Background
The effect of COVID-19 in pregnancy on maternal outcomes and its association with preeclampsia and gestational diabetes mellitus have been reported; however, a detailed understanding of the effects of maternal positivity, delivery mode, and perinatal practices on fetal and neonatal outcomes is urgently needed.
Objective
To evaluate the impact of COVID-19 on fetal and neonatal outcomes and the role of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission.
Study Design
In this cohort study that took place from March 2020 to March 2021, involving 43 institutions in 18 countries, 2 unmatched, consecutive, unexposed women were concomitantly enrolled immediately after each infected woman was identified, at any stage of pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed up until hospital discharge. COVID-19 in pregnancy was determined by laboratory confirmation and/or radiological pulmonary findings or ≥2 predefined COVID-19 symptoms. The outcome measures were indices of neonatal and perinatal morbidity and mortality, neonatal positivity and its correlation with mode of delivery, breastfeeding, and hospital neonatal care practices.
Results
A total of 586 neonates born to women with COVID-19 diagnosis and 1535 neonates born to women without COVID-19 diagnosis were enrolled. Women with COVID-19 diagnosis had a higher rate of cesarean delivery (52.8% vs 38.5% for those without COVID-19 diagnosis, P <.01) and pregnancy-related complications, such as hypertensive disorders of pregnancy and fetal distress (all with P <.001), than women without COVID-19 diagnosis. Maternal diagnosis of COVID-19 carried an increased rate of preterm birth ( P ≤.001) and lower neonatal weight ( P ≤.001), length, and head circumference at birth. In mothers with COVID-19 diagnosis, the length of in utero exposure was significantly correlated to the risk of the neonate testing positive (odds ratio, 4.5; 95% confidence interval, 2.2–9.4 for length of in utero exposure >14 days). Among neonates born to mothers with COVID-19 diagnosis, birth via cesarean delivery was a risk factor for testing positive for COVID-19 (odds ratio, 2.4; 95% confidence interval, 1.2–4.7), even when severity of maternal conditions was considered and after multivariable logistic analysis. In the subgroup of neonates born to women with COVID-19 diagnosis, the outcomes worsened when the neonate also tested positive, with higher rates of neonatal intensive care unit admission, fever, gastrointestinal and respiratory symptoms, and death, even after adjusting for prematurity.
Breastfeeding by mothers with COVID-19 diagnosis and hospital neonatal care practices, including immediate skin-to-skin contact and rooming-in, were not associated with an increased risk of newborn positivity.
Conclusion
In this multinational cohort study, COVID-19 in pregnancy was associated with increased maternal and neonatal complications. Cesarean delivery was significantly associated with newborn COVID-19 diagnosis. Vaginal delivery should be considered the safest mode of delivery if obstetrical and health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding were not risk factors for newborn COVID-19 diagnosis, thus well-established best practices can be continued among women with COVID-19 diagnosis.
Introduction
The COVID-19 pandemic is likely to continue to affect large numbers of pregnant individuals and their offspring. Although immunization programs have reduced infections overall, vaccine hesitancy in pregnancy is common , ; in addition, vaccine availability remains limited, particularly in low-income settings.
Why was this study conducted?
This study aimed to describe and quantify any association between COVID-19 during pregnancy and newborn outcomes, and to assess the safety of perinatal care practices, including breastfeeding, in mothers with a COVID-19 diagnosis.
Key findings
Patients with COVID-19 diagnosis in pregnancy and the postnatal period are at substantial risk of neonatal morbidity and mortality compared with unexposed counterparts, with the most severe effects observed in test-positive neonates born to women with COVID-19 diagnosis. Cesarean delivery was significantly associated with neonatal positivity. Vaginal delivery should be considered as the preferred mode of delivery even in symptomatic women when obstetrical and general health conditions allow it. Mother-to-child skin-to-skin contact, rooming-in, and direct breastfeeding are not risk factors for neonatal test positivity; thus, well-established best evidence-based practices can be continued among women with COVID-19 diagnosis.
What does this add to what is known?
COVID-19 in pregnancy is associated with adverse newborn outcomes; unless otherwise indicated, cesarean delivery should not be the preferred mode of delivery in positive mothers. Skin-to-skin contact and breastfeeding should be encouraged.
Whereas increasing data are becoming available with regard to maternal outcomes associated with COVID-19, less is known about the association with neonatal outcomes. Preliminary reports suggest that SARS-CoV-2 infection in the neonatal period causes mild disease without significant impact on newborn health. Considering the deleterious effects on pregnancy of COVID-19 and other coronavirus infections, such as severe acute respiratory syndrome (SARS) , and Middle East respiratory syndrome coronavirus (MERS-CoV), , a detailed understanding of the effects of COVID-19 on neonatal outcomes is urgently needed.
It is within this context that, in March 2020, the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) initiated INTERCOVID, a prospective, multicountry, multicenter, observational study with the aim of assessing maternal and neonatal outcomes in pregnant individuals with a COVID-19 diagnosis, as compared with concomitantly enrolled pregnant individuals without a COVID-19 diagnosis. The overall effects of COVID-19 on maternal outcomes and the association with preeclampsia and gestational diabetes mellitus have recently been reported. The present report focuses on the impact of COVID-19 on neonatal outcomes and the effects of mode of delivery, breastfeeding, and early neonatal care practices on the risk of mother-to-child transmission.
Materials and Methods
Study design
From March 2, 2020 to March 18, 2021, we enrolled women from 43 institutions in 18 countries (Argentina, Brazil, Egypt, France, Ghana, India, Indonesia, Italy, Japan, Mexico, Nigeria, North Macedonia, Pakistan, Russia, Spain, Switzerland, United Kingdom, and the United States). The distribution by country is presented in Supplemental Figure 1 . Data on ethnicity were not collected.
We enrolled a total of 742 women, aged ≥18 years, at any stage of pregnancy or at delivery, with a COVID-19 diagnosis based on: (1) laboratory confirmation of SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR) (n=687) and (2) ≥2 predefined COVID-19 symptoms or signs, without laboratory confirmation (n=55). When a woman with COVID-19 diagnosis was identified antenatally, 2 immediately concomitant women without COVID-19 diagnosis aged ≥18 years of similar gestational age (±2 weeks), receiving standard antenatal care, were enrolled on the same day to create an unbiased sample of all pregnant individuals without COVID-19 diagnosis in these institutions. If this was not possible or if the women without COVID-19 diagnosis were lost to follow-up, we enrolled 2 women without COVID-19 diagnosis who were admitted at the same level of care and delivered immediately after the woman with COVID-19 diagnosis. The same selection strategy was used when a woman with COVID-19 diagnosis was identified at hospital admission and delivery was likely during that admission. As a quality check, we confirmed from a biweekly random 10% sample that the 2 women without COVID-19 were appropriately chosen; we excluded 5 women with COVID-19 diagnosis and the corresponding women without COVID-19 diagnosis where such confirmation was missing.
For the present analysis, we excluded mother–newborn dyads when the neonate was not tested for COVID-19 even if clinically indicated, or when the reason was not clearly described.
Live and stillborn and singleton and multiple pregnancies were included, along with even those with congenital anomalies. In keeping with reporting requirements during the pandemic, we excluded mothers and newborns from the final analysis if their data had already been published in any comparative study with women without COVID-19 diagnosis, other than INTERCOVID-related papers.
The Oxford Tropical Research Ethics Committee and all local ethics committees approved the study. Informed consent (oral or written) was obtained from participants according to local requirements, except when a waiver or exemption from such consent was granted by a local committee. We adhered to the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol, including the laboratory tests used, has been previously published.
Outcomes definition
The primary outcome was the association between maternal COVID-19 exposure and neonatal positivity; the secondary outcome was the association of time of exposure, mode of delivery, breastfeeding, and neonatal care practices with neonatal outcomes.
Data on maternal and pregnancy history, delivery mode, indication for cesarean delivery, newborn outcomes, and feeding practices were collected with standardized forms used in the INTERGROWTH-21st project. In addition, we recorded detailed data on each mother’s health and condition at admission, perinatal management, and in-hospital practices (eg, skin-to-skin contact, isolation from the neonate, and use of masks and hand washing by mothers and hospital staff). We also recorded information regarding the timing and results of SARS-CoV-2 testing and COVID-19–related symptoms for mothers and neonates.
Gestational age estimation was based on ultrasound measurement of fetal crown-rump length (<14 weeks’ gestation). If early ultrasound dating was not performed, the “best obstetrical” estimate was used based on all clinical and ultrasound data available at the time of delivery.
The total time of exposure to SARS-CoV-2 was defined as the number of days between the woman testing positive or the onset of symptoms and delivery. We chose a 10-day cutoff to study the risk in different populations (ie, women still infectious during labor and women most probably not infectious during labor) given that the horizontal infectiousness of patients with symptoms or a positive test >10 days before labor onset seems very low. , The maternal symptom severity score was defined as a continuous variable composed of the sum of preset values attributed to each maternal COVID-19–related symptom, according to the severity of the symptom.
In the data collection form, the indications for delivery that are often used in medical records were recorded. For the analyses, in mothers who delivered by cesarean delivery, those indications were grouped into potentially COVID-19–related and others. We included in the potentially COVID-19–related indications hypertensive disorders of pregnancy, fetal distress, fetal growth restriction, suspected smallness for gestational age (SGA) or fetal growth restriction, premature rupture of membranes, and infections. SGA was defined as being born with weight below the 10th percentile on the basis of INTERGROWTH-21st international standards for newborn weight.
Newborn weight, length, and head circumference were assessed against the international INTERGROWTH-21st standards following a standardized protocol. Measurement instruments were regularly calibrated and used by trained staff. Data on neonatal health outcomes, diagnostics, and treatments were collected in detail and grouped into the following categories: (1) neurologic problems including seizures, hydrocephalus, neurologic disorders, any hypoxic-ischemic encephalopathy, and periventricular hemorrhage/leukomalacia grade 3 or 4 per Papile criteria; (2) gastrointestinal conditions including no enteral feeding for >24 hours, necrotizing enterocolitis, stoppage of enteral feeding for >3 consecutive days, gastro-esophago-pharyngeal reflux, persistent vomiting, and diarrhea; (3) infections including sepsis, hypotension requiring inotropic steroids, and pneumonia or acute respiratory infections; and (4) respiratory conditions including pneumonia or bronchiolitis, apnea of prematurity, bronchopulmonary dysplasia (BPD), and corticosteroids for BPD.
Detailed data regarding feeding were recorded and included: type of feeding, that is, any breastfeeding (defined as exclusive or partial breastfeeding) and no breastfeeding (defined as exclusive formula or only parenteral nutrition); and mode of feeding, that is, direct breastfeeding, bottle feeding, or tube feeding. Furthermore, information regarding hospital newborn care practices, including immediate skin-to-skin contact, rooming-in, and hygiene measures were recorded for neonates tested for COVID-19. All data were collected on newborn care forms during hospital stay and at discharge.
Because of the unavailability of COVID-19 testing kits at various times in different countries, it was not possible to standardize newborn testing policies. A list of the diagnostic tests used to assess maternal and neonatal COVID-19 status across the participating countries is available in the Study Documents on the INTERCOVID website. Whereas most centers tested all newborns from mothers with COVID-19 diagnosis, a few tested only newborns with clinical signs, such as fever, respiratory distress, or need for respiratory support. The analysis was therefore conducted in 3 different groups born to women with a COVID-19 diagnosis: (1) neonates who tested negative for COVID-19 (99.7% tested using RT-PCR); (2) neonates who had no clinical signs of COVID-19 and were not tested; and (3) neonates who tested positive for COVID-19 (92.7% tested using RT-PCR).
Statistical analysis
We used chi-square tests for proportions and t -tests for continuous variables to compare maternal baseline characteristics and early outcomes between neonates born to mothers with and without a COVID-19 diagnosis; similarly, for neonatal characteristics and other outcomes, we compared the 3 groups of neonates. We used negative binomial models to calculate relative risks for neonatal outcomes among the 3 groups; neonates born to mothers without COVID-19 diagnosis were the reference group. We adjusted for the following covariates that were selected using directed acyclic graphs : maternal age, tobacco use, parity, history of pregnancy complications, and gestational age. To complement the crude, unadjusted analysis, we explored logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for neonates testing positive for COVID-19 stratified by the number of days between maternal diagnosis and delivery, and adjusting for mode of delivery for comparison.
Among neonates tested for COVID-19 and born to women with COVID-19 diagnosis, we collected complete information from newborn care forms to determine if factors during delivery and after birth were related to the neonates testing positive. We used chi-square tests to compare the reasons for cesarean delivery among neonates that tested positive vs negative for COVID-19 born to women with COVID-19 diagnosis. We used logistic regression models to calculate ORs and 95% CIs for predictors of the neonates testing positive for COVID-19. We stratified by the time between diagnosis and delivery (≤24 hours or >24 hours) and used chi-square tests to evaluate delivery outcomes, neonatal outcomes, and newborn care practices. Finally, for sensitivity analysis we assessed the associations between neonatal COVID-19 status and neonatal outcomes among neonates born to mothers with a positive COVID-19 test only.
Results
We enrolled a total of 742 women with a COVID-19 diagnosis based on: (1) laboratory confirmation of SARS-CoV-2 infection by RT-PCR (n=687) and (2) ≥2 predefined COVID-19 symptoms or signs, without laboratory confirmation (n=55). Mother–newborn dyads in which the neonate was not tested for COVID-19 were excluded (n=180 neonates and 173 mothers).
Therefore, we included in this analysis 569 women with and 1500 women without COVID-19 diagnosis. Because multiple pregnancies were included, a total of 586 newborns of mothers with COVID-19 diagnosis and 1535 newborns of mothers without COVID-19 diagnosis were included, all with broadly similar demographic characteristics to those described in previous papers. Supplemental Figure 2 provides the study enrollment flowchart.
Table 1 presents maternal baseline characteristics for women with and without COVID-19 diagnosis, with the former group subdivided into those with neonates who tested positive or negative for COVID-19 and those with neonates without clinical signs who were not tested. Women with COVID-19 diagnosis had higher rates of hypertensive disorders of pregnancy and pregnancy-induced hypertension, and higher occurrence of gestational diabetes mellitus, previous neonatal death, previous preterm birth, and previous low birthweight newborns than women without COVID-19 diagnosis. Compared with those without COVID-19 diagnosis, pregnant persons with COVID-19 diagnosis had higher incidence of cesarean delivery, preterm birth, medically-indicated preterm birth, and related prophylactic antenatal corticosteroid therapy given for fetal lung maturation, all with P <.01, reflecting higher rates of pregnancy complications in this group. For all these variables, women with COVID-19 diagnosis had higher rates ( P <.01) than women without COVID-19 diagnosis.
| Maternal characteristics | Mothers without COVID-19 diagnosis (n=1500) n (%) or mean±SD | Mothers with COVID-19 diagnosis | |||
|---|---|---|---|---|---|
| All mothers with COVID-19 diagnosis (n=569) n (%) or mean±SD | Neonate COVID-19 negative (n=353) n (%) or mean±SD | Neonate without signs not tested (n=163) n (%) or mean±SD | Neonate COVID-19 positive (n=53) n (%) or mean±SD | ||
| Maternal age, mean±SD | 30.3±6.1 | 29.8±6.1 | 30.2±6.2 | 28.8±5.6 | 29.7±6.8 |
| Maternal smoking | 60 (4.0) | 16 (2.8) | 12 (3.5) | 2 (1.2) | 2 (3.8) |
| Previous preterm birth | 81 (6.1) | 38 (7.6) | 24 (7.9) | 10 (6.8) | 4 (8.2) |
| Previous low birthweight newborn | 104 (7.8) | 45 (9.2) | 25 (8.3) | 15 (10.2) | 5 (10.2) |
| Previous neonatal death | 41 (3.1) | 29 (5.8) a | 16 (5.3) | 10 (6.8) | 3 (6.1) |
| Prenatal multivitamins/minerals | 702 (47.1) | 286 (51.6) | 179 (2.0) | 74 (47.1) | 33 (62.3) |
| Gestational diabetes mellitus | 125 (8.4) | 66 (11.6) a | 34 (9.7) | 26 (16.1) | 6 (11.3) |
| Maternal hypertension, preeclampsia, or eclampsia | 140 (9.4) | 85 (15.0) a | 50 (14.2) | 26 (16.0) | 9 (17.0) |
| Premature rupture of membranes | 271 (18.5) | 92 (16.6) | 59 (17.0) | 25 (16.1) | 8 (15.1) |
| Prophylactic corticosteroids | 83 (5.7) | 66 (12.0) a | 43 (12.5) | 14 (9.0) | 9 (17.0) |
| Fetal distress | 122 (8.2) | 72 (12.7) a | 49 (13.9) | 14 (8.6) | 9 (17.0) |
| Cesarean delivery | 576 (38.5) | 300 (52.8) a | 165 (46.9) | 98 (60.1) | 37 (69.8) |
| Induced labor | 336 (22.4) | 123 (21.6) | 82 (23.2) | 33 (20.3) | 8 (15.1) |
| Preterm birth | 200 (13.4) | 132 (23.2) b | 83 (23.5) | 32 (19.8) | 17 (32.1) |
| Medically-indicated preterm birth | 130 (8.7) | 113 (19.9) b | 70 (19.8) | 26 (16.1) | 17 (32.1) |
b P ≤.001, comparing neonates born to mothers with COVID-19 diagnosis with neonates born to mothers without COVID-19 diagnosis.
Women with COVID-19 diagnosis had a cesarean delivery rate ( Table 1 ) of 52.8% vs 38.5% for those without COVID-19 diagnosis ( P <.01). Among women with COVID-19 diagnosis, those with neonates that tested positive for COVID -19 had a cesarean delivery rate of 69.8% vs 46.9% for those with neonates who tested negative ( P <.01). Reasons for cesarean delivery did not significantly differ between groups, neither individually nor when grouped by COVID-19–related indications vs other indications ( Supplemental Table 1 ). In a multivariable logistic regression analysis ( Supplemental Table 2 ) including time of exposure and immediate mother–newborn skin-to-skin contact, birth via cesarean delivery was statistically significantly associated with neonates testing positive for COVID-19 (adjusted OR [aOR], 2.4; 95% CI, 1.2–4.7).
Moreover, we investigated if cesarean delivery was independently associated with neonatal positivity and found no interaction between direct breastfeeding and cesarean delivery ( P -interaction=.93). In addition, the interaction term between skin-to-skin contact and cesarean delivery was marginally significant ( P -interaction=.17). With skin-to-skin contact and the interaction between skin-to-skin contact and cesarean delivery in the model, the OR for neonates testing positive with cesarean delivery increased to 3.4 (1.4–8.2), but the CIs were much wider.
As presented in Table 1 , fetal distress was lowest in neonates of women without COVID-19 diagnosis, higher among COVID-19–negative neonates of women with COVID-19 diagnosis, and highest among COVID-19–positive neonates whose mothers also had a COVID-19 diagnosis.
Table 2 presents early neonatal outcomes by maternal COVID-19 diagnosis and neonatal test status. Among the newborns of women with COVID-19 diagnosis (including multiple births), 366 (62.5%) tested negative (99.7% tested with RT-PCR), 56 (9.5%) tested positive (92.7% tested with RT-PCR), and 164 (28%) had no clinical signs and were not tested. Among COVID-19–positive neonates of women with COVID-19 diagnosis, the time between maternal diagnosis and delivery was significantly longer than in the group of COVID-19–negative neonates (13.3 days vs 6.4 days, P =.007), whereas the gestational age at diagnosis was significantly lower (35.3 weeks vs 37 weeks, P =.002).
| Neonatal characteristics | Mother without COVID-19 diagnosis (n=1535) a n (%) or mean±SD | Mother with COVID-19 diagnosis | ||
|---|---|---|---|---|
| Neonates COVID-19 negative (n=366) a n (%) or mean±SD | Neonates without signs not tested (n=164) a n (%) or mean±SD | Neonates COVID-19 positive (n=56) a n (%) or mean±SD | ||
| Total time of exposure (days from positive swab to delivery) b | NA | 6.4 ± 16.4 | 16.4 ± 34.0 c | 13.3 ± 23.8 c |
| Positive at delivery = total time of exposure (days from positive swab to delivery) ≤10 | NA | 314 (88.7) | 100 (73.5) | 38 (67.9) |
| Gestational age at diagnosis | NA | 37.0±3.5 | 35.7±2.9 d | 35.3±4.5 d |
| Any maternal symptoms | NA | 178 (48.6) | 103 (62.8) | 30 (53.6) |
| Maternal symptom severity score b | NA | 4.3±5.7 | 5.7±6.3 | 5.0±6.7 |
| Number of maternal symptoms b | NA | 1.4±1.8 | 1.8±1.9 | 1.7±2.2 |
| Days of maternal symptoms b | NA | 7.7±14.4 | 7.9±14.1 | 10.6±16.7 |
| Maternal radiological signs | NA | 74 (20.6) | 21 (13.5) | 8 (14.6) |
| Mother admitted to ICU | 25 (1.6) | 35 (9.6) | 7 (4.3) | 4 (7.1) |
| Gestational age at delivery b | 38.5±3.2 | 37.8±2.8 | 38.0±2.8 | 37.3±3.6 e |
| Testing within 24 h after birth | NA | 195 (53.3) | NA | 26 (46.4) |
| Testing within 48 h after birth | NA | 276 (75.4) | NA | 40 (71.4) |
| Male sex (%) | 804 (52.8) | 185 (50.6) | 84 (51.5) | 29 (52.7) |
| Birthweight (kg) b | 3.09±0.67 | 2.92±0.69 | 2.96±0.64 | 2.79±0.84 e |
| Birth length (cm) b | 49.1±3.9 | 48.4±4.1 | 48.6±5.1 | 47.2±5.7 d |
| Head circumference at birth (cm) b | 34.1±2.1 | 33.6±2.2 | 34.1±2.4 | 33.2±2.7 d |
| Birthweight SDS b | −0.02±1.07 | −0.07±1.09 | −0.11±1.17 | −0.15±1.13 |
| Birth length SDS b | 0.40±1.27 | 0.37±1.29 | 0.51±1.39 | 0.22±1.28 |
| Head circumference at birth SDS b | 0.53±1.15 | 0.53±1.14 | 0.59±1.19 | 0.45±1.15 |
| 5-min Apgar score | 9.0±1.7 | 9.1±1.2 | 8.6±2.0 | 8.8±1.7 |
| 5-min Apgar score <7 | 61 (4.0) | 16 (4.4) | 10 (6.2) | 4 (7.1) |
| Intrauterine distress | 96 (6.3) | 35 (9.6) | 12 (7.3) | 9 (16.1) e |
| Meconium aspiration | 8 (0.5) | 5 (1.4) | 0 (0.0) | 2 (3.7) e |
| NICU admission (%) | 164 (10.8) | 121 (33.5) e | 15 (9.4) | 28 (50.0) e |
| Days in NICU (median and IQR) | 5 (1–12) | 4 (2–12) | 3 (2–7) | 7 (3–13) |
| Respiratory distress syndrome | 74 (4.9) | 37 (10.2) e | 8 (5.0) | 9 (16.1) e |
| Transient tachypnea of newborn | 39 (2.6) | 25 (6.9) d | 6 (3.7) | 7 (12.5) e |
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