Perinatal Outcomes of Newborns of COVID-19-Infected Pregnant Women: An Updated Systematic Review and Meta-Analysis

In this systematic review and meta-analysis, we aimed to review the characteristics and outcomes of the newborns of Coronavirus disease 2019 (COVID-19) infected pregnant women. We conducted an online bibliographic search using the following electronic databases: MEDLINE via PubMed, Scopus, Web of Science, and Cochrane Central. Studies were deemed eligible if they recruited newborns from mothers with confirmed COVID-19 and reported the perinatal outcomes of neonatal COVID-19 cases. A total of 20 studies were included. Neonates born to mothers with positive COVID-19 results have been shown to have significantly lower birth weights (mean difference, MD = -48.54 g, p = 0.04), increased risks of fetal distress (odds ratio, OR = 1.76, p < 0.00001), respiratory distress (OR = 1.96, p = 0.006), premature birth (OR = 2.08, p < 0.00001), neonatal death (OR = 2.20, p = 0.004), and a lower 5-minute Apgar score (OR = 1.44, p = 0.02). Additionally, they were more likely to be admitted to the neonatal intensive care unit (NICU) (OR = 2.25, p = 0.007) and test positive for COVID-19 themselves (OR = 9.88, p = 0.03). However, other parameters, such as risks for malformations, mechanical ventilation, hypoglycemia, and sepsis, appeared to be comparable between the two groups. Maternal infection with COVID-19 during pregnancy is associated with several neonatal outcomes, some of which are adverse and others that do not show significant deviation from norms. While our meta-analysis clearly illustrates heightened risks associated with premature birth, reduced neonatal weight, and other challenges, it also emphasizes that not all neonatal outcomes can be directly attributed to maternal SARS-CoV-2 infection.

Congenital viral infections can cause death, multisystem organ damage, sepsis, and permanent disability in newborns [5].In ten infants delivered to women with COVID-19 infection, Zhu H et al. found evidence of impaired liver function, thrombocytopenia, respiratory distress, premature labor, and fetal distress; however, all the newborns tested negative for the virus.Vertical transmission of the virus is a rare occurrence, but many of the newborn problems are attributable to premature birth [6].In a recent investigation, Zhang ZJ et al. found only four affected infants in China who presented between 30 hours and 17 days after delivery, indicating a nosocomial infection.These newborns had minor or no illnesses, did not require special care, and appeared to be in good health.Three of the infants were separated from their mothers shortly after delivery and were not breastfed [7].The mechanisms of viral vertical transmission during pregnancy are not well understood [8,9].Possible routes of fetal infection include spread from the maternal bloodstream to fetal capillaries, ascending urogenital infections, infected maternal macrophages, and contact between maternal endothelium and cytotrophoblasts [10].Finally, maternal infections can be passed on to newborns during delivery.In this systematic review and meta-analysis, we aimed to review the characteristics and outcomes of newborns born to mothers with a COVID-19 infection at the time of birth.

Literature Search
This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [11].

Eligibility Criteria
We included studies that met the following inclusion criteria: (I) Population: Studies including pregnant women with clinically or laboratory-confirmed COVID-19; (II) Comparison: Studies including pregnant women with negative COVID-19 as a control group; (III) Outcomes: Studies assessing the prenatal or neonatal outcomes of infected vs. non-infected pregnant women; (IV) Study Design: Observational studies, including cohort, case-control, and cross-sectional studies.We excluded case reports and case series, reviews, book chapters, theses, editorials, and letters.Additionally, we excluded studies comparing pregnant women vs. non-pregnant women, pregnant women pre vs. during COVID-19 or lockdown, infected hospitalized women vs. non-hospitalized women, infected neonates vs. non-infected neonates, and mild COVID-19 cases vs. severe COVID-19 cases.

Selection Process
After the database searches, all citations were imported into the EndNote X9 Windows version.Duplicate references resulting from database content overlap were identified and removed.Two independent reviewers (K.A and Y.E) screened the titles and abstracts of all unique citations against the predefined inclusion and exclusion criteria.Any disagreements between the two reviewers at this stage were resolved through discussion, or, if necessary, a third reviewer (M.S) was consulted.Studies that appeared to meet the inclusion criteria, or for which there was insufficient information in the title and abstract to make a clear decision, were advanced to full-text review.Again, two independent reviewers (M.E.H and M.H) assessed each full-text article to determine its eligibility.Disagreements at this stage were resolved through consultation with a third reviewer (M.S).The reference lists of all included studies were scanned to identify additional studies that might have been missed during the initial database searches.Any potentially relevant studies identified through this process were subjected to full-text review and included if they met the criteria.

Data Collection Process and Data Items
For studies that met the inclusion criteria, relevant data were extracted using a standardized data extraction form.This form was piloted on a subset of included studies and refined as needed.Data extracted included study characteristics (study ID, design, country, groups, sample size, inclusion criteria, conclusion), patient characteristics (age, race, body mass index, comorbidities, pregnancy-related conditions), and neonatal outcomes (weight, death, NICU admission, sepsis, fetal distress, respiratory distress, premature death, Apgar score, need for mechanical ventilation, continuous positive airway pressure (CPAP), or oxygen therapy).

Quality Assessment
The methodological quality of the included studies was evaluated using the Journal Impact Benchmark (JIB) tool, chosen for its comprehensiveness and applicability to case-control, cohort, and cross-sectional designs.Each study was meticulously appraised based on standardized criteria provided by the JIB tool, encompassing aspects such as study design, participant selection, exposure and outcome assessment, and statistical analysis.

Statistical Analysis
Data were pooled in pairwise comparisons when suitable.Continuous data were pooled as mean difference (MD) and 95% confidence interval, and dichotomous outcomes as odds ratio (OR) and 95% confidence interval.Statistical heterogeneity was assessed using the Chi-Square test, with its extent measured by the I-Square test.A random-effects model was used to estimate effect sizes.Sensitivity analysis was performed using a one-out model.Publication bias and the effect of small studies were assessed using funnel plot visualization.Review Manager (RevMan, Cochrane Collaboration) version 5.4 was used for pooling studies.PRISMA: Preferred reporting items for systematic review and meta-analysis.

Characteristics of Included Studies
A total of 20 studies were included from multiple countries, including the US, Sweden, China, Spain, India, Chile, France, Italy, Iran, and Romania.Four studies were case-control, one study was cross-sectional, and 15 studies were cohort studies.Notably, while many studies highlighted an increased risk of various pregnancy-related complications due to COVID-19, such as pre-eclampsia, preterm labor, fetal distress, premature rupture of membranes, venous thromboembolism, and other adverse maternal and neonatal outcomes [14,15,19,20,29,30], several others found no significant association between the infection and severe complications [16,22].Specific findings also suggested that vaginal delivery could reduce the risk of intrapartum SARS-CoV-2 transmission and that the severity of maternal and neonatal outcomes might depend on the severity of the COVID-19 infection [26].

Quality Assessment
Based on the JIB tool, the quality of the four case-control studies and the fifteen cohort studies was deemed as "High."Similarly, the cross-sectional study by Díaz-Corvillón P et al. [14] showed high quality.The results of the quality assessment are presented in The total number of women with positive COVID-19 was 6,271, while the total number of those without COVID-19 was 109,850.The average age of the included patients was 29.88 years.Racial demographics, when reported, showed diverse populations, with notable representations from White non-Hispanic, Hispanic or Latina, and Black non-Hispanic groups, among others.BMI values, where specified, hovered around the mid-20s to low 30s, suggesting a mix of normal to overweight and obese populations.The prevalence of obesity varied across studies, with some indicating higher rates in the positive COVID-19 group than in the negative.Appendix 1 summarizes the demographics and pregnancy-related conditions of the included patients.

Neonatal Weight
Twelve studies reported data on neonatal weight.The random-effects model showed that neonates of mothers with positive COVID-19 were associated with significantly lower weight compared to those of mothers with negative COVID-19 (MD = -48.54g, 95% CI: -95.08 to -2.00, p = 0.04), as shown in Figure 2a.

Premature Death
Six studies reported data on premature death.The random-effects model showed that neonates of mothers with positive COVID-19 were associated with a significantly higher risk of premature death compared to those of mothers without COVID-19 (OR = 2.08, 95% CI: 1.69 to 2.56, p < 0.00001), as shown in Figure 4c.

Small for Gestational Age
Seven studies reported data on small for gestational age.The random-effects model showed that neonates of mothers with positive COVID-19 were associated with a non-significantly higher risk of being small for gestational age compared to those of mothers without COVID-19 (OR = 1.14, 95% CI: 0.97 to 1.34, p = 0.11), as shown in Figure 7a.Pooled data were homogeneous (I 2 = 0%, p = 0.98).

Low Birth Weight
Four studies reported data on low birth weight.The random-effects model showed that neonates of mothers with positive COVID-19 were associated with a significantly higher risk of low birth weight compared to those of mothers without COVID-19 (OR = 1.86, 95% CI: 1.27-2.72,p = 0.001), as shown in Figure 7b.Pooled data were homogeneous (I 2 = 13%, p = 0.33).

Sepsis
Three studies reported data on sepsis.The random-effects model showed that neonates of mothers with positive COVID-19 had a comparable risk of sepsis compared to those of mothers without COVID-19 (OR = 1.14, 95% CI: 0.61-2.12,p = 0.68), as shown in Figure 8c.Pooled data were homogeneous (I 2 = 0%, p = 0.39).

Mechanical Ventilation
Three studies reported data on mechanical ventilation.The random-effects model showed that neonates of mothers with positive COVID-19 were associated with an insignificantly higher risk of mechanical ventilation compared to those of mothers without COVID-19 (OR = 2.42, 95% CI: 0.5-0.59,p = 0.24), as shown in Figure 9a.Pooled data were homogeneous (I 2 = 52%, p = 0.13).

Oxygen Therapy
Two studies reported data on oxygen therapy.The random-effects model showed that neonates of mothers

Discussion
In this systematic review and meta-analysis, we assessed the potential effects of maternal COVID-19 positivity on various neonatal outcomes.The findings indicate that neonates born to mothers with positive COVID-19 results have significantly lower neonatal weight, higher risks of fetal distress, respiratory distress, premature death, reduced gestational age, and an increased likelihood of a 5-minute Apgar score below 7.Moreover, they face significantly higher risks of being diagnosed with low birth weight and testing positive for COVID-19.However, certain outcomes, such as malformations, hypoglycemia, sepsis, mechanical ventilation, and CPAP, showed no significant difference between groups, suggesting that while COVID-19 in expectant mothers may present specific neonatal challenges, not all observed outcomes can be attributed directly to maternal infection.
The impact of the current COVID-19 epidemic on pregnant women and their newborns is a critical aspect.Numerous studies have now been published on the negative effects of COVID-19 on pregnant women, their infection status, and the clinical features of their newborn babies.Their findings revealed that pregnant women with confirmed COVID-19 had a greater rate of preterm birth; however, this was not necessarily due to severe maternal respiratory illness.There was no indication of intrauterine transmission of COVID-19 when the infants' outcomes from the group of pregnant women with COVID-19 were examined [3,[32][33][34].
To investigate the possibility of vertical transmission, Moreno and his colleagues conducted a retrospective study of pregnant women diagnosed with COVID-19 (positive COVID-19 rRT-PCR) during the third trimester.Their findings demonstrated no detected cases of COVID-19 in the delivered neonates; however, 62% of them were admitted to a NICU, 46.1% were premature, and the mean period of NICU stay was 5.5 ± 6.4 days [35].Many studies have also suggested no vertical transmission of COVID-19 [36][37][38][39], including a systematic review and meta-analysis of six studies [40].A neonate delivered to a pregnant woman with COVID-19 tested positive for COVID-19 in a pharyngeal swab sample 36 hours after birth.Still, the qRT-PCR screening was negative for COVID-19 when taken from the placenta and cord blood, implying that intrauterine vertical transmission did not occur [41,42].Two articles highlighted the probability of vertical transmission of COVID-19 due to the presence of IgM antibodies in blood obtained from three neonates delivered to women with COVID-19, while the respiratory samples were all negative for COVID-19 [43,44].
Our meta-analysis showed that newborns from COVID-19-positive mothers had a significantly higher incidence of premature death, which is the most prevalent unfavorable pregnancy outcome in COVID-19 patients.A meta-analysis conducted by Di Mascio et al. showed that the incidence of preterm birth was 41.1% in pregnant patients with COVID-19; of these, 25% were less than 37 weeks, and 19.6% were less than 34 weeks [40].In a recent cohort, preterm birth before 37 weeks was found in 38.1% [35].Future studies should include a larger sample of patients from other centers to detect variations in preterm delivery rates and determine whether premature birth is a significant adverse outcome in women with COVID-19 infection.
In terms of stillbirth, we could not find a significant difference between both groups.Similarly, a previous meta-analysis showed no correlation between maternal infection and stillbirth [45].Contrary to our findings, a systematic review observed that women with COVID-19 were 2.84 times more likely to experience stillbirth than those uninfected, based on a small sample of 35 stillbirths, with nine from the COVID-19 cohort [46].Furthermore, a comprehensive study involving over 340,000 pregnancies in England reported an elevated risk of stillbirth with an adjusted OR of 2.17 (95% CI: 1.96-2.42)[47].Potential discrepancies in results might arise from various analytical approaches.For instance, our definition of stillbirth was any fetal demise from 28 weeks' gestational age onwards [48], whereas some studies set an earlier gestational age.Given the rarity of stillbirth, further insights are essential to gauge potential risks and discern if risk fluctuations occur based on COVID-19 infection timing and severity.
Interestingly, our study did not identify any association between COVID-19 infection during pregnancy and neonates being categorized as small for their gestational age.This observation aligns with the results from the INTERCOVID study and a previous meta-analysis, which reported comparable outcomes [20,45].Thus, the combined results hint at a lack of correlation between COVID-19 infection during pregnancy and intrauterine growth restriction.However, it would be prudent to delve deeper into this issue, especially considering the potential impact of the timing and intensity of the infection during gestation.

Clinical implications
The findings of our review have pivotal clinical implications.Health professionals should be vigilant when providing prenatal and postnatal care to mothers infected with COVID-19, ensuring both maternal and neonatal health are paramount.It is essential to have a thorough risk assessment, which can guide timely interventions, thereby potentially reducing adverse outcomes.Clinicians should also be updated about the potential risks and effects of COVID-19 during pregnancy to offer the best possible care.

Future directions
The effects of maternal COVID-19 infection on neonates warrant further exploration, especially in larger cohorts and across different regions.Future research should focus on longitudinal studies that track neonatal outcomes over the long term, understanding the developmental and health implications as they grow.Moreover, the specific mechanisms underlying the observed outcomes remain elusive and merit further investigation.Studies examining the effects of maternal vaccination on neonatal outcomes will also be invaluable as we progress in our fight against the pandemic.

Limitations
While our meta-analysis provides critical insights, it is not devoid of limitations.The number of studies included was relatively small, which limits the comprehensiveness of our findings.We observed considerable heterogeneity in some pooled analyses, which can affect the generalizability of our conclusions.The inability to perform a subgroup analysis due to the lack of available studies further restricts our understanding.Additionally, variations in study design, population demographics, and clinical settings among the included studies might have introduced biases, potentially impacting the robustness of our results.Further studies are required to examine the association between the timing of infection (first, second, and third trimester) and the complication rate.In addition, the causes of neonatal death or mortality were not well investigated in the included studies.

Conclusions
Maternal infection with COVID-19 during pregnancy presents with several neonatal outcomes, some of which are adverse and others that do not show significant deviation from the norms.While our metaanalysis clearly illustrates heightened risks associated with premature birth, reduced neonatal weight, and other challenges, it also emphasizes that not all neonatal outcomes can be directly attributed to maternal SARS-CoV-2 infection.Discrepancies observed in outcomes across various studies underscore the intricate nature of the virus's impact on neonatal health and the importance of considering factors like timing, severity, and the presence of other confounding variables.

FIGURE 2 :
FIGURE 2: a) Forest plot of neonatal weight, b) Sensitivity analysis of neonatal weight.

FIGURE 5 :
FIGURE 5: a) Forest plot of NICU admission, b) Sensitivity analysis of NICU admission.

FIGURE 6 :
FIGURE 6: a) Forest plot of neonatal death, b) Forest plot of stillbirth, c) Forest plot of Apgar score <7.

FIGURE 7 :
FIGURE 7: a) Forest plot of gestational age, b) Sensitivity analysis of gestational age.

FIGURE 8 :
FIGURE 8: a) Forest plot of malformation, b) Forest plot of hypoglycemia, c) Forest plot of sepsis.

FIGURE 9 :
FIGURE 9: a) Forest plot of mechanical ventilation, b) Forest plot of CPAP, c) Forest plot of oxygen therapy.CPAP: Continuous positive airway pressure.

Table 1
summarizes the characteristics of the included studies.

TABLE 1 : Characteristics of included studies.
QA: Quality assessment; DIC: Disseminated intravascular coagulation; US: United States; QA: Quality assessment.

TABLE 2 : Demographics and pregnancy-related conditions of the included patients.
DM: Diabetes mellitus; HTN, Hypertension; CVD: Cardiovascular disease.