Main findings

There was no significantly different rates of composite unfavorable obstetric and neonatal outcomes between COVID-19-positive women in the first trimester compared to a cohort of SARS-CoV-2-negative women matched for gestational age. There was no evidence of vertical transmission; a single case of thoracic venous anomaly associated with a cardiac anomaly (atrial septal defect) was recorded. After excluding congenital chromosomal anomalies; however, no association with COVID-19 could be clearly demonstrated. Finally, the incidence of maternal symptoms was negligible.

Strengths and limitations

The main strengths and limitations of our prospective study stem from the strict inclusion criterion that precluded recruitment of patients beyond 1 month of the date of the first reported COVID-19 case in Piedmont. This ensured the selection of cases with an infection that most certainly occurred during the first trimester of pregnancy; however, it also restricted the sample size and increased the probability of a type II error.

The SARS-CoV-2-negative (control) group was recruited at the same center and in the same timeframe as the SARS-CoV-2-positive (case) group; thus, establishing similar conditions and minimizing selection biases. Unlike previous reports,10, 11 the entire cohort underwent repeated seromolecular testing until delivery. Control group patients who tested positive at subsequent tests were excluded from the study. In this way, a noninfected control group was maintained. In addition, since all the women underwent sero and molecular testing, also those asymptomatic patients testing negative for antibodies but positive for RT-PCR were included in the case group.

Finally, the case group was a relatively healthy, real-world cohort without underlying uncontrolled medical conditions associated with increased severity of coronavirus infection. Moreover, although hospitalized patients were also included, a selection bias cannot be fully ruled out since the recruitment criteria may have allowed the inclusion of asymptomatic women, as SARS-CoV-2-positive patients with serious symptoms would not have attended the scheduled outpatient hospital visits.

Interpretation

There is a paucity of data on the risks associated with SARS-CoV-2 infection during the first trimester of pregnancy. The bulk of the literature consists of reports on women in the second and the third trimester of pregnancy and many studies lack a control group. There are only two prospective studies that include patients who acquired the infection in the first trimester.12, 13 However, at present writing, follow-up data have been obtained until mid-gestation and information on delivery is likely to be forthcoming in future reports.

Consistent with our previous work,14 in the present study, we did not find evidence of increased rate of fetal defects or abnormal fetal growth at delivery. Our previous and present findings may be reassuring for women exposed to SARS-CoV-2 infection during early pregnancy, as it does not appear to be associated with either an increased risk of early pregnancy loss15 or subsequent complications such as preterm birth, preeclampsia or IUGR. Moreover, the neutralizing-antibody titer seems to persist at least until delivery16 and such pregnancies could benefit from the transplacental passage of antibodies, which are critical to protect infants during the first months of life.

Most descriptive studies that support an association between SARS-CoV-2 infection and adverse birth outcomes involved symptomatic or severely ill women in the second/third trimester. SARS-CoV-2 infection seems to be associated with higher rates of symptomatic disease and severity in third- compared to first-trimester pregnancy,12, 17, 18 probably because the third trimester is associated with major hemodynamic and respiratory changes that might predispose a pregnant woman to a more severe clinical course of COVID-19.19 Moreover, symptomatic COVID-19-positive women were noted to have a modest, albeit significant, increase in the risk of infection-related obstetric morbidity and adverse outcomes, regardless of the trimester of infection.12 Our study cohort was composed of relatively young healthy women without apparent risk factors for severe COVID-19. Whether the favorable outcomes were due to these low risk characteristics remains arguable.

We recorded no unfavorable perinatal outcomes in our cohort and no cases of infection by vertical transmission in utero, intrapartum or postpartum. While in utero SARS-CoV-2 transmission is possible, viremia due to SARS-CoV-2, although infrequent (10%), appears to be more likely to occur in women with severe disease.18 Also, viral infection of the cells at the maternal-fetal interface is a necessary but not sufficient condition to induce direct fetal teratogenic effects. Organs without ACE2 expression are not the target of virus-related insult. There is conflicting evidence for the expression of ACE2 and TMPRSS2 receptors at the fetal organs.20-23 The cardiac malformation recorded in a newborn in a COVID-19-positive mother was not unequivocally traceable to the effect of SARS-CoV-2 infection. Although maternal viral infection in early pregnancy may be associated with an increased risk of CHDs in the offspring, it is still uncertain whether SARS-CoV-2 can cause cardiac malformations.24 In our patient, the RT-PCR for SARS-CoV-2 in the amniotic fluid sample was negative, providing no support for a specific etiological role of SARS-CoV-2 infection.

Rectal swabs collected at delivery tested negative and SARS-CoV-2 fecal contamination of the neonatal oro/nasopharynx during vaginal birth was excluded, as would be expected in women who were infected early during pregnancy.25-27

Finally, SARS-CoV-2 can be associated with vascular damage, including hypercoagulopathy in pregnant women and ischemic injury to the placenta. SARS-CoV-2 could indirectly affect the fetus via this route without direct infection of placental tissues. Most of the available data on histopathological placental findings derive from patients who contracted SARS-CoV-2 during the third trimester of pregnancy. A systematic literature review reported findings consistent with fetal and/or maternal vascular malperfusion in 35.3% and 46% of placentas, respectively.28 In our cohort, we also identified findings suggestive of FVM in several patients (4/16, 25%), including one high-grade FVM, with no repercussions on the newborn.

Inflammatory changes are another commonly reported finding in the placenta from COVID-19-positive patients. In a recent case–control study, a higher prevalence of chronic villitis of unknown etiology (VUE) was observed after limiting the comparison between the placentas delivered by asymptomatic COVID-19 patients and those from the controls.29 We observed VUE in the present series (4/16 patients, 25%). Chronic villitis/VUE can be caused by autoimmune phenomena or viral infections,30, 31 so it is not surprising that a subset of placentas delivered after SARS-CoV-2 infection may show changes consistent with VUE. Although VUE in general has been suggested to be associated with adverse obstetrical outcomes such as IUGR, preeclampsia, stillbirth, and preterm labor,32 the obstetric outcomes in the present study did not differ between the COVID-19-positive cases and the COVID-19-negative controls probably because the VUE were low-grade. This observation is consistent with previous data that reported placental changes in COVID-positive pregnancies without an apparent impact on neonatal outcomes.28, 33 Our data suggest that SARS-CoV-2 infection during the first trimester of pregnancy may cause some subclinical placental alterations but the clinical impact seems negligible.