key: cord-1050456-evpmtr33
authors: Hcini, Najeh; Maamri, Fatma; Picone, Olivier; Carod, Jean-Francois; Lambert, Véronique; Mathieu, Meredith; Carles, Gabriel; Pomar, Léo
title: Maternal, fetal and neonatal outcomes of large series of SARS-CoV-2 positive pregnancies in peripartum period: a single-center prospective comparative study
date: 2020-12-01
journal: Eur J Obstet Gynecol Reprod Biol
DOI: 10.1016/j.ejogrb.2020.11.068
sha: 24d13e1393acac216e53297922c99e82f2fa3a6d
doc_id: 1050456
cord_uid: evpmtr33

OBJECTIVE: To describe the proportions of asymptomatic, mild and severe diseases in infected pregnant women admitted for delivery. To compare maternal, fetal and neonatal outcomes of SARS-CoV-2 infected pregnant women with those of non-infected patients. STUDY DESIGN: Through an universal PCR testing for SARS-COV-2 at admission (not symptoms-based), this prospective cohort study enrolled all pregnant women admitted for delivery between 16(th) of June and the 16(th) of August 2020 in the West French Guiana Hospital Center. RESULTS: 507 pregnant women were included during the study period, of which 137 (27%) were infected with SARS-COV-2. On admission, only 34/137 (24.8%) of these patients presented with clinical symptoms. Among asymptomatic women, 16 /103 (15%) became symptomatic after diagnosis. Throughout the delivery hospitalization and follow-up, 87/137 (63.5 %) remained always asymptomatic, 45/137 (32.8%) developed a mild COVID-19 and 5/137 (3.6 %) developed a severe infection. SARS-CoV-2 infected patients were more likely to have post-partum hemorrhage >500 ml (14.2 % vs 7.2 %, RR 2.0 [95%CI 1.1-3.4]), to be transfused (5.5% vs 1.1 %, RR 4.9 [1.5-16.6]), and to be hospitalized in ICU (3.6% vs 0.8%, RR 4.5 [95%CI 1.1-18.6] than uninfected ones. Intra-uterine fetal demises were more common in infected mothers compared to controls (5.1% vs 1.1%, RR 4.7 [95% CI 1.4-45.9). Among 108 neonates from infected mothers tested at birth, none tested positive (0/108). When tested between 25 and 42 hours after delivery, 4/29 (13.7%) were positive for SARS-CoV-2 RT-PCR on nasopharyngeal swabs and remained asymptomatic. CONCLUSION: Pregnant women admitted for delivery and diagnosed with a SARS-COV-2 infection through an universal screening were symptomatic in only a quarter of cases. Their risks of post-partum hemorrhage, transfusion and admission to ICU were higher than those of uninfected patients. They also presented a higher risk of intra-uterine fetal demise. There were no other differences in maternal, obstetrical or neonatal outcomes.

The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a public health emergency declared by WHO as a global public health emergency [1] . Although there is a growing understanding of SARS-CoV-2, the outcomes associated with SARS-CoV2 infection during pregnancy remain limited and unclear. Based on previous viral exposition, pregnant women are particularly vulnerable to infections with potential for adverse pregnancy or perinatal outcomes [2, 3] . Unfortunately, the lack of a comparative group makes COVID 19 studies not strong enough to found adequate power to assess these outcomes. Unfortunately, the infection is re-emerging in many countries; it is an urgent need to analyze the result of the first wave.

The lack of an universal screening at admission (most of patients tested being symptomatic) may lead to selection biases and to a misunderstanding of the potential consequences of SARS-COV-2 infection during pregnancy [4, 5, 6] .

On the fetal side, many questions arise about the effect of symptomatic and asymptomatic SARS-CoV-2 infection during pregnancy. A few reports, based on biological and histological findings of electron microscopy and immunohistochemistry suggest vertical transmission of SARS-CoV-2 [7] but evidence is still uncertain.

In the last weeks, as many countries in Latin America, Covid-19 has rapidly spread to French Guiana territory, a French department located in South America, north of Brazil. Early in the beginning of the epidemic, we implemented universal testing with RT-PCR on nasopharyngeal swabs to identify SARS-COV-2 infections in pregnant women admitted to the maternity of the West French Guiana Hospital Center (Centre Hospitalier de l'Ouest Guyanais, CHOG).

The aims of this study were to describe the proportions of asymptomatic, mild and severe diseases in infected pregnant women admitted for delivery; and to compare maternal, fetal and J o u r n a l P r e -p r o o f neonatal outcomes of SARS-CoV-2 infected pregnant women with those of non-infected patients.

This observational prospective cohort study carried out in the Department of Obstetrics and Gynecology of the CHOG (referral center of western French Guiana) during the first 8 weeks of the SARSCoV-2 outbreak in the West French Guiana territory, from the 16 of June to the 16 of August 2020.

The west French Guiana territory was spared from COVID 19 before the beginning of this report. At the beginning of the outbreak, our hospital implemented a systematic screening for all pregnant women admitted for delivery using SARS-CoV-2 real-time reverse-transcriptase polymerase-chain-reaction (RT-qPCR) assays (Xpert Xpress, Cepheid, Sunnyvale, USA) on nasopharyngeal swabs. At admission, both RT-qPCR and serological analysis were performed.

Results were obtained after 51 minutes using a machine installed in the delivery room. Positive patients were isolated. Serologies were performed on Abbott ARCHITECT SARS-CoV-2 IgG assay (Abbott, Longford, Ireland). Testing for SARS-CoV-2 in placental tissue was performed using RT-qPCR in the National Reference Center of the Pasteur Institute, French Guiana.

The reason of this policy was to better manage hospitalization, avoid intra hospital contamination and to protect others parturient and medical staff. Antenatal care was provided by obstetricians and midwifes in accordance with the clinical practice of the French College of Gynecologists and Obstetricians. All patients were clinically evaluated. Fetal wellbeing was confirmed by cardiotocography. If necessary, ultrasonographic evaluation was performed. All women presented with a fever were also screened for Dengue virus.

CHOG policy authorize mothers to practice skin-to-skin care and breastfeed in the delivery room. She had to wear a surgical mask and to practice proper hand hygiene before skin-to-skin J o u r n a l P r e -p r o o f contact, breastfeeding, and routine care. All patients were monitored 14 days after hospital discharge either by telephone call or by home visit according to their clinical forms.

Inclusion criteria were pregnant women admitted for delivery beyond 15 weeks of gestation and tested for SARS-CoV-2 infection on an RT-PCR assay performed on a nasopharyngeal swab. This population was divided into two groups: an exposed group, defined as confirmed SARS-CoV2 infected pregnant women (positive RT-PCR); and a control group, defined by a negative SARS-CoV2 RT-PCR with negative serology when available.

We evaluated the proportions of asymptomatic, mild and severe diseases among SARS-COV-2 infected pregnant women, according to the World Health Organization criteria [8] .

Adverse maternal outcomes included maternal death, intensive care unit (ICU) admission and oxygen support (non-invasive ventilation, endotracheal intubation). Adverse obstetrical outcomes included preterm delivery (spontaneous or induced delivery <34wg), operative vaginal delivery or emergency cesarean section, acute fetal distress, postpartum hemorrhage (>500mL) and transfusion.

Adverse fetal outcomes included late miscarriages (>14wg) and intra-uterine fetal demises (spontaneous antepartum fetal death >20wg).

Adverse neonatal outcomes included per-partum or neonatal death, NICU admission, respiratory distress, seizures, Apgar score ≤ 7 at 1 min, umbilical venous lactate ≥ 5 mmol/l at birth and a low birthweight (<3 rd percentile, according to Intergrowth21st charts).

Secondary outcomes: All maternal, obstetrical and neonatal complications directly related or not related to COVID-19 infection were reported. Neonatal testing for SARS-COV-2 infection J o u r n a l P r e -p r o o f at birth and 24 to 48 hours after birth, using RT-PCR assays on naso-pharyngeal swabs, was also reported.

Data were collected prospectively and anonymously using an excel spreadsheet. The follow-up was completed on August 31, 2020. In compliance with the Regulation (EU) 2016/679 of the European Parliament on the protection of personal data a privacy impact assessment of the study was carried out according to the methodology described by the French data protection (CNIL). The risk mapping report was approved by the establishment's ethics committee (decision CHOG 2020-08-17).

Data were analyzed using STATA® v13.0. Student's t-test was used to compare continuous variables, whereas the comparison of proportions was performed using the chi-square test or

Fisher's exact test, as appropriate. The unpaired Student's t-test and the Mann-Whitney U-test were used to compare groups of continuous normally and non-normally distributed variables, respectively. Presented P-values were two-sided and the significance level was set to 5% (p = 0.05) for all statistical tests. Relative risks were estimated using a generalized linear model, adjusted for unbalanced maternal characteristics that could represent confounding factors and stratified for potential interactions with primary outcomes. Neonatal outcomes analysis included a robust variance option for twin pregnancies in the model.

During the study period, 507 pregnant women were admitted for delivery at the CHOG. Among There were 127 alive neonates from positive mothers and 364 neonates ≥ 25 WG from negative mothers including five sets of twins. We have documented 11 stillbirths, 4 termination of pregnancy for fetal anomalies and 6 extremely preterm infants 22-25WG (live births followed by a neonatal death).

Maternal characteristics and comorbidities are presented in table 1.

There were no significant differences between the two groups of infected and non-infected pregnant women for age, BMI, BMI >30 kg/m2, comorbidities, gravida, parity, scarred uterus, and pathologies during pregnancy before testing. Twin pregnancies were only present in the control group (5/370, 1.4%). The commonest laboratory abnormalities were raised inflammatory markers of C-reactive protein or procalcitonin (35%), thrombopenia (10.1%), lymphopenia (2.1%) and elevated transaminases (3.6%).

There were no differences in mode of delivery (operative vaginal delivery, cesarean section before labor, or cesarean section in labor) and abnormal fetal heart rate (table 2).

There were no significant differences in spontaneous births before 37 weeks' gestation (8.6% vs 10%, p=0.78) and before 34 weeks' gestation (0.7% vs 2.5%, p= 0.46). The risk of iatrogenic preterm birth and caesarean delivery was not significatively increased (0% vs 0.8 %, p= 0.57).

None of the cesarean sections were performed for worsening maternal respiratory status. In two patients with severe COVID-19, C-section extraction was contemplated for women under oxygen therapy at 35+1 WG and 34+6 WG. 

There were statistically significant differences between the two groups concerning fetal adverse outcomes (table 2) . SARS-CoV-2 infected pregnant women were less likely to give birth to alive neonates. The incidence of intra-uterine fetal demise was significantly higher in SARS-CoV-2 infected pregnant women compared to uninfected ones: 5.1% (7/137) vs 1.1% (4/370), In all cases (7 patients), induction of labor was performed using association of mifepristone and Misoprostol and they delivered normally.

There were no differences in the main clinical (birth weight, Apgar score, respiratory distress, oxygen administration, NICU admission, neonatal seizure, or neonatal death) or biological J o u r n a l P r e -p r o o f (umbilical venous lactate) neonatal outcomes between the two groups ( Table 3 ). All neonates continued to be clinically well and are growing appropriately.

Among 108 neonates from infected mothers tested at birth, none tested positive (0/108). When tested between 25 and 42 hours after delivery, 4/29 of neonates (13.7%) were positive for SARS-CoV-2 RT-PCR on nasopharyngeal swabs. Two neonates were retested positive 3 and 6 days after. Newborns were breastfed, never separated from their mothers, and received medical surveillance at home for one month. All positive neonates remained asymptomatic. In our population, we noticed a high rate of positive pregnant women (27%) in comparison to other reported series (< 1% in Southern California [6] and 13.7 % New York City [19] ). The damage of the virus in the vascular system has been reported and could influence the fetoplacental unit, notably with coagulopathy associated with COVID-19 [9, 10] . The SARS-CoV-2 virus binds to angiotensin-converting enzyme 2 (ACE2) [11] found in many different human organs. ACE2 is a key part of the renin angiotensin system (RAS) and a counterbalance to angiotensin-converting enzyme 1 (ACE1) and angiotensin II. Angiotensin II is proinflammatory, vasoconstrictive [12] . The mechanism is similar to those described in preeclampsia and HELLP syndrome. Federici et al reported hypertension and biological disorders suggesting pre-eclampsia and HELLP syndrome in a pregnant woman at 23.5 weeks of gestation with Covid-19 complications (acute respiratory distress syndrome treated with invasive mechanical ventilation) [13] .

Regarding mode of delivery, early experiences reported an important rate of cesarean section (50 to 91%) [14, 15] among severe cases of Covid 19.

Fortunately, epidemic studies in pregnant women reported that as much as 90% of SARS-CoV-2-positive cases were asymptomatic [16, 17, 18] . In our experience, we did not find an increased risk of cesarean section in either the symptomatic or asymptomatic group compared to the control group. It might be due to the protective effect of ethnicity [19] , genetic diversity of the virus [20] or the relatively small sample of severe SARS-CoV-2 infection. Severe forms of J o u r n a l P r e -p r o o f COVID 19 or administration of oxygen therapy should not be an indication for premature extraction if stabilization of respiratory condition is possible. This was the case for two of our patients and another one reported by Federici et al [14] .

Many authors [21, 22, 23] CoV-2 infection [22] . Changes in obstetric services and health system disruption may have played a role in observed adverse outcomes in our cohort but it would also have affected the control group.

Although first findings from a small group of cases suggested there is no vertical transmission in women who develop COVID-19 [24, 25] , rare observations reported vertical transmission of SARS-CoV-2 with biological (RT-PCR in amniotic fluid) and histological findings based on electron microscopy and immunohistochemistry [26, 27] .

To the best of our knowledge, this is the first comparative study to report such increasing risks in mothers positive for SARS-CoV-2 infection. We have ensured that the groups were highly comparable considering homogeneous population and a single protocol of management in order to minimize the effect of any confounding factors that can influence outcomes. Given the reemergence of the virus in many countries and the lack of vaccine, our findings could help inform patients and healthcare providers, as well as develop appropriate management protocols for pregnant women with COVID-19. SARS-COV-2 testing in all patients admitted for J o u r n a l P r e -p r o o f delivery, regardless of their symptoms at admission and without lost to follow-up, ensures a risk of selection bias as low as possible.

The findings of this study must be seen in light of some limitations. Firstly, this single-center cohort presents a relatively small number of patients infected with SARS-COV-2. We chose to limit the study at the first period of the epidemic to avoid including patients who tested positive for SARS-CoV-2 but without active infection (pre-partum infection with negative PCR at admission). Our group of infected patients permitted to highlight higher risks of adverse maternal and fetal outcomes, but we cannot exclude that a larger group could have permitted to describe more subtle consequences of COVID-19 during pregnancy. At the opposite, the small number in control group might affect comparisons of some adverse outcomes as post-partum haemorrhage.

Secondly, ethnicity and socioeconomic status were not reported in this study. Social precariousness and co-morbidities during pregnancy are particularly high in western French Guiana and could increase the risk of infection as well as the risk of adverse outcomes, and then be considered as a confounding factors. The rates of co-morbidities were relatively balanced across the groups. The socio-economic status of patients enrolled was not reported, and it is paramount to acknowledge that it might contribute to the increase of adverse outcomes observed in SARS-COV-2 infected patients if it was lower in this group.

Thirdly, at the beginning of the outbreak, we did not collect placenta and fetal samples for RT-PCR testing in the first cases of stillbirth. This could underestimate the risks of vertical transmission and subsequent adverse fetal outcomes.

Finally, French Guiana territory is epidemic of other virus such as Dengue Virus. Active circulation of Dengue virus during the same period can influence the outcomes of pregnancy but not the comparison between the two groups. The small number of positive cases during the study period minimizes the influence of this factor on the results.

In conclusion, SARS-CoV-2 infection in parturient admitted for delivery seems to be symptomatic in only a quarter of cases. SARS-CoV-2 infected mothers presented higher risks of maternal and fetal adverse outcomes: ICU admission, post-partum hemorrhage, transfusion and fetal loss. Fetal outcomes did not depend on the clinical form of Covid 19. For mothers, special awareness should be taken about significant risks of post-partum hemorrhage. Until more is known about this disease, it is paramount to perform close monitoring for infected pregnant women especially in immediate post-partum period.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Twins (n=5, non-infected group) were considered as two separate neonates, the model included a robust variance option for twin pregnancies.

No separation of mother -newborn, skin-to-skin and breakfasting allowed. Mothers were delivered protective measures (hand washing, breast cleaning and wearing a mask when breakfasting). 

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