Clinical Outcome of Neonates Born to SARS-CoV-2 Positive Mothers in India: A Systematic Review and Meta-Analysis

During the SARS-CoV-2 pandemic, India accounted for 10-50% of cases reported across the world. Perinatal care from a developing country during this period has its own importance. This study was conducted to evaluate the health outcome of neonates born to SARS-CoV-2 positive mothers in India from the published literature by a systematic review and meta-analysis. Articles reporting neonates born from SARS-CoV-2 confirmed mothers in India, published in PubMed, Scopus®, and Embase® databases, were analyzed. After registration with the International Prospective Register of Systematic Reviews (PROSPERO), the study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The primary outcomes were the mode of delivery, perinatal asphyxia, preterm birth, breastfeeding, neonatal mortality, SARS-CoV-2 infectivity among neonates of SARS-CoV-2 mothers. The pooled rate was expressed with a 95% confidence interval. Heterogeneity and study level effect size were assessed using I² statistics and DerSimonian and Laird random effect method of meta-analysis. Data analysis was made by Stata 15.1 (StataCorp LLC, College Station, Texas, USA). Total 3,551 neonates born from 3,542 SARS-CoV-2 positive mothers were included from 14 studies (four prospective and 10 retrospective studies). The pooled rates of premature birth, Caesarean delivery, breastfeeding, and neonatal mortality were 18.89%, 55.89%, 67.79%, respectively, with 12.64/1000 live births. SARS-CoV-2 positivity rate was 5.28%; 11.76% were symptomatic, and five (1.7%) died from 281 SARS-CoV-2 positive neonates. There was an increase in the number of Caesarean delivery, premature birth, and lower mortality among neonates born to SARS-CoV-2 positive mothers compared to the Indian neonatal database. Around five percent of neonates delivered to SARS-CoV-2 positive mothers were infected, and the majority of them had good clinical outcomes.


Introduction And Background
SARS-CoV-2 viral infection originated from Wuhan, China, and spread to a pandemic across the globe within a few months [1]. By June 1, 2021, 171.3 million people of the world were already infected with the SARS-CoV-2 virus, out of which 28.3 million (16.52%) were from India [2]. Neonates were infected during the pandemic either during the early neonatal period through possible vertical transmission or later through horizontal transmission from community or family members [3]. Neonatal health in India has always been unique as a major contributor to global live births and neonatal deaths. India is a large subcontinent, and Indian perinatal statistics are also highly heterogeneous in different states [4].
As India is one of China's neighboring countries, the upsurge of cases in India followed the peak in China and European countries. Few meta-analyses have been published regarding the health status of neonates delivered to SARS-CoV-2 positive mothers, where the majority of Indian studies were not enrolled [5][6][7][8][9]. In this context, this systematic review and meta-analysis intend to analyze the clinical outcomes and SARS-CoV-2 infectivity of neonates born to SARS-CoV-2 positive mothers in India from published literature.

Search strategy
A comprehensive search of PubMed, Scopus®, and Embase® databases with a pre-defined sensitive search strategy, including the search terms for SARS-CoV-2, neonatal, India, and its states, was done on June 22, 2021. The detailed search strategy is provided in the appendix. Literature published from 2020 to June 22, 2021, was included.

Study selection
All extracted records from all three databases were merged, and duplicates were removed to make a database of unique records. All extracted records were screened based on title and abstract against pre-defined inclusion criteria in the first phase independently by two authors. Articles reporting original data on neonates born to SARS-CoV-2 mothers were included without any language restriction. All records that had the eligible title and abstract screening underwent full-text review by two authors independently. Manuscripts with less than 20 neonates and lack of complete information about maternal SARS-CoV-2 confirmed status were excluded along with guidelines and systematic reviews. For any excluded article in this phase, the reason for exclusion is specified.

Data extraction
Data extraction was performed by two authors independently. Each study was critically appraised, and data was extracted from reported text/tables. The information regarding author, study site, study period, design, number of infected mothers and neonates, the timing of testing of neonates along with clinical outcomes were documented. The mode of delivery, perinatal asphyxia, preterm birth, breastfeeding, mortality, SARS-CoV-2 infectivity among neonates of SARS-CoV-2 mothers are the primary outcomes.

Statistical analysis
For all the outcomes, proportions were synthesized. Heterogeneity in study-level effect size was assessed using I² statistics [11]. Since there was moderate to high heterogeneity, the DerSimonian and Laird random effect method of the meta-analysis was used to synthesize the prevalence of binary outcomes like neonatal virus positivity, neonatal death, the study level prevalence [12]. Publication bias was visualized using a funnel plot and tested using Egger's test. All statistical analyses were conducted using Stata 15.1 (StataCorp LLC, College Station, Texas, USA).

Risk of bias
The quality of the studies was assessed using Joanna Briggs Institute (JBI) critical appraisal tool as appropriate for study, and scores were assigned ( Table 1). Two authors independently assessed the quality of each of the included studies. Any discrepancy was resolved by consensus.

Discussion
This systematic review and meta-analysis is a comprehensive overview of the health status of neonates born to SARS-CoV-2 positive mothers from 14 Indian studies comprising 10 retrospective and four prospective studies [13,20,22,26]. Apart from one multicentre study [13], the rest data is from monocentric studies. Moderate to the high degree of heterogeneity was found in all primary neonatal outcome variables. There were increasing trends of Caesarean delivery and premature birth from SARS-CoV-2 positive mothers; however, the prevalence of perinatal depression and neonatal mortality was not increased in comparison to pre-COVID-19 Indian health statistics [4].

Mode of Delivery
The majority of SARS-CoV-2 mothers delivered by Caesarean section in India, similar to the high prevalence of Caesarean birth (83-85%) reported in two meta-analyses (studies mostly from China and European countries) [5,6]. In this meta-analysis, five monocentric studies reported increased Caesarean births, whereas three studies, including the multicentric study with the largest sample size, reported more vaginal birth. In Gupta et al., the Caesarean birth rate was two times higher in SARS-CoV-2 positive in comparison to SARS-CoV-2 negative mothers [25]. Elective Caesarean delivery in SARS-CoV-2 infected mothers, previous Caesarean section, presence of fetal distress, and failed induction were mentioned as indications of increased Caesarean section in some studies. Most of the study sites were the COVID-19 referral units covering a vast population, and many local logistic issues related to the pandemic such as lack of isolated space for labor, facilities for intrapartum fetal monitoring, and delayed referral could explain increasing Caesarean delivery [20,23]. Mode of delivery didn't affect neonatal infectivity in Sehra et al. [21].

Perinatal Asphyxia
The reporting of perinatal asphyxia was not uniform across the enrolled studies. The need for resuscitation, appearance, pulse, grimace, activity and respiration (APGAR) score at birth, APGAR score less than seven at five minutes, and neonates admitted for asphyxia were considered as perinatal asphyxia in the current study. The perinatal depression rate in this meta-analysis is higher compared to other systematic reviews done by Di Toro et al. and Juan et al. from overseas [5,7]. In the multicentric study, SARS-CoV-2 infected neonates required more resuscitation compared to non-infected neonates [13].

Prematurity
The preterm birth rate in India (18.8%) is slightly higher than the UK registry (16.1%) and in the USA registry (15.7%) of the American Academy of Pediatrics -The Section on Neonatal-Perinatal Medicine (AAP-SONPM) in SARS-CoV-2 mothers [8]. In two different meta-analyses by Di Toro et al. and Huntley et al. conducted during the early stage of the pandemic, the prematurity rates were 23% and 20.1%, respectively [5,41]. However, a lower prematurity burden was reported in two studies of this meta-analysis by Kumar et al. (6.2%) and Malik et al. (4.78%) [13,16]. SARS-CoV-2 infected mothers (28.3%) had more preterm babies vs. non-infected mothers (14.6%) as per the study by Gupta et al. [25]. Anand et al. reported the highest percent of premature births and also the highest percent of symptomatic mothers in this metaanalysis [15]. In a systematic review, preterm birth was the adverse outcome in SARS-CoV-2 infected pregnant mothers [9].

Breastfeeding
There is limited evidence for the existence of the SARS-CoV-2 virus in breast milk; rather, it protects neonates with SARS-CoV-2 antibodies [42]. Exclusive breastfeeding practice for neonates of SARS-CoV-2 mothers is recommended by The Federation of Obstetric and Gynecological Societies of India (FOGSI) and the National Neonatology Forum, India [43]. The breastfeeding practice was prevalent in 67.8% in India, whereas 73% of hospitals from Europe and 66.9% from the USA have practiced breastfeeding during the COVID-19 pandemic [44,45].
Around 93% of the breastfed neonates have tested negative in Anand et al. [15]. Rooming-in rather than types of feeding marginally increased the risk of infection as per the study by Kumar et al. [13]. Charki et al. reported the absence of perinatal transmission with strict adherence to respiratory and hand hygiene practice even with rooming-in and breastfeeding [26]. Lack of space for maintaining six feet distance between mother-infant dyad and compliance with appropriate hand hygiene are major concerns for possible horizontal transmission as raised by Kalamdani et al. [24]. There are favorable clinical outcomes with exclusive breastfeeding practice in all enrolled studies, including SARS-CoV-2 infected neonates as reported by Nambiar et al. and Kalamdani et al. [17,24].

Neonatal Mortality
The pooled mortality rate (12.64%) in neonates of SARS-CoV-2 mothers is lower compared to the country's projected neonatal mortality rate for 2020 [4]. The institutional delivery in a tertiary care setup and better compliance of infection control policy in COVID-19 hospitals may have helped the reduction. There is an increase in neonatal NICU admission rate among neonates of SARS-CoV-2 positive mothers compared to negative mothers, but the neonatal mortality rate is comparable between both groups in Gupta et al. [25]. Asphyxia, sepsis-like conditions and prematurity were major indications of NICU admission and neonatal mortality. There is only three early neonatal mortality per 1,000 live births in a systematic review from developed countries [8].

Neonatal SARS-CoV-2 Infectivity
In this meta-analysis, neonatal SARS-CoV-2 positivity was 5.28%, with the majority of them being infected within the first 72 hours. In contrast, two-thirds of infected neonates were diagnosed beyond 72 hours in a systematic review by Raschetti et al. [46]. Compared to the present study, there is a lower neonatal infectivity rate in the AAP registry (2.1%) of SARS-CoV-2 mothers [8].
The possibility of vertical transmission was not explored from maternal or neonatal body fluids (i.e., amniotic fluid, placenta, or IgM level in neonates, etc.) except by Sharma et al. [22]. The absence of virus in body fluids samples favors the low possibility of vertical transmission. The only early testing policy may not predict true infectivity burden when the practice of exclusive breastfeeding and rooming-in is used. The neonates of SARS-CoV-2 mothers were not infected in three studies during hospital stay [14,25,26]. In Sehra et al., the average timing of neonatal positivity beyond 72 hours may be attributed to the absence of early rooming-in and direct breastfeeding [21]. In one study, maternal viral loads didn't affect neonatal infectivity [15]. Early neonatal infectivity in this study may be influenced by neonatal care practice during testing, without any strong evidence for vertical transmission.

Neonatal SARS-CoV-2 Outcome
In this review, 11.67% of SARS-CoV-2 neonates were symptomatic, in contrast to the systemic review by Dhir et al. where they found that around 50 percent of SARS-CoV-2 infected babies were symptomatic with zero mortality [3].
It is very difficult to distinguish between early neonatal morbidity and isolated SARS-CoV-2 related symptoms, but SARS-CoV-2 infection increased neonatal morbidity in two studies [13,16]. The risk of neonatal sepsis, poor feeding, respiratory support, and deaths in SARS-CoV-2 positive neonates is increased compared to negative groups in Malik et al. [16]. In the multicentric study, SARS-CoV-2 infected neonates need more resuscitation, symptomatic and respiratory support, but there is no effect on mortality compared to those non-infected [13].

Limitation and Strength
Taking published manuscripts from different parts of India, a huge data on neonates of SARS-CoV-2 mothers were analyzed from a single country. Our study may guide the public health preparedness for perinatal outcomes in the present and future pandemic disasters in India and other low-and middle-income countries. Despite existing heterogeneity in local health arrangements and practice policy, all study sites followed the existing Indian Council of Medical Research (ICMR), National Neonatology Forum (NNF) FOGSI, COVID-19 related testing, and clinical management guidelines [47]. Case reports and case series with a sample size of less than 20 were excluded from analysis; hence reporting bias is eliminated to some extent.
This meta-analysis reported only early neonatal outcome data, mostly during the hospital stay, with few post-discharge follow-up data. As neonates of SARS-CoV-2 mothers are the targeted study participants, detailed maternal morbidity was not covered. Marked heterogeneity is reported across studies, and the appropriate statistical measures were taken to overcome that.

Conclusions
The results of this meta-analysis based on Indian studies provides unique information for neonate SARS-CoV-2 mothers in low to middle-income countries. There is an increasing trend of Caesarean delivery and premature birth in comparison to the pre-pandemic era. The majority of SARS-CoV-2 neonates are infected within the first 72 hours and have good clinical outcomes. Due to the scarcity of strong evidence for vertical transmission, strong advocacy to abate the rising trend of Caesarean delivery should be done. As an increased need for resuscitation for neonates of SARS-CoV-2 mothers and a higher perinatal asphyxia rate were observed compared to developed countries, authors recommend aggressive fetal monitoring during the intrapartum period and timely intervention. SARS-CoV-2 infection among neonates was influenced by neonatal care practices. Breastfeeding and rooming-in practice should be encouraged with the appropriate hand and respiratory hygiene. As SARS-CoV-2 infected neonates have increased morbidity, close monitoring should be done for positive neonates. Future research should be conducted to create a population-based registry to report and compare neonatal outcomes among infected and non-infected neonates. Future research should explore the maternal SARS-CoV-2 characteristics and severity with premature delivery, fetal distress, and neonatal sickness. Further studies on predictors of symptomatic disease among SARS-CoV-2 infected neonates may be conducted in India.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.