Neonatal COVID-19 in French Guiana, a Case-Control study.


 BackgroundThis study aims to assess the risk of transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS COV-2) to newborns in the context of breastfeeding practice as part of routine care.MethodsIn this prospective study, we identified neonates born between May 14th and August 31st, 2020, to mothers who tested positive for SARS-CoV-2 at the time of delivery. From the cohort of 974 deliveries, we performed a nested case-control study. ResultsDuring the study period, 133 (13.7%) were positive by RT‐PCR for SARS‐CoV‐2. Among the 35 pregnant women with symptomatic COVID-19 (26.3%), cough was the most common symptom, occurring in half of the cases. Among them, 3 developed fever as other symptoms during hospitalization and 4 have progressed to critical pneumonia requiring transfer to intensive care unit. Among the neonates born from mothers with positive RT‐PCR for SARS‐CoV‐2, 32 were tested for SARS-COV-2 at 48 hours-7 days. Of them, 3 asymptomatic neonates tested positive. There were no significant differences in fetal distress, meconium-stained amniotic fluid, preterm birth, and neonatal asphyxia between the two groups Most infants were breastfed at birth, regardless of their mothers' COVID-19 status. In COVID-19-positive pregnant women admitted to intensive care unit, the proportion of preterm births ( OR=12.5 [1.7-90.5]), fetal death in utero (OR=25.9 [2.2-305]) and admission in neonatal intensive care unit admission (OR=13.4 [3.0-60]), appeared higher than the controls. No maternal deaths were recorded.ConclusionsOur data suggest that under breastfeeding conditions with rigorous hygiene precautions and parental education, the risk of vertical transmission of the SARS-COV-2 virus is unlikely.


Conclusions
Our data suggest that under breastfeeding conditions with rigorous hygiene precautions and parental education, the risk of vertical transmission of the SARS-COV-2 virus is unlikely.

Background
Since the start of the global Severe Acute Respiratory Syndrome Coronavirus 2 (SARS COV-2) pandemic in December 2019, 1 several publications have reported the outcomes of neonates born to mothers with suspected or con rmed SARS-CoV-2 infection. [2][3][4] Pregnant women are considered a high-risk group for SARS-CoV-2 severe acute respiratory syndrome, and the potential adverse effects of the virus on maternal and perinatal outcomes are of concern. Transmission of SARS-CoV-2 to newborns is now known to occur primarily through respiratory droplets during the postnatal period when newborns are exposed to mothers or caregivers infected with SARS-CoV-2 (5). As for the possibility of intrauterine, intrapartum or peripartum transmission, there is currently no solid data to con rm this hypothesis. [6][7] Most studies con rm that clinical symptoms in newborns with CoronaVIrus Disease 2019 (COVID-19) are most often mild and the outcome favorable. [2][3][4] Most often the newborn is critically ill from prematurity, perinatal asphyxia or sepsis, rather than infection with SARS-CoV-2. 5 Although a newborn's risk of developing COVID-19 during the perinatal period is unknown, [8][9][10] best practices for infection control in mothernewborn couples should drastically reduce the transmission of SARS COV-2 to newborns. 11,12 The present study aims to assess the risk of transmission of SARS COV-2 to newborns in the context of breastfeeding practice as part of routine care.

Study design and participants
In this prospective cohort study, we included all neonates born between May 14th and August 31st, 2020, at Andrée Rosemon Regional Hospital in Cayenne, French Guiana to mothers who tested positive for SARS-CoV-2 from a nasopharyngeal swab sample at the time of delivery. As a result of inadvertent exposure of health-care professionals to SARS-CoV-2 from asymptomatic pregnant women, and concern that symptoms of labour such as aches and pains, diarrhea can mimic those of COVID-19, universal screening of all pregnant women presenting in our hospital was implemented in our Gynecology and Obstetrics Unit and Labour and Delivery units since May 1st, 2020. Mode of delivery in a suspected or con rmed COVID positive pregnant women was guided by her obstetrical assessment. Neonatal resuscitation was done in a separate room adjacent to the delivery room. Mother and newborn were kept together in a designated isolation room.
From the cohort of 974 deliveries that occured between May 14th and August 31st, 2020, we performed a nested case-control (NCC) study. Cases were the 133 SARS-COV-2 positive mothers. From the list of all deliveries, SARS-COV-2 positive mothers were randomly sampled in order to obtain four controls per case, matched by age. First, we describe differences in outcomes between pregnant women with and without COVID-19. Secondly, we describe neonatal outcomes between COVID-19 pregnant women with and without severe pneumonia.

Statistical analysis
All descriptive analyses were performed using STATA 15.0 (Stata Corp LP, College Station, TX, USA) software. Quantitative variables were categorized according to statistical criteria using the rst and third quartiles and the median. Single comparisons were performed using Student's t-test for quantitative variables and the CHI2 or Fisher's exact test for qualitative variables. Bivariate analysis was used to study covariates and their relationships with the outcome measures based on the crude odds ratio and its con dence interval. The covariates that were associated with the outcomes were then included in an unconditional multivariate logistic regression model. We expressed the results as the means, odds ratios and con dence intervals. P-values < 0.05 were considered to be statistically signi cant. A priori, the following variables were considered to be potential confounders, and all models were adjusted for maternal age, birthplace, occupation, parity and gravity. We conducted an initial analysis to determine the maternal outcomes. Second, we conducted a separate analysis to evaluate the neonatal outcomes.
Pearson's goodness of t test was used.

Role of the funding source
There was no funding source related to this study.
Newborn COVID-19 Testing Procedures Diagnosis was con rmed by testing for SARS-CoV-2 Ribo Nucleid Acid (RNA) by reverse transcription polymerase chain reaction (RT-PCR). Detection of SARS-CoV-2 RNA was performed using nasopharynx swab samples. Both symptomatic and asymptomatic neonates born to mothers biologically con rmed COVID-19, underwent a single testing performed before discharge at approximately 48 hours of age.
The standard of care in our maternity ward is to initiate skin-to-skin contact with newborns within the rst hour of life if medically appropriate, and to breastfeed newborns with mothers wearing surgical masks near their newborn and practicing good hand hygiene before contact with the skin, breastfeeding and routine care. All newborns who stayed with their mothers were kept in a nearby cradle.
The data used in this study were collected from inpatient medical records at time of birth and the outpatient medical record at the neonatal clinic visits on days 7, 14 and 1 month of life.
The data collected included demographic data, neonatal and maternal clinical presentation at the time of delivery, during hospitalization and after discharge from hospital, microbiological results (PCR-SARS-CoV-2 test). Newborns were assessed while in hospital and at home for fever, hypothermia, respiratory distress, lethargy, cough, rhinorrhea, irritability, rash, diarrhea, and food intolerance. The mothers were evaluated during their hospitalization and at home by the midwife for fever, cough, anosmia, ageusia, shortness of breath, sore throat, rhinorrhea, myalgia, vomiting and diarrhea.

Results
During the study period, 974 pregnant women were admitted for delivery, of whom 133 (13.7%) were positive by RT-PCR for SARS-CoV-2 ( Figure 1). Among the 35 pregnant women with symptomatic COVID-19 (26.3%), cough was the most common presenting symptom, occurring in half of the cases. These women had few additional symptoms on admission. Among them, 3 developed fever as other symptoms during hospitalization and 4 have progressed to critical pneumonia requiring their transfer to intensive care unit. Among the neonates born from mothers with positive RT-PCR for SARS-CoV-2, 32 were tested for SARS-COV-2 at 48 hours-7 days. Of them, 3 asymptomatic neonates tested positive. Table 1 describes the characteristics of the study population. There was no signi cant difference in demographic, clinical and comorbidity between infected and non-infected mothers. There were no signi cant differences in the median age at the time of delivery, in the gravity and parity (all p>0.05). Table 2 describes the obstetrical outcomes. There were no signi cant differences in the delivery method, in preeclampsia, in the intraoperative blood loss and birth weight of the newborn between the two groups (all P>0.05).
There were no signi cant differences in fetal distress, meconium-stained amniotic uid, preterm birth, and neonatal asphyxia between the two groups (all P>0.05) ( Table 3). Most infants were breastfed at birth, regardless of their mothers' COVID-19 status (p>0.05).

Discussion
This study allowed longitudinal follow-up of newborns born to mothers who tested positive for SARS-CoV-2 at the time of delivery and who were then followed by serial and clinical tests up to 1 month of life.
In our case series, only 3 infants had tested positive for SARS-CoV-2 virus, detected by a nasopharyngeal swab in the postnatal period between 48 hours and 14 days of life. Since the start of the epidemic, there have been several case reports of newborns who have tested positive for SARS-CoV-2. 5, 6 Cases of suspected congenital SARS-CoV-2 infection have also been reported. [13][14][15] These authors recommended blood, nasopharyngeal, placenta and umbilical cord testing as soon as possible after birth, after a thorough cleansing of the newborn. This would help to establish the overall risk of COVID-19 infection due to in-utero or perinatal exposure. In addition, all infants infected with SARS COV-2 remained asymptomatic or paucisymptomatic during the study period. These results con rm previously published data. 4,5 According to other authors, 2, 16 the clinical presentation in newborns may be slightly different from that of older children with a higher proportion of newborns with a severe pro le. The COVID-19 virus appears to directly infect cells via the Angiotensin-Converting Enzyme 2 (ACE2) receptor. 17 This is expressed in various organs, including the lung. Cells in children's lungs express this receptor less than cells in adult lungs. This may be one of the reasons that the infection affects children less severely. Regarding the newborn, the situation seems a little different because the respiratory physiology in newborns is immature and different from that of older children and adults. 18 It is this difference that explains why newborns can become seriously ill when they have respiratory disease. Indeed, perinatal transmission of COVID-19 is unlikely if correct hygiene precautions are taken. 11,12 In addition, in our practice, allowing newborns to live with their mother and be breastfed is part of routine care. This care was framed by effective parental education on infant protective strategies. In our study, we found high rates of preterm birth, especially when the mother had a SARS-COV2-severe pneumonia requiring transfer to ICU. Our results con rm those of the studies published at the beginning of the pandemic that described a high risk of preterm birth. 2,3,19,20 The explanation for this risk is the elective cesarean section delivery, in order to end the pregnancy, and to allow maternal salvage. On the other hand, the rates of premature rupture of the membranes, intrauterine growth retardation, abnormalities of the fetal heart rate and congenital malformations were identical to the controls'. Indeed, there were fewer newborns admitted in neonatal unit. This last result is contrary to the published data where pregnant women with covid-19, their neonates are more likely to be admitted to a neonatal unit. 20 Vertical transmission of SARS-CoV-2 was not detected. This con rms that with appropriate precautions, despite breastfeeding, the risk of transmission of the SARS-COV-2 virus to the newborn is low. Indeed, human milk is the gold standard for infant feeding and World Health Organization (WHO) insists on the importance of continuing breastfeeding during SARS-COV-2 outbreak. 21 There are few reports documenting vertical transmission of severe acute respiratory syndrome coronavirus 2. [22][23][24][25] Main ndings Our study analyzed the relationship between COVID-19 exposure and infection-related obstetrical outcomes. We found, that most often SARS-COV-2 infection in pregnant women was asymptomatic or paucisymptomatic, and that had little impact on the neonatal outcomes. In contrast, infants born from mothers with SARS-COV-2 severe pneumonia were at greater risk of preterm births, fetal death in utero, and neonatal intensive care unit admission. We advocated continued breastfeeding, with appropriate precautions. The risk of transmission of the SARS-COV-2 virus to the newborn was low.
Our study has several limitations. First, the study is limited by the sample size and a follow-up period of 1 month. Second, a large proportion of neonates was not tested for SARS-COV-2. However, no serological test was performed on patients who had a negative PCR test, because the tests were not available at the time of recruitment.
In conclusion, our data suggest that the risk of preterm birth, fetal death in utero, and neonatal intensive care unit admission is greater in newborns born to mothers with severe SARS-COV-2 pneumonia. In addition, under breastfeeding conditions with rigorous hygiene precautions and parental education, the risk of vertical transmission of the SARS-COV-2 virus is unlikely. All procedures performed in this study involving human participants were in accordance with the ethical standards of the Medical Ethical Committee of Cayenne Hospital. However, the requirement for written informed consent was waived by the ethics committee. An informed written consent to participate in the study has been obtained from each parent or legal guardian.

Consent for publication
An informed written consent for publication has been obtained from each parent or legal guardian.

Availability of data and material
Our database is available from the corresponding author on reasonable request. Tables   Table 1. Maternal demographic and clinical characteristics   IQR =interquartile range   Table 2. Obstetric outcomes Table 3. Neonatal outcomes according to SARS-COV-2 maternal status *out of 32 tested newborns Table 4 summarizes the clinical characteristics and outcomes of the 4 women transferred in intensive care unit (ICU).