The INTERCOVID Multinational Cohort Study
Question To what extent does COVID-19 in pregnancy alter the risks of adverse maternal and neonatal outcomes compared with pregnant individuals without COVID-19?
Findings In this multinational cohort study of 2130 pregnant women in 18 countries, women with COVID-19 diagnosis were at increased risk of a composite maternal morbidity and mortality index. Newborns of women with COVID-19 diagnosis had significantly higher severe neonatal morbidity index and severe perinatal morbidity and mortality index compared with newborns of women without COVID-19 diagnosis.
Meaning This study indicates a consistent association between pregnant individuals with COVID-19 diagnosis and higher rates of adverse outcomes, including maternal mortality, preeclampsia, and preterm birth compared with pregnant individuals without COVID-19 diagnosis.
Importance Detailed information about the association of COVID-19 with outcomes in pregnant individuals compared with not-infected pregnant individuals is much needed.
Objective To evaluate the risks associated with COVID-19 in pregnancy on maternal and neonatal outcomes compared with not-infected, concomitant pregnant individuals.
Design, Setting, and Participants In this cohort study that took place from March to October 2020, involving 43 institutions in 18 countries, 2 unmatched, consecutive, not-infected 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.
Exposures COVID-19 in pregnancy determined by laboratory confirmation of COVID-19 and/or radiological pulmonary findings or 2 or more predefined COVID-19 symptoms.
Main Outcomes and Measures The primary outcome measures were indices of (maternal and severe neonatal/perinatal) morbidity and mortality; the individual components of these indices were secondary outcomes. Models for these outcomes were adjusted for country, month entering study, maternal age, and history of morbidity.
Results A total of 706 pregnant women with COVID-19 diagnosis and 1424 pregnant women without COVID-19 diagnosis were enrolled, all with broadly similar demographic characteristics (mean [SD] age, 30.2 [6.1] years). Overweight early in pregnancy occurred in 323 women (48.6%) with COVID-19 diagnosis and 554 women (40.2%) without. Women with COVID-19 diagnosis were at higher risk for preeclampsia/eclampsia (relative risk [RR], 1.76; 95% CI, 1.27-2.43), severe infections (RR, 3.38; 95% CI, 1.63-7.01), intensive care unit admission (RR, 5.04; 95% CI, 3.13-8.10), maternal mortality (RR, 22.3; 95% CI, 2.88-172), preterm birth (RR, 1.59; 95% CI, 1.30-1.94), medically indicated preterm birth (RR, 1.97; 95% CI, 1.56-2.51), severe neonatal morbidity index (RR, 2.66; 95% CI, 1.69-4.18), and severe perinatal morbidity and mortality index (RR, 2.14; 95% CI, 1.66-2.75). Fever and shortness of breath for any duration was associated with increased risk of severe maternal complications (RR, 2.56; 95% CI, 1.92-3.40) and neonatal complications (RR, 4.97; 95% CI, 2.11-11.69). Asymptomatic women with COVID-19 diagnosis remained at higher risk only for maternal morbidity (RR, 1.24; 95% CI, 1.00-1.54) and preeclampsia (RR, 1.63; 95% CI, 1.01-2.63). Among women who tested positive (98.1% by real-time polymerase chain reaction), 54 (13%) of their neonates tested positive. Cesarean delivery (RR, 2.15; 95% CI, 1.18-3.91) but not breastfeeding (RR, 1.10; 95% CI, 0.66-1.85) was associated with increased risk for neonatal test positivity.
Conclusions and Relevance In this multinational cohort study, COVID-19 in pregnancy was associated with consistent and substantial increases in severe maternal morbidity and mortality and neonatal complications when pregnant women with and without COVID-19 diagnosis were compared. The findings should alert pregnant individuals and clinicians to implement strictly all the recommended COVID-19 preventive measures.
We conducted a large-scale, prospective, multinational study to assess the symptoms and associations between COVID-19 in pregnancy and maternal and neonatal outcomes that included, to our knowledge for the first time, immediately concomitant pregnant women without COVID-19 diagnosis from the same populations, carefully enrolled to minimize selection bias.
We demonstrated that women with COVID-19 diagnosis, compared with those without COVID-19 diagnosis, were at substantially increased risk of severe pregnancy complications, including preeclampsia/eclampsia/HELLP syndrome, ICU admission or referral to higher level of care, and infections requiring antibiotics, as well as preterm birth and low birth weight. The risk of maternal mortality was 1.6%, ie, 22 times higher in the group of women with COVID-19 diagnosis. These deaths were concentrated in institutions from less developed regions, implying that when comprehensive ICU services are not fully available, COVID-19 in pregnancy can be lethal. Reassuringly, we also found that asymptomatic women with COVID-19 diagnosis had similar outcomes to women without COVID-19 diagnosis, except for preeclampsia.
Importantly, women with COVID-19 diagnosis, already at high risk of preeclampsia and COVID-19 because of preexisting overweight, diabetes, hypertension, and cardiac and chronic respiratory diseases,28 had almost 4 times greater risk of developing preeclampsia/eclampsia, which could reflect the known association with these comorbidities and/or the acute kidney damage that can occur in patients with COVID-19.29
Our data support reports of an association between COVID-19 and higher rates of preeclampsia/eclampsia/HELLP syndrome,19,30 but it is still uncertain whether COVID-19 manifests in pregnancy with a preeclampsialike syndrome or infection with SARS-CoV-2 results in an increased risk for preeclampsia. Uncertainty persists because the placentas of women with COVID-19, compared with controls, show vascular changes consistent with preeclampsia,31 but the state of systemic inflammation and hypercoagulability found in nonpregnant patients with severe illness and COVID-19 is also a feature of preeclampsia.32
It is known that in nonpregnant patients, distinct subtypes may be predictive of clinical outcomes.33 We found the presence of any COVID-19 symptoms was associated with increased morbidity and mortality. Specifically, severe pregnancy and neonatal complication rates were highest in women if fever and shortness of breath were present, reflecting systemic disease; their presence for 1 to 4 days was associated with severe maternal and neonatal complications. This observation should influence clinical care and referral strategies.
The risks of severe neonatal complications, including NICU stay for 7 days or longer, as well as the summary index of severe neonatal morbidity and its individual components, were also substantially higher in the group of women with COVID-19 diagnosis. The increased neonatal risk remained after adjusting for previous preterm birth and preterm birth in the index pregnancy; thus, a direct effect on the newborn from COVID-19 is likely.
Overall, our results were consistent across morbidities and mostly at an RR near or greater than 2 for maternal and neonatal outcomes, with narrow CIs excluding unity, and above 3 to 4 in several estimates. Sensitivity and stratified analyses confirmed the observed results. They are probably conservative because overall, 41% of women with COVID-19 diagnosis were asymptomatic, a subgroup with a low risk of complications. Hence, higher morbidity and mortality risk should be expected for the general pregnant population, especially in low- to middle-income countries.
We found 12.1% of neonates born to test-positive women also tested positive, a higher figure than in a recent systematic review.34 We speculate whether contamination at the time of cesarean delivery was responsible because the rate in this mother/neonate positive subgroup was 72.2%. Reassuringly, as SARS-CoV-2 has not been isolated from breast milk,35 breastfeeding was not associated with any increase in the rate of test-positive neonates.
Our results mostly reflect COVID-19 diagnosed in the third trimester. Thus, women with COVID-19 diagnosis or whose pregnancy ended earlier in pregnancy are underrepresented either because our study was exclusively hospital based or earlier infection may manifest with mild symptoms, which are either ignored or managed in primary care. Alternatively, most women might have avoided the hospital until late in pregnancy or when in labor. Clearly, the effect of COVID-19 early in pregnancy needs urgently to be studied.
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