated IgG was highly prevalent in pregnant women with COVID-19, estimated as 72.7%; the pooled mean for IgG was significantly different from the normal range, estimated as 76.90 AU/ml. Interestingly, 67.1% of infants born to mothers with COVID-19 had elevated IgG levels. The pooled mean for neonatal IgG was significantly different from the normal range, estimated at 72.47 AU/ml. This indicates that infants with mothers with COVID-19 may gain natural passive immunity through IgG crossing the placenta during late pregnancy (72) . IgM has a larger molecular structure, making it more difficult to cross the placenta (72), though not impossible; this is reflected in the lower prevalence of elevated IgM levels (20.6%). Furthermore, the transfer of antibodies across the placenta is supported by the results of the meta-regression since there are significant positive relationships between maternal IgG and their neonate's IgG, and between maternal IgM and their neonate's IgM (P < 0.01, P = 0.03 respectively).

The major limitations of this systematic review are the retrospective design in almost all of the included studies, the lack of universal testing for COVID-19, the lack of standardized management and timing of women with COVID-19 and the inconsistent treatment and reporting for their newborns, and the lack of standardized blood testing. A significant proportion of the pregnancies were affected by COVID-19 during the third trimester, so we cannot meaningfully comment on early exposure. While common outcomes in blood assay, such as WBC and CRP, are commonly reported, other factors such as lactate dehydrogenase, BUN, D-dimer, and all neonatal outcomes should be tested more often so we can better verify if they are good tools to predicting the symptoms of COVID-19. Lastly, our review did not include studies that were recently published in the literature, particularly in languages other than English.

This systematic review and meta-analysis corroborated with previous studies that pregnant women with COVID-19 are at higher risk of preterm birth, are more likely to undergo cesarean section, and have elevated CRP levels and prolonged PT. In contrast to previously published reviews, we did not find an association between COVID-19 and thrombocytopenia, elevated lactate dehydrogenase, and elevated PCT to be prevalent symptoms for COVID-19. We report additional findings associated with COVID-19-infected mothers, including high neutrophil counts, low hemoglobin, and risk of preterm birth. Consistent with other reports, we found little evidence for vertical transmission. In neonates, we observed that infants born to mothers with COVID-19 are more likely to have elevated PCT levels and NS, but also may gain passive immunity to COVID-19 through antibody transfer via placenta. More testing and laboratory data are needed to clarify the relationships we found between D-dimer and thromboembolism, and between BUN and gestational age. Since the evidence is still increasing, this review provides information that can guide future systematic reviews for more meaningful results and can guide current health care during the current SARS-CoV-2 pandemic.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: Mendeley Data: http:// dx.doi.org/10.17632/fh557t857g.1.

Available online at

Pregnancy and perinatal outcomes of women with COVID-19 pneumonia: a preliminary analysis

Handbook of Obstetric Medicine

Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status

ACE2 expression and activity are enhanced during pregnancy

Transplacental transmission of SARS-CoV-2 infection

SARS-CoV-2 can infect the placenta and is not associated with specific placental histopathology: a series of 19 placentas from COVID-19-positive mothers

Clinical manifestation and maternal complications and neonatal outcomes in pregnant women with COVID 19: an update a systematic review and meta-analysis

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan

General Package for Meta-Analysis

R: A Language and Environment for Statistical Computing

Quantifying publication bias in meta-analysis

The effect of publication bias magnitude and direction on the certainty in evidence

Imputing missing standard deviations in meta-analyses can provide accurate results

Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China

Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

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

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

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection during pregnancy in China: a retrospective cohort study. medRxiv

Clinical characteristics of 19 neonates born to mothers with COVID-19

Infants born to mothers with a new coronavirus (COVID-19). Front Pediatr

Severe COVID-19 during pregnancy and possible vertical transmission

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

Clinical features and outcomes of pregnant women suspected of coronavirus disease (2019)

Maternal death due to COVID-19

Coronavirus disease 2019 in pregnancy

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vertical transmission in neonates born to mothers

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

Coronavirus disease 2019 in pregnant women: a report based on 116 cases

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

Antibodies in infants born to mothers with COVID-19 pneumonia

An uncomplicated delivery in a patient with Covid-19 in the United States

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

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

Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2) infection during late pregnancy: a Report of 18 patients from Wuhan, China

Clinico-radiological features and outcomes in pregnant women with COVID-19: compared with age-matched non-pregnant women

Emergency cesarean section performed in a patient with confirmed severe acute respiratory syndrome Coronavirus-2 -a case report

Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study. medRxiv

Covid 19 infected mothers and antibodies transmission to their babies

IgM AND IgG ANTIBODIES AGAINST SARS-COV-2 IN NEONATES BORN TO MOTHERS WITH COVID-19

Coronavirus disease 2019 (COVID-19) during pregnancy: a case series

Novel coronavirus in a 15-day-old neonate with clinical signs of sepsis, a case report

The global epidemiology of preterm birth

National, regional, and worldwide estimates of low birthweight in 2015 with trends from 2000: a systematic analysis

Birth weight for gestational age: a reference study in a tertiary referral hospital in the middle region of Turkey

Global epidemiology of use of and disparities in caesarean sections

SARS-CoV-2 infection in pregnancy: a systematic review and metaanalysis of clinical features and pregnancy outcomes

Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) -United States

Laboratory findings in coronavirus disease 2019 (COVID-19) patients: a comprehensive systematic review and meta-analysis. medRxiv

Clinical presentations, laboratory and radiological findings, and treatments for 11,028 COVID-19 patients: a systematic review and meta-analysis

A metaanalysis of 67 studies with presenting symptoms and laboratory tests of COVID-19 patients

Maternal thrombocytopenia in pregnancy

Publication bias: what are the challenges and can they be overcome?

Increment of absolute neutrophil count in the third trimester and increased risk of small-for-gestational-age birth: Hirakata Risk Associated with Pregnancy Assessment Research (HIRAPAR)

Diagnostic value of neutrophil-lymphocyte ratio in preeclampsia

First trimester neutrophil to lymphocyte ratio (NLR) and pregnancy outcome

Changes in d-dimer levels in pregnant women according to gestational week

Large D-dimer fluctuation in normal pregnancy: a longitudinal Cohort Study of 4,117 samples from 714 healthy Danish Women

Pregnancy and laboratory studies: a reference table for clinicians

National Collaborating Centre for Women's and Children's Health. Antenatal Care: Routine Care for the Healthy Pregnant Woman

The importance of low blood urea nitrogen levels in pregnant patients undergoing hemodialysis to optimize birth weight and gestational age

Kidney involvement in COVID-19 and its treatments

The interleukin-1, interleukin-2, interleukin-6 and tumour necrosis factor alpha serological levels in localised and systemic sclerosis

The role of interleukin-6 in the early diagnosis of sepsis in premature infants

The immunologic status of newborns born to SARS-CoV-2-infected mothers in Wuhan

Leukocyte adhesion deficiency type 1 presenting as leukemoid reaction

The significance of isolated elevation of serum aminotransferases in infants and young children

Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis

The placentas of patients with severe acute respiratory syndrome: a pathophysiological evaluation

CZ and HC conceived the study. CZ and JZ searched the literature and extracted the data. CZ performed the statistical analysis and drafted the manuscript. YV and HC helped to edit the manuscript. All authors contributed to the article and approved the submitted version.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgwh. 2021.647072/full#supplementary-material