Pregnant women experience physiological changes such as pulmonary adaptation due to an elevated diaphragm and altered cell immunity. These factors can predispose pregnant women to enhanced susceptibility to severe viral pneumonia infection, leading to adverse pregnancy outcomes associated with increased mortality and morbidity in neonates. Currently, the COVID-19 pandemic has reported over 230 million cases reported globally and generated evidence on raising concerns about maternal infection on the added risk of adverse neonatal outcomes. The review aims to evaluate the effects of COVID- 19 on neonatal outcomes of infected pregnant women. We conducted the systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. To identify relevant articles based on the inclusion and exclusion criteria on COVID-19 infected pregnancies and the neonatal outcomes, we searched four databases (PubMed, Embase, Scopus and Web of Science) from January 01, 2020 to June 20, 2021 by using medical subject heading and keywords under the PECO concept (P = pregnant women, E = COVID-19, O = neonatal outcome). We also assessed the risk of bias of the selected articles. We found that newborns of COVID-19 positive mothers are more likely to be born prematurely and by caesarean section. They need NICU admissions mainly due to prematurity related to maternal COVID-19 status at delivery. We did not find any evidence linking maternal COVID-19 status to low Apgar score, low birthweight, neonatal resuscitation at birth and neonatal death. Neonatal SARS-CoV-2 positive status was infrequently reported. The possibility of vertical transmission was raised, which may contribute to a large number of preterm births and caesarean deliveries in the COVID-19 positive mothers, but there is a paucity of evidence on vertical transmission. There is a shift in focus from vertical to horizontal transmission in the case of neonatal COVID-19 infection, thereby emphasizing the implementation of safety precautions while balancing the need to allow breastfeeding and mother-to-infant skin contact. This systematic review provides evidence on the necessity of close monitoring of neonates of COVID-19 positive mothers and taking preventive measures against the acquisition of COVID-19 in neonates.
Systematic Review Pregnant Women COVID-19 Neonatal Outcomes1. Introduction
The COVID-19 disease was identified in late 2019 [1] [2] [3] [4], leading to severe respiratory consequences. It was caused by a new mutation of the coronavirus and is now known as SARS-CoV-2 [1] [5]. Worldwide, the viral outbreak has led to an accumulation of 230 million cases as of September 25, 2021 [6]. An estimation of 1 in 200 pregnant women was affected with COVID-19 during their pregnancy [7].
This novel coronavirus shares a similarity of 80% and 50%, respectively, in terms of the viral genome with two other well-known coronaviruses that were responsible for causing the severe acute respiratory syndrome (SARS) and middle-east respiratory syndrome (MERS), namely the SARS-CoV and MERS-CoV [1] [5] [8] [9]. Previous studies have linked maternal infection and systemic inflammation to a risk of progression into undesirable obstetrical and neonatal outcomes like pre-eclampsia, preterm birth, stillbirth, small-for-gestational-age, and low birth weight due to disruption in the placental hemodynamics [10]. Moreover, during pregnancy, women experience physiological changes such as an elevated diaphragm in response to the accommodation of the developing foetus, leading to decreased pulmonary functional residual volume and respiratory tract mucosal oedema and friability due to high levels of oestrogen. These pulmonary changes and altered cell immunity can predispose pregnant women to enhanced susceptibility to severe viral pneumonia infections and lead to adverse pregnancy outcomes [11] [12] [13] [14].
To date, the possibility of mother-child vertical transmission remains controversial. The incidence of COVID-19 infection in newborns to mothers with SARS-CoV-2 positive status has been reported in many studies. The angiotensin-converting enzyme 2 (ACE-2) receptors, where SARS-CoV 2 binds to for cell entry, are also abundantly detected in the placenta, supporting the biological plausibility of intrauterine transplacental vertical transmission [15]. However, several studies challenged the feasibility of vertical transmission, be it through the placenta, during vaginal delivery or breastfeeding, as SARS-CoV-2 was not discovered in the samples of amniotic fluid, cord blood and breast milk [16]. Thus, this study aims to identify the potential neonatal outcomes associated with a COVID-19 infected pregnancy by critically appraising the latest available evidence. In addition, it aims to summarise the incidence rates of the interested neonatal outcome and provide a comprehensive logical discussion based on previously established scientific facts. Thus, this review finding will contribute to providing a consensus on the management of neonates of COVID-19 positive mothers, including isolation precautions and the safety for breastfeeding after birth.
2. Methods2.1. Search Strategy
We conducted this systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method to identify relevant articles on COVID-19 infected pregnancies and the neonatal outcomes. We searched the relevant articles in four databases (PubMed, Embase, Scopus and Web of Science) published from January 01, 2020 to June 20, 2021. The primary reviewers' institution subscribes to these four electronic databases; hence, it was convenient to get access to full-text resources. It did not limit the scope of the study as we need full text to extract data. All databases were searched using subject headings and keywords related to COVID-19 infection, pregnant women and neonatal outcomes (Table 1).
Keywords and subject headings according to PECO concept
The typical search string, which was used across all databases, is [(“Covid” OR “SARS-CoV-2” OR “Covid-19” OR “Coronavirus disease 2019” OR “2019-nCoV”) AND (“Pregnancy” OR “Pregnant” OR “Pregnant woman”) AND (“Neonatal outcomes” OR “Newborn outcomes” OR “Infant outcomes” OR “Perinatal outcomes”)]. We further refined the search results by applying filters including “only English language articles, females with ages ranging from 19 to 44 years and newborns of 0 to 12 months as the research population”.
2.2. Selection Criteria
1) Inclusion criteria: We identified the following criteria to include the relevant studies in this review:
・ Study types: Cohort study, randomized controlled trials, database analysis;
・ Study sample size: More than 100 newborns whose mothers were COVID-19 positive during pregnancy;
・ Neonatal outcomes of COVID-19 infected pregnancies are reported;
・ If the full text is available;
・ English language.
2) Exclusion criteria: Following criteria were considered before excluding any study from this review:
・ Study types: Case reports, case series, cross-sectional studies, protocol papers, review articles;
・ Study sample size: Less than 100 newborns whose mothers were COVID-19 positive during pregnancy;
・ Incomplete trials or duplicate publications of the same study that yield similar results;
・ If the specific neonatal outcomes are not mentioned;
・ If the language is not in English.
2.3. Screening
We decided to screen the articles published from January 01 2020 onwards, as Covid-19 became pandemic on March 11, 2020. Primarily, we identified 2504 articles from the four databases and exported them to Endnote, a citation manager, where we identified the duplicated and removed them. Primary reviewers concurrently screened all the prospective articles by title and abstract based on the inclusion and exclusion criteria and went through the full text of the shortlisted eligible articles. Finally, they included 13 articles in this review based on their consensus (Figure 1).
2.4. Data Extraction
To extract data, two primary reviewers (JK and JT1) developed a standardized form, which includes: study design, sample size, main study findings and conclusion, and pull out all the potential data independently from 13 finally selected
articles. Thereafter, they compared their individual data and reached a consensus before exporting the data into Nvivo for analysis. In the data analysis, the neonatal outcomes of interest were: APGAR scores at 1 and 5 minutes; neonatal intensive care unit (NICU) admission; neonatal investigations for COVID-19; neonatal mortality rate. They invited the 3rd reviewer, either SSSH or NKJ2, when they could not resolve any raised disagreement between them.
2.5. Quality Assessment:
We employed the Newcastle-Ottawa Scale (NOS), a quality assessment tool for both cohort and case-control studies included in a systematic review, to assess the quality of the selected studies (Table 2). We decided to use this NOS tool as
Risk of bias assessment of the selected cohort studies using the newcastle-ottawa scale
First author; Country; Year
Selection
Comparability
Outcome
Total
Representation of COVID-19 infected pregnant women
Selection of non-COVID-19 exposed pregnant women
Confirmation of COVID-19 infection through nasopharyngeal swab or RT-PCR
Maternal outcomes of interest were not present at the beginning of the study
Adjustments of important risk factors
Adjustments for additional risk factors
Assessment of maternal outcomes
Follow up until end of pregnancy
All patients were followed up adequately
Al-Matary et al.; Saudi Arabia; 2021
7
Angelidou et al.; USA; 2021
8
Gabriel et al.; Spain; 2020
8
Gupta et al.; India; 2021
7
Hcini et al.; France; 2020
9
Khoury et al.; USA; 2020
8
Maraschini et al.; Italy; 2020
7
Norman et al.; Sweden; 2021
9
Oncel et al.; Turkey; 2021
9
Saccone et al.; Multinational; 2021
9
Sánchez-Luna et al.; Spain; 2021
7
Singh et al.; India; 2021
8
most of our included studies were cohort studies, either prospective or retrospective. While assessing the selected studies’ quality using the NOS tool, we had to consider three parameters: selection = 4, comparability = 2 and outcome = 3. Two primary reviewers assessed the quality independently and invited the third reviewer to resolve any disagreement.
3. Results
In this systematic review, we included 5183 neonates who were born to the COVID-19 positive mothers [17] - [29]. The median gestational age at birth ranged from 38 to 39 weeks, while the mean gestational age at birth ranged from 36.6 to 39.2 weeks [17] [18] [20] [22] [25] [26] [27] [28]. The main study findings and conclusion are summarized in Appendix TableS1.
3.1. Pregnancy Characteristics and Exposure
The median age of COVID-19 positive mothers included in this review ranged from 25 to 33 years [17] [21] [22] [24] [28], while the mean age was from 24.7 to 32.2 years [18] [20] [25] [27]. A majority of the mothers were diagnosed with COVID-19 in the third trimester of pregnancy (69.8% to 92.1%) [17] [19] [27]. The percentage range of asymptomatic COVID-19 positive mothers was extensive, from 24.2% to 86.1%. [18] [19] [20] [21] [22] [24] [27] [28] [29]. As for the symptomatic women, 26.5% to 34.29% of them presented with mild-to-moderate COVID-19 symptoms [21] [22] [28] [29]. The majority (61.1%) of the symptomatic mothers do not require any form of respiratory support [17]. Meanwhile, a lesser percentage (0.76% to 26.1%) of pregnant women were classified as having severe or critical COVID-19 disease [21] [22] [28] [29]. We found that 1.4% to 19.2% of mothers required some form of respiratory support, which included nasal cannula, face mask, high flow nasal cannula, continuous positive airway pressure (CPAP), mechanical ventilation, and intubation [17] [21] [22] [24] [27] [28].
3.2. Maternal Comorbidities
Overweight or obesity was the most commonly reported maternal pre-existing comorbidities in eight studies, recording 55.1% as the highest incidence rate [17] [21] [22] [24] [25] [27] [28] [29]. It was reported that a maternal BMI of more than 30 kg/m2 had an impact on the disease severity of COVID-19 [22]. We found that 0.6% to 4.1% mothers had a diagnosis of type 2 diabetes mellitus [17] [24] [28], while 0.6% to 3.4% of them had pregestational hypertension [17] [21] [24] [26] [28]. The rates of gestational diabetes ranged from 4.6% to 14.8% [20] [21] [25] [26] [28] [29]. We also found that 2% to 13.64% of the COVID-19 positive mothers experienced hypertensive disorders of pregnancy, which included gestational hypertension and pre-eclampsia [17] [20] [21] [26] [28] [29].
3.3. Neonatal Outcomes
The median Apgar score at 1 min was 8 - 9 (IQR: 7 - 9) [19] [26] [28], and 87.1% to 89% of the neonates achieved a 1 min Apgar score of >7 for those who were born to symptomatic COVID-19 mothers [21] [24]. As for the 5-min Apgar score, 93.52% to 97.9% of the newborns had a score of >7 [20] [21] [24] [25], and the median score achieved was 9 - 10 (IQR: 9 - 10) [19] [22] [28]. One study found that newborns with a positive SARS-CoV-2 infection had significantly lower 5th minute Apgar score than those who were negative [8 (7 - 9) vs. 9 (9 - 10), p = 0.039, 95% CI: 0.263 - 0.998] [26]. We also found that 76% to 85% of the newborns of COVID-19 positive mothers had a birthweight of more than 2500 g [17] [23] [24]. The mean birthweight ranged from 2590 g to 3436 g [18] [19] [20] [21] [25] [27] [28] [29]. Neonates from symptomatic COVID-19 mothers had a lower birthweight compared to those born to asymptomatic mothers (2821 ± 846 g vs. 3149 ± 496, p = 0.004) [27]. The percentage of newborns who were identified as small for gestational age (SGA) or intrauterine growth restriction (IUGR) ranged from 1.5% to 11.3% [17] [18] [21] [23] [25] [27] [29]. The rate of perinatal losses, inclusive of miscarriage, termination of pregnancy, and stillbirth, varied from 0.8% to 5.1% [17] [20] [21] [22] [24] [27] [29]. There were 30 neonatal deaths reported from six studies [18] [23] [25] [27] [28] [29].
We found that 4.8% to 28.7% of the neonates were premature [17] - [29], and 15% to 71.2% of the newborns were delivered via caesarean section [17] - [22] [24] - [29]. Up to 23.8% of the caesarean deliveries were indicated due to maternal COVID-19 status and severity [19] [22] [24] [28]. There was a huge variability observed between the studies for the rate of neonatal intensive care unit (NICU) admission (2.3% - 86.4%) [17] - [29]. The reasons for high rates of NICU admission were linked to maternal COVID-19 status and severity, neonatal complications, requirements for isolation from the COVID-19 infected mothers, and hospital management difficulties in organizing rooming-in for the newborns [17] [25] [26] [28] [29].
Among the neonatal complications reported, prematurity and low birth weight were the most common [22]. For neonates who were admitted to the NICU due to clinical symptoms, their median length of hospital stay was longer than those under normal care (2.5 days, IQR: 2.5 - 7 days vs. 2 days, IQR: 2 - 2.33 days) [28]. While a big proportion (89.5%) of the neonates born to COVID-19 positive mothers do not require any form of respiratory support [19], it is found that in other studies, the need for respiratory support in the form of mechanical ventilation, continuous positive airway pressure (CPAP), or intubation ranged from 1.0% to 15.7% [17] [18] [23] [25] [29]. The demand for CPAP and mechanical ventilation was also found to be higher in neonates born to mothers infected with COVID-19 (4.9% vs. 3.8%; OR, 1.32; 95% CI, 1.06 - 1.64; 1.6% vs. 0.5%; OR, 3.51; 95% CI, 1.856.65) [25]. The percentage of neonates requiring any form of resuscitation at birth ranged from 3.6% to 30% [18] [19] [22] [23] [25] [28]. Newborns from COVID-19 positive mothers were more likely to receive resuscitation in the form of assisted ventilation (CPAP or face mask) and intubation at birth compared to those who were born to non-COVID positive mothers (6.4% vs. 5.1%; OR, 1.28; 95% CI, 1.05 - 1.55; 0.6% vs. 0.3%; OR, 1.90; 95% CI, 1.002 - 3.59) [25].
SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) testing was done for most of the neonates from mothers who were positive for COVID-19 disease [17] - [29]. Among the 5052 (97.5% of 5183) neonates who tested for COVID-19 infection, 116 of them (2.3%) were found to have a positive SARS-CoV-2 RT-PCR test result within 96-hour of post-birth (Table 3) [17] - [29].
In particular, 101 of them were diagnosed with COVID-19 within 24-hours of life [18] [19] [22] - [29], and 30.3% of the neonates who tested positive for COVID-19 were symptomatic of the disease [23]. It was reported that newborns with a positive SARS-CoV-2 status were at a higher risk of neonatal death (OR 4.8, 95% CI 1.25 - 18.36) [23]. All the placenta samples tested for SARS-CoV-2 infection were negative [21] [28]. COVID-19 infected newborns had a significantly lower neutrophil count than those who tested negative for the infection [3235 (2235 - 5500) vs. 8445 (4965 - 12,385), 95% CI: 1.002 - 1.005, p = 0.024]
Number of neonatal COVID-19 infections with nasopharyngeal swab testing or RT-PCR from included articles in the review
Article; Study country; Year of Publication
No. of neonates tested
No. of neonates with positive SARS-CoV-2 status within 96 hours of life
No. of neonates with positive SARS-CoV-2 status detected within 24 hours of life
No. of neonates with positive SARS-CoV-2 status detected after 24 hours of life
Al-Matary et al.; Saudi Arabia; 2021
200
N/A
N/A
N/A
Angelidou et al.; USA; 2021
225
5
5
N/A
Gabriel et al.; Spain; 2020
230
13
11
2
Gupta et al.; India; 2021
108
N/A
N/A
N/A
Hcini et al.; France; 2020
108
4
N/A
4
Khoury et al.; USA; 2020
236
6
6
N/A
Malik et al.; India; 2021
523
33
33
N/A
Maraschini et al.; Italy; 2020
138
9
5
4
Norman et al.; Sweden; 2021
2323
21
20
N/A
Oncel et al.; Turkey; 2021
120
4
4
N/A
Saccone et al.; Multinational; 2021
251
1
1
N/A
Sánchez-Luna et al.; Spain; 2021
469
18
14
4
Singh et al.; India; 2021
121
2
2
N/A
Total
5052
116
101
14
*1 case of positive SARS-CoV-2 was detected post-neonatal period (28 days). *N/A: Not available.
[26]. They also had a higher demand for mechanical ventilation or CPAP, and longer hospitalization compared to non-COVID-19 infected neonates (75% vs. 19%, 95% CI: 1.271 - 128.5, p = 0.028); [26 (15 - 48.5) vs. 7 (3 - 11) days, 95% CI: 1.018 - 1.148, p = 0.033] [26]. The same study also reported that mothers who gave birth to SARS-CoV-2 positive newborns, compared to those who had non-infected newborns, were diagnosed with COVID-19 at an earlier stage of pregnancy, which warrants further evaluation to establish a link (35 weeks vs. 37 weeks, p = 0.306) [26].
We found that 40.2% to 59.6% of COVID-19 positive mothers breastfeed their children. [18] [19] [26] [27] [28]. At discharge, as high as 94.4% of the mothers were breastfeeding [25]. The rates of maternal-neonate separation after birth varied greatly between different studies, ranging from 8% to 92% [18] [19] [23] [26] [28] [29], and there was even one study that did not practice any isolation at all [21]. For studies that promoted separation between the mother and neonate, the rationales given were isolation from the infected mother and organizational limitations such as the mother being in a COVID-19 ward instead of an isolated room [19] [23] [26].
4. Discussion
We found that a majority of the newborns of COVID-19 positive mothers had a birthweight of more than 2500 g, with the mean birth weight ranging from 2590 g to 3436 g. This finding was consistent with the findings from other systematic reviews, with the median and mean birth weight at 3120 g and 3144.71 g, respectively [30] [31]. Despite the reassuring results, it was suggested that women who were infected with COVID-19 early in pregnancy or who suffered from chronic hypoxia require more frequent monitoring of the foetal growth to assess for intrauterine growth restriction or retardation [32]. However, Tadas et al. demonstrated a statistically significant higher mean birthweight in newborns of COVID-19 positive mothers compared to the controls. The difference was attributed to the baseline nutritional and socioeconomic status variability, where most cases originated from urban areas with adequate nutrition [33]. Low birthweight was reported to be associated with a higher rate of perinatal death, while IUGR was speculated to be common in SARS-CoV-2-infected pregnancies according to previous experience from other SARS pandemics [34] [35]. However, our rate of perinatal losses in COVID-19 affected pregnancies ranged from 0.8% to 5.1%, a mean rate similar to that of a systematic review by Chamseddine et al. [35]. The rate of stillbirth was higher than in the pre-COVID-19 era, but the further evaluation has to be explored to identify a link between COVID-19 and stillbirth rates [36].
Low 5-minute Apgar scores have been reported to have a 20- to 100-fold increase in relative risk for cerebral palsy compared with neonates with good scores of 7 to 10 [37] [38] [39]. From our findings, most of the neonates born to COVID-19 positive mothers have a good Apgar score of more than 7 at 1-minute and 5-minute, which is a trend supported by other systematic reviews [40] [41]. Verma et al. added that APGAR scores were similar between asymptomatic and symptomatic COVID-19 positive pregnant women [42]. It was thought that a low Apgar score in babies of COVID-19 positive mothers was likely to be secondary to pulmonary immaturity if the neonates were born preterm [43]. Our review found that NICU admission rates were not uniform across included studies, in which neonatal complications and implementation of maternal-infant isolation contributed to the higher rates. Similar reasons were demonstrated in the study by Dube et al., where the main indications for NICU admission were for isolation and prematurity-related complications [43].
Premature babies face an increased risk of short-term and long-term morbidities and mortality. In fact, prematurity is the leading cause of death in children under the age of 5 [12]. Complications that are commonly associated with preterm infants include higher rates of respiratory distress syndrome, bronchopulmonary dysplasia, infections (inclusive of sepsis), necrotising enterocolitis, periventricular leukomalacia, seizures, cerebral palsies, intraventricular haemorrhage, hypoxic-ischaemic encephalopathy, feeding issues, and problems with vision and hearing [44] [45] [46]. It was found that maternal pneumonia can result in adverse maternal and neonatal outcomes. Preterm labour, intrauterine foetal death, intrauterine growth restriction, and neonatal death are common adverse outcomes associated with pneumonia during pregnancies [47] [48] [49] [50].
In our review, it was found that up to one-third of the newborns were premature. Theories have proposed that maternal COVID-19 may lead to hypoxemia, leading to an increased risk of foetal distress, causing birth asphyxia or meconium-stained amniotic fluid [51]. The increased demand for oxygen in the COVID-19 affected mother secondary to severe foetal hypoxemia and acidemia may indicate an early delivery [52]. COVID-19 infection during pregnancy leads to an increased rate of medically indicated preterm delivery, as described by a systematic review by Allotey et al., stating that the rates of spontaneous preterm births in COVID-19 affected mothers were mainly similar to the pre-pandemic rates [53]. However, whether preterm births were secondary to iatrogenic causes linked to maternal or foetal compromise, or other etiologies, will need to be explored further before coming to a conclusion [54].
A high proportion of the newborns in our review were born via caesarean section. The rationale behind the increased rate of caesarean deliveries was to reduce the risk of infection from the COVID-19 positive mothers and reduce the burden of maternal effort during labour [55] [56]. However, current recommendations indicate that COVID-19 infection should not be the sole indication for caesarean delivery and preterm births [52] [54] [57]. A Spanish study with a 6.9% (5/72) of neonatal COVID-19 infection rates mentioned no difference between vaginal and caesarean deliveries [58]. The decision for caesarean section should take into account the maternal disease severity and comorbidities, maternal and foetal status, and gestational age [52] [59] [60]. Studies have supported the safety of vaginal delivery as none of the vaginal secretions samples from COVID-19 positive pregnant women were tested positive for SARS-CoV-2 [61] [62]. In addition, maternal vaginal secretions exposure was found to be associated with the development of immunogenic response in neonates [63].
A huge concern arises when pregnant women are infected with COVID-19, as the risk of cross-infection to the in-utero foetus cannot be neglected. It also contributes to the decision of perinatal management with the priority to prevent maternal and neonatal adverse outcomes, be it short-term or long-term. Neonatal SARS-CoV-2 may be acquired from the vertical transmission, either during the intrauterine period through the placenta or amniotic fluid, or the intrapartum period from exposure to infected maternal vaginal secretions, urine and faeces, or via postpartum contact with infected mothers or healthcare workers [64]. In our review, we reported a rate of 2.3% for neonatal COVID-19 infections, which accounted for 116 cases. In particular, 87.9% (102/116) of those infected were detected with SARS-CoV-2 within the first day of life. Similar findings (2.0%; 208/10188) of neonatal SARS-CoV-2 test positivity were reported in the National Perinatal COVID-19 (NPC-19) Registry by the American Academy of Paediatrics [65]. Pooled data from other systematic reviews also reported a rate of 2% for the newborns who tested positive for SARS-CoV-2 virus via nasopharyngeal swab [66] [67]. To date, there was unclear evidence to confirm the absolute risk of vertical transmission [59]. Samples of amniotic fluid, umbilical cord blood and breastmilk were explored for SARS-CoV-2 using RT-PCR in the study by Chen et al., with all nine results returning as negative [68].
In contrast to our findings, another study by Penfield et al., identified three placental samples with positive SARS-CoV-2 test results among the 11 tested [56]. However, there was no neonatal COVID-19 infection detected. Theories support the role of the placenta as a physical barrier to viral entry and mediation of antiviral immune response by the placental immune cells [11] [69] [70]. In addition, 14 among the total of 16 infected infants in the study by Woodworth et al. were born to mothers who were diagnosed with COVID-19 within the period of 14 days before birth, thereby suggesting the possibility of intrapartum or postpartum vertical transmission [71]. There may be a role for SARS-CoV-2 specific IgM antibodies as a better detection tool for in-utero infections as IgM antibodies do not cross the placenta [72] [73].
Early postpartum neonatal SARS-CoV-2 acquisition has gained more attention, with Raschetti et al. attributing 70% of the 176 neonatal COVID-19 infections to horizontal transmission by exposure to infected mothers or healthcare personnel during the care immediately after birth [74]. In view of mitigating the risk of horizontal transmission, studies have looked into the implementation of maternal-infant separation, which includes social distancing measures and the safety of immediate breastfeeding. The practice of maternal-newborn separation varied distinctively in our paper. To date, skin-to-skin contact has been recommended as a consequence of shared decisions between individual mothers and healthcare teams after weighing the risks and benefits as no clear evidence exists to support the increased risk of COVID-19 transmission by allowing skin-to-skin contact [75] [76] [77].
A systematic review which included a total of 82 breast milk samples analysis found that 13% (9/68) of breast milk samples tested positive for SARS-CoV-2, and one sample (7%, from another 14 samples tested for antibodies) had identified SARS-CoV-2 IgG antibodies [78]. Sahin et al. has reported 1 case of positive test result for SARS-CoV-2 in breast milk samples among the 533 mothers tested [79]. Nonetheless, breastfeeding has not been shown to be a vector of SARS-CoV-2 transmission [63] [64]. Instead, breastfeeding provides passive immunity for the infants against COVID-19 as breast milk contains anti-SARS-CoV-2 antibodies [63] [80] [81]. In our review, breastfeeding rates among COVID-19 infected mothers were not optimum (40.2% to 59.6%).
For COVID-19 infected mothers, breastfeeding is not contraindicated but should be practised with safety precautions to minimize postpartum horizontal transmission, where infants are exposed to infectious respiratory droplets from mothers or care providers and environmental sources of infection [82]. Infected mothers are recommended to wear surgical masks, maintain hand and breast hygiene during breastfeeding, and keep social distance with infants between feedings while staying in the same room [64] [82] [83]. Overall, breastfeeding offered nutritional, immunological and developmental benefits, which outweigh the relatively small potential risk of transmission [84] [85].
Our review concluded low rates of SARS-CoV-2 acquisition among neonates. Literature has suggested possible aetiologies of lower infection rates and milder presentation in newborns to be associated with the passive protection from maternal transfer of IgG antibodies and the immature immune system, while further research is needed to bridge the gap [86] [87] [88] [89]. Reduced ACE2 expression in newborns and younger children compared to adults was also found to have contributed to less inflammation, dampened immune response, milder symptoms and subsequent quicker recovery in infants [86] [90] [91]. Interestingly, we found data reporting significantly lower neutrophil counts in COVID-19 infected neonates when compared to those non-infected [26]. While age-related ACE2 expression was linked to COVID-19 presentations and severity, placental expression of ACE2 seemed to be elevated with the advancement of pregnancy [59] [92]. ACE2 receptors in the placenta were found to be at an exceptionally low level in the first-trimester of gestation, thereby making first-trimester vertical transmission unlikely [59]. In contrast, we found that COVID-19 positive neonates were more likely to be born to mothers diagnosed with COVID-19 at the earlier stage of pregnancy [26].
5. Conclusions
The outlook of neonates born to COVID-19 positive mothers seems to be relatively reassuring as most newborns had a 5-min Apgar score of more than 7 and minimal symptoms despite increased caesarean and preterm deliveries rates in the infected pregnancies. Current evidence suggests that iatrogenic preterm births should not be indicated due to the sole reason of maternal COVID-19 status or the prevention of vertical transmission. Instead, it should take into account the maternal and foetal compromise on a case-to-case basis.
While the risk of vertical transmission cannot be safely excluded from currently available evidence, horizontal transmission during intrapartum and postpartum periods has been speculated to cause higher rates of neonatal SARS-CoV-2 acquisition. However, the possibility of cross-infection should not restrict breastfeeding, and skin-to-skin contact after delivery as both of them offer greater benefits for the overall development of the infants over the potential risk of SARS-CoV-2 infection. Nonetheless, disease prevention strategies including social distancing, use of surgical masks and hand hygiene along with close monitoring should continue to be undertaken to minimize neonatal exposure to SARS-CoV-2 through close contact with the mother and the hospital environment. This systematic review provides a new focus on the potential of horizontal transmission being the main culprit for neonatal SARS-CoV-2 infection, which warrants further research to develop a link between the two factors.
Nonetheless, our study has a few identifiable limitations. We could not conduct a meta-analysis due to the lack of a sufficient number of homogenous studies that can generate more accurate pooled data for comparisons and conclusion-making. We also could not search other databases like MedRxiv and Cochrane databases in order to identify additional potentially eligible articles; as those are not subscribed by the primary reviewer’s institution.
Acknowledgements
The authors would like to express their gratitude to the Monash University Library for providing permission to utilize the extensive resources, especially to get access to full-text articles and software (Endnote and Nvivo) for this systematic review.
Conflicts of Interest
The authors also declare no conflicts of interest regarding the publication of this paper.
Cite this paper
Khong, J., Teoh, J., Hashim, S.S.S. and Jahan, N.K. (2021) Neonatal Outcomes of COVID-19 Positive Pregnant Women: A Systematic Review. Open Access Library Journal, 8: e8019. https://doi.org/10.4236/oalib.1108019
List of Abbreviation
95% CI 95% Confidence Interval
ACE-2 Angiotensin-converting enzyme 2
BMI Body Mass Index
COVID-19 Coronavirus Disease 19
CPAP Continuous Positive Airway Pressure
EMCO Extracorporeal Membrane Oxygenation
ICU Intensive Care Unit
IUGR Intra-uterine Growth Restriction
MERS Middle East Respiratory Syndrome
MeSH Medical Subject Headings
NICU Neonatal Intensive Care Unit
NOS Newcastle-Ottawa Scale
OR Odds Ratio
RT-PCR Real Time Polymerase Chain Reaction
SARS Severe Acute Respiratory Syndrome
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
SGA Small for Gestational Age
WHO World Health Organization
Appendix
List of included articles in this review with main study findings and conclusion
Article; Study country; Year of Publication [Reference no.]
Type of study
Sample size (No. of neonates)
Main Findings
Conclusion
Al-Matary et al.; Saudi Arabia; 2021 [17]
Retrospective Cohort Study
204
・ Mean gestational age at delivery was 39 weeks (IQR 35 - 40). ・ The majority of neonates had normal laboratory results. ・ 43% of neonates admitted to NICU. ・ 7% of neonates required mechanical ventilation. ・ None of neonatal COVID-19 infections was detected. ・ 4 neonatal deaths were reported.
There was no evidence of vertical transmission of COVID-19 infection.
Angelidou et al.; USA; 2021 [18]
Retrospective Cohort Study
255
・ 225 (88.2%) neonates were tested for COVID-19 infection and 2.2% were tested positive. ・ High maternal social vulnerability increased the likelihood of neonatal COVID-19 test positivity (adjusted odds ratio, 4.95; 95% CI, 1.53 - 16.01; p = 0.008). ・ Adverse neonatal outcomes were observed among preterm deliveries due to worsening maternal COVID-19 symptoms. ・ 1 positive result of COVID-19 testing was reported from the follow-up data of 151 newborns.
Maternal biological and social factors affect the perinatal outcomes of COVID-19 infections.
Gabriel et al.; Spain; 2020 [19]
Retrospective Cohort Study
248
・ Maternal admission for COVID-19 infection increased the risk of premature delivery (p = 0.006). ・ 115 (46.3%) neonates were admitted to the neonatal unit with 87 admissions due to organizational difficulties. ・ None of neonatal COVID-19 infections nor neonatal deaths was detected. ・ Exclusive breastfeeding rate at discharge and 1-month was 41.7% and 40.4% respectively.
Vertical transmission of COVID-19 was not detected during delivery and up to the newborns’ first month of life. Exclusive breastfeeding was less frequent than expected.
Gupta et al.; India; 2021 [20]
Retrospective Cohort Study
108
・ Mothers with positive RT-PCR test results for COVID-19 were associated with statistically significant higher rates of prematurity, lower mean birth weight, lower Apgar score and increased prevalence of foetal distress when compared to pregnant women with negative test results. ・ None of neonatal COVID-19 infections was detected.
COVID-19 infection can lead to adverse maternal and perinatal outcomes. Mother-to-child vertical transmission of COVID-19 infection may be possible.
Hcini et al.; France; 2020 [21]
Prospective Cohort Study
127
・ Infected mothers were associated with higher rates of intrauterine foetal demise as compared to controls (5.1% vs. 1.1%, RR 4.7 [95% CI: 1.4 - 45.9). ・ None of neonatal COVID-19 infections was detected at birth (0/108). ・ Among 29 neonates who were tested again between 25 to 42 hours of life, 4 had positive test results for COVID-19 and remained asymptomatic.
Infected pregnant women were at higher risk of intrauterine foetal demise than those uninfected mothers.
Khoury et al.; USA; 2020 [22]
Prospective Cohort Study
245
・ 2.5% of neonates had positive test results for COVID-19 infection immediately after birth. ・ Maternal COVID-19 severity was linked to BMI 30 or higher (p = 0.001). ・ Cesarean delivery was done for 52.4% of women with severe and 91.7% with critical COVID-19.
Disease severity was associated with obesity and higher cesarean birth rates.
Malik et al.; India; 2021 [23]
Database Analysis
524
・ 6.3% of the neonates to mothers with COVID-19 were tested positive for SARS-CoV-2. ・ Infected neonates had a 4.09 [95% CI 1.28 - 13.00] fold higher risk to develop sepsis as compared to the non-infected newborns (p = 0.031). ・ Infected neonates were significantly more likely to experience poor feeding as compared to the non-infected newborns (p = 0.017). ・ A total of 13 neonatal deaths was reported with 3 deaths from the COVID-19 infected group.
There is an increased risk of adverse neonatal outcomes, including sepsis and death for the newborns infected with COVID-19 as compared to the non-infected.
Maraschini et al.; Italy; 2020 [24]
Prospective Cohort Study
149
・ 6% of neonates had positive test results for COVID-19 infection at birth. ・ Neonatal mortality was not reported.
Clinical features and outcomes of COVID-19 in pregnant women had similar clinical features and outcomes of COVID-19 as the general population
Norman et al.; Sweden; 2021 [25]
Prospective Cohort Study
2323
・ Maternal SARS-CoV-2 test positivity was significantly associated with higher rates of neonatal care admission, neonatal morbidities such as respiratory distress syndrome, any neonatal respiratory disorder, and hyperbilirubinemia. ・ 0.9% of the newborns to mothers with COVID-19 were tested positive for SARS-CoV-2 in the neonatal period, of those 9 had diagnoses with unclear relation to COVID-19.
Pregnant women with COVID-19 infection had a significant but slightly increased risk for some neonatal morbidities.
Oncel et al.; Turkey; 2021 [26]
Prospective Cohort Study
125
・ Cesarean delivery, prematurity, and low birthweight rates were 71.2%, 26.4%, and 12.8%, respectively. ・ Most newborns (86.4%) were admitted to the isolation rooms in NICU. ・ 3.3% of neonates had positive test results for COVID-19 infection at birth, including one sampling of deep tracheal aspirate from an intubated newborn. ・ A total of 3 neonates were detected for SARS-CoV-2 after negative test results on the first day of life.
Maternal COVID-19 infection was associated with maternal mortality, increased rates of cesarean delivery and preterm birth, suspected possibility of vertical transmission, and low breastfeeding rate.
Saccone et al.; Multinational; 2021 [27]
Retrospective Cohort Study
251
・ Neonatal ICU admission rate was 27.5%. ・ Five (2.0%) neonatal deaths were reported. ・ The overall perinatal mortality rate was 4.1%. ・ Only one (0.4%) infant, born to a mother with COVID-19 diagnosed during the third trimester, had positive RT-PCR test results for SARS-CoV-2.
There is negligible risk for vertical transmission of COVID-19.
Sánchez-Luna et al.; Spain; 2021 [28]
Prospective Cohort Study
503
・ The most frequently performed diagnostic test for neonatal COVID-19 infection was RT-PCR test at a median age of 3 hours after birth. ・ Almost one-half of neonates had skin-to-skin contact with mothers after delivery. ・ Delayed umbilical cord clamping was performed in 43% of newborns. ・ Rooming-in was allowed in 62.3% of asymptomatic neonates. ・ 76.5% of neonates received maternal milk, with 204 of them exclusively breastfed.
There is no role of mothers-newborn separation. Delayed cord clamping, skin-to-skin contact and breastfeeding were allowed in the majority of newborns to COVID-19 infected mothers.
Singh et al.; India; 2021 [29]
Retrospective Cohort Study
121
・ The mean birth weight was reported as 2.59 kg. ・ Forty (33.05%) newborns were admitted to NICU. ・ Two neonates (1.65%) were detected for SARS-CoV-2 infection within the first day of life.
COVID-19 in pregnancy is associated with increased rates of prematurity and NICU admission. Perinatal mortality remains uncommon. The incidence of neonatal SARS-CoV-2 infection is low and most cases were asymptomatic, yet suggesting the possibility of vertical transmission.
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