Abstract
Background
SARS-CoV-2 can lead to several types of complications during pregnancy. Variant surges are associated with different severities of disease. Few studies have compared the clinical consequences of specific variants on obstetrical and neonatal outcomes. Our goal was to evaluate and compare disease severity in pregnant women and obstetrical or neonatal complications between variants of SARS-CoV-2 that have circulated in France over a two-year period (2020–2022).
Method
This retrospective cohort study included all pregnant women with a confirmed SARS-CoV-2 infection (positive naso-pharyngeal RT-PCR test) from March 12, 2020 to January 31, 2022, in three tertiary maternal referral obstetric units in the Paris metropolitan area, France. We collected clinical and laboratory data for mothers and newborns from patients’ medical records. Variant identification was either available following sequencing or extrapolated from epidemiological data.
Results
There were 234/501 (47%) Wild Type (WT), 127/501 (25%) Alpha, 98/501 (20%) Delta, and 42/501 (8%) Omicron. No significative difference was found regarding two composite adverse outcomes. There were significantly more hospitalizations for severe pneumopathy in Delta variant than WT, Alpha and Omicron respectively (63% vs 26%, 35% and 6%, p<0.001), more frequent oxygen administration (23% vs 12%, 10% and 5%, p = 0,001) and more symptomatic patients at the time of testing with Delta and WT (75% and 71%) versus Alpha and Omicron variants (55% and 66% respectively, p<0.01). Stillbirth tended to be associated with variants (p = 0.06): WT 1/231 (<1%) vs 4/126 (3%), 3/94 (3%), and 1/35 (3%) in Alpha, Delta and Omicron cases respectively. No other difference was found.
Conclusion
Although the Delta variant was associated with more severe disease in pregnant women, we found no difference regarding neonatal and obstetrical outcomes. Neonatal and obstetrical specific severity may be due to mechanisms other than maternal ventilatory and general infection.
Keywords: COVID-19, SARS-CoV-2, Pregnancy, Outcome, Variant
Introduction
The Coronavirus Disease pandemic, due to the SARS-Coronavirus-2 has been affecting our world since 2020, causing pneumonia, acute respiratory distress syndrome (ARDS), and multiorgan failure [1]. Thrombotic events have also been described [2], [3], [4]. Up to autumn of 2022, it has led to over 6 500 000 deaths in the world [5].
This RNA-messenger virus has been affected by several mutations that had an impact on virus transmissibility, disease severity, immune, therapeutic or diagnostic performances [6,7].
Since the emergence of these genetic modifications there has been questioning about their clinical implications. For example, the Alpha variant was characterized by increased virulence and transmissibility. [8] From the early July 2021, the Delta variant became the world's predominant form of SARS-CoV-2 variant and was associated with more transmission(8) and a higher risk of hospitalization or death [9,10]. Finally, the latest variant, Omicron, has been found to be associated with lesser severity [11].
Being pregnant is a risk factor for poor outcome, with greater need for oxygen administration, intensive care unit hospitalization or mechanical ventilation when compared to non-pregnant population [12,13]. There are also specific obstetrical complications of Covid-19, principally an increased rate of preterm birth, which can be spontaneous or medically induced if required by maternal illness severity. An increased risk of stillbirth directly related to SARS CoV-2 infection, but also potentially driven by placental lesions, has also been reported [14], [15], [16].
Few studies have compared clinical consequences of specific variants on obstetric and neonatal outcome. Our goal was to evaluate and compare disease severity in pregnant women and obstetrical or neonatal complications between variants of SARS-CoV-2 that have circulated in France over a two-year period (2020–2022).
Material and methods
Study design
This retrospective cohort study included all pregnant women with a confirmed SARS-CoV-2 infection (positive naso-pharyngeal RT-PCR test) from March 12, 2020 to January 31, 2022, in three tertiary maternal referral obstetric units in the Paris metropolitan area, France. The reasons for sampling were either maternal symptoms or contact case or systematic screening applied for every hospital admission in all centers regardless of the indication for admission, whether for inpatient care, labor or surgery, as recommended in France since May 2020r. Our study population comprised thus women who were or were not hospitalized.
Sample collection
Nasopharyngeal swabs were collected in Virocult viral transport media (Sigma, https://www.sigmaaldrich.com) and processed following US Center for Disease Control and prevention Guidelines [17]. All specimens were kept at +4 °C and tested within 24 h.
RT-PCR
Viral RNA was extracted from clinical samples and RealStar® SARS-CoV-2 RT-PCR Kit 1.0 (Altona Diagnostics GmbH, https://www.altona-diagnostics) targeting the E gene (specific for lineage B-betacoronavirus) and the S gene (specific for SARS-CoV-2) was used according to manufacturer's recommendations. Alternatively, Thermofisher assay (Thermo Fisher Scientific, https://www.thermofisher.com) targeting the S-gene and ORF1AB gene was used. Both assays include a heterologous amplification system as internal positive control to identify possible RT-PCR inhibition and to confirm the integrity of the reagents of the kit. A 45 thermal cycling was performed. A cycle threshold <40 was interpreted as positive for SARS-CoV-2 RNA.
Variant identification
Variant identification was either available following sequencing, and if not available, it was extrapolated from epidemiological data as already done in some studies. Seasely et al., Birol et al., and Adhikari et al., for example, used local or official resources outlining periods of variants dominance to divide variants periods and thus patients groups. [18], [19], [20], [21]
In our study, we used data regionally collected and weekly edited by Santé Publique France. Extrapolation was made if the predominant variant over the considered week accounted for more than 75% of the overall positive tests [22]. If the variant was not identified by sequencing AND the patient reported a positive test in a period with no variant exceeding 75% of tests positivity, this patient was excluded from our analysis (no extrapolation possible).
Variant screening with TaqPath assay (ThermoFisher, Waltham, Massachusetts, USA) and VirSNiP SARS-CoV-2 Spike 484K-501Y assay (TIB Molbiol, Berlin, Germany) allowed detecting common variants circulating during the period in France. Variants were further confirmed by Sanger sequencing of the S gene, and sequences analyzed on SeqScape 4 software.
Data
We collected retrospectively clinical and laboratory data for mothers and newborns that was prospectively entered in medical records.
Socio-demographic data included age, geographic origin, parity, body mass index (BMI), pre-existing medical condition and smoking status. Data collected concerning SARS-CoV-2 infection were gestational age at testing, reason for testing (symptoms or screening), symptoms at testing, hospitalization, oxygen administration, and management of severe disease if relevant.
We assessed the presence of suggestive lesions of viral pneumopathy in computed tomography chest scans when available as proven pneumopathy. Of note, not all women had a CT scan performed, even in case of severe disease.
Severity evaluation was performed using clinical criteria defined by Wu and MacGoogan and used by World Health Organization (WHO): mild disease (non-pneumonia, mild pneumonia), severe (dyspnea, polypnea, blood oxygen saturation < 93%) or critical disease (respiratory failure, septic shock, multiple organ dysfunction) [23].
Hospitalization was systematic in case of severe or critical disease or in case of concomitant obstetrical motive (i.e. non-reassuring fetal heart rate tracing). In mild pneumopathy, pregnant women would be admitted to maternity in case of relevant comorbidities or if occuring at an advanced gestational age.
Pregnancy data collected were presence of preeclampsia or not, delivery mode, and post-partum hemorrhage or not. Neonatal data collected were gestational age at birth, birth weight Z-score, arterial cord pH and Apgar scores, and neonatal intensive care unit (ICU) hospitalization and neonatal death.
Fetal macrosomia was suspected if estimated fetal weight was above the 95th centile of the national curves recommended by the French Fetal Ultrasound College. Small for gestational age was defined by a birthweight Z score less than −1.28 according to the reference curves of Salomon et al. [24].
The two primary outcomes were composite outcomes and were similar to those previously published. [25]
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The composite adverse obstetric outcome (CAOO) included preterm delivery (<37 WG), preeclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, unscheduled cesarean delivery, deep venous thrombosis (DVT), pregnancy loss at <24 WG, intrauterine fetal demise (fetal loss occurring after 15 WG), or maternal death.
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•
The composite adverse neonatal outcome (CANO) included low birthweight (<2500 g), neonatal intensive care unit (NICU) admission, or APGAR score of <7 at 5 min.
Secondary outcomes were disease severity (hospitalization for severe respiratory distress, oxygen administration, intubation, proven COVID pneumonia with characteristic CT-scan lesions), Intensive care unit (ICU) hospitalization, ARDS), neonatal acidosis, induction of labor due to maternal covid, cesarean delivery, neonatal complications, maternal complications (infection, postpartum hemorrhage), hospitalization rate, preterm labor, premature preterm rupture of membrane, and all compounds of both composite adverse obstetrical and neonatal outcomes.
Statistics
For descriptive statistics, we calculated means and standard deviations for continuous variables and percentages for categorical variables.
Comparisons between variants were conducted using Pearson's and Fisher's exact tests.
Sensitivity analysis
A sensitivity analysis was conducted by restricting the study population to women with symptoms at time of testing. Concerning delivery outcomes, because of higher missing data in this group, we conducted a sensitivity analysis with exclusion of the Omicron group.
Statistics were performed with Stata 14.2.
Ethics
The research protocol was approved by the institutional review board of the French College of Obstetricians and Gynecologists (approval no. CEROG 2021 – OBST – 0602). All data were de-identified. Written consent was not needed for this non interventional research.
Results
Descriptive data
Overall, 594 patients met the inclusion criteria during the study period. By comparison, there were nearly 11,500 deliveries in these three hospitals during this two-year period (respectively 3500, 3000 and 2500 deliveries per year).
Among them, 340/594 (57%) variants were identified by sequencing and 161/594 (27%) were extrapolated from epidemiological data. We excluded 84 patients for whom variant was unavailable nor extrapolated. We further excluded nine patients with rare variants (ie 2 “Belgian”, 4 Beta, 1 Gamma, 2 others unknown). Centers 1, 2 and 3 respectively included 197, 159, and 145 patients. Fifteen (15/501, 3%) patients were lost to follow up. SARS-CoV-2 variants identified during the period were 234/501 (47%) wild type, 127/501 (25%) Alpha, 98/501 (20%) Delta, and 42/501 (8%) Omicron.
Regarding variants, three periods can be differentiated according to the regional Ile-de France descriptive data. Alpha variant was predominant from the second week of February 2021 through the first week of June 2021. Delta variant became prevalent in the first week of July 2021, until the Omicron variant outbreak, in December 2021, which has been largely dominating until the end of the study period (March 2022).
Population description at diagnosis
Mean maternal age was 32.4 years (26.9 – 37.8 years). Most patients were multiparas (65%, N = 326/501). Comorbidities were 9/501 (2%), pre-existing diabetes, 10/501 (2%) hypertension and 35/501 (7%) asthma. Active smoking was reported in 35/501 (7%) of women and 109/501 (22%) patients were obese (BMI ≥ 30 kg/m2).
Reasons for testing for SARS-CoV-2 were missing in 4% (22/501). Patients were symptomatic in 64% (322/501) and asymptomatic diagnosed by screening in 31% (157/501) .
Cough was the most common clinical symptom of SARS-CoV-2 infection, reported in 180/501 (36%) cases, followed by 158/501 (31%) sinusitis, 113/501 (22%) fever, and 85/501 (17%) dyspnea.
Less frequently reported symptoms were low back pain, asthenia, dysphagia, chest pain, hemoptysis, pyrosis, pruritus, vertigo and heart palpitations. In 3 cases, women consulted for decreased fetal movements and were diagnosed by systematic screening.
Parity, maternal age, and BMI did not differ significantly between groups with each variant, nor did the presence of preexisting medical conditions hence there was no difference regarding risk factors for severe infection. Gestational age at testing was significantly higher for the Omicron variant (93% being over 37 WG vs only 63% in WT, p<0.001) (table 1 ).
Table 1.
Maternal characteristics at diagnosis.
| Wild type (N = 234) | Alpha (N = 127) | Delta (N = 98) | Omicron (N = 42) | p | ||
|---|---|---|---|---|---|---|
| N (%) | N (%) | N (%) | N (%) | |||
| Maternal characteristics | ||||||
| Maternal age (years) | ||||||
| < 25 | 14 (6) | 12 (9) | 6 (6) | 5 (12) | 0.77 | |
| 25–34 | 135 (58) | 72 (57) | 59 (60) | 22 (52) | ||
| ≥ 35 | 85 (36) | 43 (34) | 33 (34) | 15 (36) | ||
| Body Mass Index (Kg/m2) | ||||||
| < 25 | 103 (44) | 60 (50) | 40 (43) | 12 (32) | 0.23 | |
| 25–29 | 84 (36) | 30 (25) | 30 (32) | 13 (35) | ||
| ≥ 30 | 45 (19) | 29 (24) | 23 (25) | 12 (32) | ||
| Missing | 2 | 8 | 5 | 5 | ||
| Geographic origin | ||||||
| Europe | 64 (32) | 27 (22) | 23 (24) | 8 (19) | 0.01 | |
| Sub Saharan Africa | 56 (28) | 25 (20) | 20 (21) | 13 (32) | ||
| North Africa | 53 (26) | 57 (47) | 43 (45) | 14 (34) | ||
| Asia | 10 (5) | 10 (8) | 4 (4) | 4 (10) | ||
| America/Caribbean | 18 (9) | 3 (2) | 5 (5) | 2 (5) | ||
| Missing | 33 | 5 | 3 | 1 | ||
| Parity | ||||||
| Nulliparous | 78 (34) | 50 (39) | 26 (27) | 16 (38) | 0.28 | |
| Missing | 2 | 0 | 2 | 0 | ||
| Previous medical condition | ||||||
| Pre existing diabetes | 4 (2) | 3 (2) | 2 (2) | 0 (0) | 0.92 | |
| Missing | 1 | 3 | 0 | 0 | ||
| Hypertension | 4 (2) | 2 (2) | 3 (3) | 1 (2) | 0.75 | |
| Missing | 2 | 3 | 0 | 0 | ||
| Smoking | 19 (8) | 6 (5) | 6 (6) | 4 (9) | 0.62 | |
| Missing | 1 | 5 | 1 | 0 | ||
| Asthma | 17 (7) | 4 (3) | 11 (11) | 3 (7) | 0.14 | |
| Missing | 0 | 3 | 0 | 0 | ||
| Gestational age | ||||||
| T1 | 20 (8) | 2 (2) | 0 (0) | 0 (0) | < 0.001 | |
| T2 | 66 (28) | 29 (23) | 22 (22) | 3 (7) | ||
| T3 | 148 (63) | 95 (75) | 76 (78) | 39 (93) | ||
| Missing | 0 | 1 | 0 | 0 | ||
Pearson test or Fisher exact test as appropriate.
BMI: Body mass index.
Gestational age: first trimester up to 13 WG and 6 days (T1), 14 to 27 WG and 6 days for the second trimester (T2) and from 28 WG onfor the third trimester.
Primary outcomes
Regarding the two composite obstetrical and neonatal adverse outcomes, we found no significant difference according to the variant. Composite adverse obstetrical outcome was reported in 24% in the Delta cohort vs respectively 27%, 31% and 20% with WT, Alpha and Omicron variants respectively (p = 0.51). Likewise, the composite adverse neonatal outcome was reported with 11% vs 19%, 19% and 15% respectively (p = 0.32) (table 2 ).
Table 2.
Delivery maternal and neonatal outcomes according to SARS-CoV-2 variants.
| WILD TYPE N = 234 | ALPHA N = 127 | DELTA N = 98 | OMICRON N = 42 | P | ||
|---|---|---|---|---|---|---|
| N (%) | N (%) | N (%) | N (%) | |||
| Pregnancy outcome | <0.001 | |||||
| Medical termination of pregnancy | 0 (0) | 2 (2) | 1 (1) | 0 (0) | ||
| Stillbirth | 1 (0) | 4 (3) | 3 (3) | 1 (2) | ||
| Late miscarriage | 1 (0) | 1 (1) | 1 (1) | 1 (2) | ||
| Livebirth | 229 (98) | 119 (94) | 89 (91) | 33 (82) | ||
| Unknown | 3 | 1 | 4 | 7 | ||
| Obstetrical outcomes | ||||||
| Induced labor | 80 (35) | 36 (29) | 35 (37) | 14 (40) | 0.44 | |
| Trial of labor | 184 (79) | 108 (86) | 80 (85) | 33 (94) | 0.09 | |
| Cesarean section | 73 (31) | 32 (26) | 24 (25) | 5 (14) | 0.16 | |
| Emergency C-section | 25 (11) | 14 (11) | 10 (11) | 3 (9) | 1 | |
| Post partum hemorrhage | 34 (15) | 11 (9) | 5 (5) | 4 (11) | 0.05 | |
| Severe post partum hemorrhage | 7 (3) | 2 (2) | 0 (0) | 2 (6) | ||
| Maternal death | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||
| Composite Adverse Obstetrical Outcome (CAOO) | 63 (27) | 39 (31) | 23 (24) | 7 (20) | 0.51 | |
| Neonatal outcomes | ||||||
| Preterm birth < 37 WG | 35 (15) | 20 (16) | 11 (12) | 3 (9) | 0.60 | |
| Severe preterm < 32 WG | 14 (6) | 4 (3) | 5 (5) | 0 (0) | 0.36 | |
| Small for gestational age | 16 (7) | 9 (7) | 6 (6) | 2 (5) | 0.99 | |
| NICU hospitalization | 31 (13) | 15 (13) | 6 (7) | 3 (9) | 0.40 | |
| Neonatal acidosis | 16 (7) | 10 (9) | 5 (6) | 3 (10) | 0.85 | |
| Neonatal Apgar score < 7 at 5 min | 4 (2) | 2 (2) | 3 (3) | 0 (0) | 0.76 | |
| Neonatal death | 2 (1) | 0 (0) | 0 (0) | 0 (0) | 0.76 | |
| Composite Adverse Neonatal Outcome (CANO) | 44 (19) | 23 (19) | 10 (11) | 5 (15) | 0.32 | |
Pearson test or Fisher exact test as appropriate.
Missing data was < 5 or 10% except for the following variable: delivery outcome.
Unknown outcome at delivery: lost to follow up (information missing over delivery even after due-date achievement).
Severe postpartum hemorrhage: total blood loss > 1000 ml.
Stillbirth*: over all non-stillbirth known pregnancy outcomes pooled together.
CAOO (composite adverse obstetric outcome): preterm delivery (<37 WG), preeclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, unscheduled cesarean delivery, deep venous thrombosis (DVT), preeclampsia, pregnancy loss at <24 WG, intrauterine fetal demise (fetal loss occurring after 15 WG), or maternal death.
CANO (composite adverse neonatal outcome): low birthweight (<2500 g), neonatal intensive care unit (NICU) admission, or APGAR score of <7 at 5 min.
NICU: Neonatal intensive care unit.
Small for gestational age: Z score <−1,28.
Neonatal acidosis: umbilical arterial pH < 7.15.
Premature birth: < 37 WG.
Severe premature birth: <32WG.
COVID severity and symptoms according to variant (table 3)
Table 3.
Disease severity depending on SARS-CoV-2 variants.
| Wild type N = 234 | Alpha N = 127 | Delta N = 98 | OMICRON N = 42 | P | ||
|---|---|---|---|---|---|---|
| N (%) | N (%) | N (%) | N (%) | |||
| Reason for testing | ||||||
| Reason for testing | ||||||
| Screening | 64 (29) | 55 (45) | 24 (25) | 14 (34) | 0.01 | |
| Symptoms | 156 (71) | 67 (55) | 72 (75) | 27 (66) | ||
| Initial symptomatology | ||||||
| Fever | 48 (20) | 30 (24) | 27 (27) | 8 (19) | <0.001 | |
| Cough | 72 (40) | 44 (38) | 52 (57) | 12 (29) | 0.01 | |
| Dyspnea | 27 (15) | 25 (21) | 30 (33) | 3 (7) | 0.001 | |
| Anosmia | 39 (21) | 18 (15) | 17 (19) | 3 (7) | 0.16 | |
| Myalgia | 41 (22) | 27 (23) | 22 (25) | 9 (22) | 0.97 | |
| Sinusitis | 54 (30) | 49 (42) | 42 (47) | 13 (32) | 0.02 | |
| GI symptoms | 13 (7) | 11 (9) | 14 (16) | 5 (12) | 0.15 | |
| Maternal severity | ||||||
| COVID-related hospitalization | 57 (24) | 29 (23) | 33 (34) | 9 (22) | 0.19 | |
| Hospitalization for severe COVID (among hospitalizations) | 26 (26) | 17 (35) | 26 (63) | 1 (6) | < 0.001 | |
| Oxygen administration | 29 (12) | 13 (10) | 22 (23) | 2 (5) | 0.01 | |
| ICU hospitalization | 16 (7) | 9 (7) | 9 (9) | 0 (0) | 0.25 | |
| Intubation | 10 (4) | 2 (2) | 6 (6) | 0 (0) | 0.18 | |
| COVID pneumonia | 27 (12) | 19 (15) | 18 (19) | 2 (5) | 0.12 | |
| ARDS | 10 (4) | 4 (3) | 4 (4) | 0 (0) | 0.68 | |
| Induced delivery because of COVID-infection | 21 (9) | 10 (8) | 8 (8) | 1 (3) | 0.75 | |
Pearson test or Fisher exact test as appropriate.
Missing data was < 5 or 10% except for the following variables: Cough (14.2%), Fever (13.7%), dyspnea (13.8%), anosmy (14.6%), myalgy (14.8%), sinusitis (14.6%), gastro-intestinal symptoms (14.8%).
GI: gastro-intestinal.
ICU: Intensive care unit.
ARDS: Acute respiratory distress syndrome.
Hospitalization for severe COVID*: overall hospitalization causes happening during pregnancy.
There were significantly more hospitalizations for severe Covid with the Delta variant than WT, Alpha and Omicron respectively (63% vs 26%, 35% and 6%, p<0.001) and more frequent oxygen administration (23% vs 12%, 10% and 5%, p = 0.01). Specific comparisons between the Delta variants and other variants grouped as one were made and were highly significant (p<0.001, data not shown) concerning those two variables.
There were no significant differences for intubation, proven pneumonia, Intensive care unit (ICU) hospitalization, ARDS or COVID-induced delivery. Chest imaging was indicated according to local protocols, as mentioned above. No difference between variants was identified regarding findings when CT-scans were performed.
There were significantly more symptomatic patients at the time of testing with Delta and WT (75% and 71%) versus Alpha and Omicron variants (55% and 66% respectively, p<0.01).
Concerning initial symptoms, the Delta variant was associated with a higher frequency of symptoms for fever (27% vs 20%, 24% and 19% for WT, Alpha and Omicron, p<0.001), cough (57% vs 40%, 38% and 29%, p = 0.01), dyspnea (33% vs 15%, 21% and 7%, p = 0.001) and sinusitis (47% vs 30%, 42% and 32%, p = 0.02).
Pregnancy outcomes according to the variant (table 2)
There were 470/501 livebirths (94%). Pregnancy outcome was significantly associated with variant, (Table 2; p<0.001), with a trend toward a lower incidence of stillbirths with the WT variant (p = 0.06).
Medical termination of pregnancy was performed in 3/501 cases (1%). Two were for antenatal diagnoses of fetal anomalies unrelated to COVID-19, a case of cystic fibrosis and a case of Dandy-Walker malformation. Both were Alpha variants, asymptomatic and detected by systematic screening.
In the last case (Delta variant) the parturient was unconscious, remained in a critical state for one month, requiring extracorporeal oxygenation, and the aggravation of her condition required prompt delivery. Furthermore, fetal ultrasound at that moment showed major fetal cerebral ventricular dilatation with a high suspicion of cerebral damage due to low cardiac output syndrome from hemodynamic distress. Termination of pregnancy was decided and followed by immediate induction of labor that allowed a prompt improvement of maternal respiratory function.
Fetal loss by late miscarriage or extreme preterm birth (< 23WG) occurred in 1/234 (<1%) WT cases vs 1/127 (1%), 1/98 (1%) and 1/42 (2%) for Alpha, Delta and Omicron cases respectively. However, only one case complicated a severe Delta infection at 22.2 WG, two days after the introduction of extra corporeal oxygenation because the mother was in critical state. The other cases occurred following mild or asymptomatic SARS-CoV-2 infection.
Stillbirth occurred in 9/501 (2%) cases: only 1/234 (<1%) 1 case in the WT group vs 4/127 (3%), 3/98 (3%), and 1/42 (2%) in Alpha, Delta and Omicron cases respectively. The etiology was extensively investigated for all except for one case where autopsy was declined by parents. There was only one case in the WT cohort, concomitant with asymptomatic infection at 18.1 WG. This case was a recurrence of stillbirth, in the context of maternal preexisting diabetes mellitus. During the Alpha period, one case occurred at 37.1 WG during mildly symptomatic infection and placental pathology showed a 90% functional volume decrease, severe acute intervillous inflammation and positive SARS-CoV-2 RT-PCR. Only one case complicated a severe Alpha variant infection requiring ICU hospitalization at 22.4 WG. One case occurred at 26.1 WG in context of multiple pregnancy and a previously diagnosed fetal malformation. Other cases occurred during mild disease between 17.5 WG and 24 WG. In the Delta variant period, 3 cases of stillbirth were diagnosed between 18 WG and 23.3 WG and occurred within 7 days of mild disease evolution. The last case was diagnosed during a non-severe Delta variant infection at 23.2 WG. The patient presented to the emergency room the previous night with mild pneumopathy and fetal ultrasound at that time showed normal fetal heartbeats and movements. The patient was discharged after routine blood sampling. She was reconvened the next day due to severe biological abnormalities with disseminated intravascular coagulation (DIC) and fetal demise was then diagnosed by sonography, 5 days after symptoms began. One case was in the Omicron cohort, occurring 7 weeks following mild disease at 41.5 WG during routine post-dates screening.
The significant association between pregnancy outcome and variants persisted in sensitivity analysis restricted to symptomatic patients or after exclusion of Omicron variants (table 5 ).
Table 5.
Severity, pregnancy course and delivery issue in symptomatic patients according to SARS-CoV-2 variants.
| WILD TYPE N = 158 | ALPHA N = 84 | DELTA N = 74 | OMICRON N = 25 | p | ||
|---|---|---|---|---|---|---|
| N (%) | N (%) | N (%) | N (%) | |||
| Pregnancy outcomes | <0.001 | |||||
| Medical termination of pregnancy | 0 (0) | 0 (0) | 1 (1) | 0 (0) | ||
| Stillbirth | 0 (0) | 3 (4) | 3 (4) | 1 (4) | ||
| Late miscarriage | 1 (1) | 0 (0) | 1 (1) | 0 (0) | ||
| Live birth | 155 (98) | 80 (95) | 65 (88) | 19 (76) | ||
| Unknown | 2 | 1 | 4 | 5 | ||
| Obstetrical outcomes | ||||||
| Induced labor | 51 (33) | 27 (32) | 27 (39) | 9 (45) | 0.6 | |
| Trial of labor | 120 (76) | 70 (84) | 58 (83) | 18 (90) | 0.28 | |
| Cesarean birth | 52 (33) | 23 (28) | 20 (29) | 5 (25) | 0.83 | |
| Emergency C-section | 15 (9) | 10 (12) | 8 (11) | 3 (15) | 0.76 | |
| Post-partum hemorrhage | 24 (15) | 9 (11) | 5 (7) | 2 (10) | 0.32 | |
| Severe post partum hemorrhage | 24 (15) | 9 (11) | 5 (7) | 2 (10) | ||
| Maternal death | 0 (0) | 0 (0) | 0 (0) | 0 (0) | ||
| Composite adverse obstetrical outcome (CAOO) | 44 (28) | 26 (32) | 19 (27) | 4 (20) | 0.75 | |
| Neonatal outcomes | ||||||
| Preterm birth < 37 WG | 28 (18) | 13 (16) | 9 (13) | 1 (5) | 0.46 | |
| Preterm < 32 WG | 12 (8) | 2 (2) | 5 (7) | 0 (0) | 0.25 | |
| Small for gestational age | 10 (6) | 7 (8) | 4 (5) | 0 (0) | 0.55 | |
| NICU hospitalization | 25 (16) | 10 (12) | 6 (9) | 0 (0) | 0.19 | |
| Neonatal acidosis | 8 (5) | 8 (11) | 4 (7) | 0 (0) | 0.35 | |
| Neonatal Apgar < 7 at 5 min | 3 (12) | 2 (2) | 3 (4) | 0 (0) | 0.74 | |
| Composite adverse neonatal outcome | 33 (21) | 15 (19) | 9 (13) | 1 (5) | 0.28 | |
Pearson test or Fisher exact test as appropriate.
Missing data was < 5 or 10% except for the following variable: delivery outcome.
Unknown outcome at delivery: lost to follow up (information missing over delivery even after due-date achievement).
Severe postpartum hemorrhage: total blood loss > 1000 ml.
CAOO (composite adverse obstetric outcome): preterm delivery (<37 WG), preeclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, unscheduled cesarean delivery, deep venous thrombosis (DVT), preeclampsia, pregnancy loss at <24 WG, intrauterine fetal demise (fetal loss occurring after 15 WG), or maternal death.
CANO (composite adverse neonatal outcome): low birthweight (<2500 g), neonatal intensive care unit (NICU) admission, or APGAR score of <7 at 5 min.
NICU: Neonatal intensive care unit.
Small for gestational age: Z score <−1,28.
Neonatal acidosis: umbilical arterial pH < 7.15.
Premature birth: < 37 WG.
Severe premature birth: <32WG.
When conducting specific comparisons between stillbirths versus all non-stillbirths with known pregnancy outcomes, we found a non-significant difference (1/231 in WT vs 4/126, 3/94 and 1/35 for Alpha, Delta and Omicron variants, p = 0.06) (table 2). This trend reached significance when restricting to symptomatic patients (p = 0.04) but further analysis was not pursued to avoid over-interpretation (data not shown).
Concerning deliveries, 165/501(34%) were induced by mechanical or hormonal methods, and 134/501 (27%) were cesarean sections of which 52 emergency C-sections. No significant association was found between variants and induced labor, cesarean birth, emergency C-section nor COVID-related delivery induction. Regarding medical reasons for induction of labor, fetal monitoring abnormalities were reported as the cause in 25 cases. In one case, emergency C-section was performed at 35 WG after diagnosis of DIC complicating COVID-19 infection. Resolution was quick in postpartum.
Post-partum hemorrhage occurred in N = 54/501 (11%) cases and appeared to be more frequent in the WT group (15%) when compared with Alpha, Delta and Omicron (9%, 5%, and 11%, p = 0.05).
No maternal death nor thrombotic event was registered in our cohort.
Neonatal outcomes (table 2)
Median birthweight was 3200 g. Median Z-score was −0.183 with 33/501 (5%) neonates being small for gestational age (SGA). Neonatal complications were essentially respiratory distress and neonatal icterus. No statistics have been made upon different complications. Neonatal intensive care hospitalization occurred in 55/501 (11%) cases and 2/501 neonates died (<1%). One of the deceased newborns was born 8 days earlier by emergency C-section at 27.6WG, his mother was infected with WT strain at time of delivery and C-section had been performed for maternal severe COVID pneumonia requiring mechanical ventilation. He had received antenatal steroids and neuronal protection by Magnesium Sulfate administration.
The second child was slightly premature (36.2WG), delivered one month after the maternal COVID by cesarean section for vaginal bleeding in the context of placenta praevia and had neonatal respiratory distress preceding his death.
No differences were found between variants concerning prematurity, severe prematurity, neonatal acidosis (umbilical arterial pH <7.15), low Apgar score at birth (<7 at 5 min,) intensive care hospitalization or death or small for gestational age.
Pregnancy course according to variant (table 4)
Table 4.
Pregnancy course according to SARS-CoV-2 variants.
| Wild type N = 234 | Alpha N = 127 | Delta N = 98 | OMICRON N = 42 | P | ||
|---|---|---|---|---|---|---|
| N (%) | N (%) | N (%) | N (%) | |||
| Hospitalization during pregnancy | 97 (42) | 47 (37) | 42 (44) | 17 (42) | 0.75 | |
| Missing | 1 | 1 | 3 | 2 | ||
| Hospitalization for premature labor | 14 (14) | 3 (6) | 2 (5) | 2 (12) | 0.30 | |
| Hospitalization for PPROM | 6 (6) | 5 (10) | 1 (2) | 1 (6) | 0.51 | |
| Prenatal ultrasound diagnosis of FGR | 22 (9) | 9 (7) | 1 (1) | 2 (6) | 0.06 | |
| Pre eclampsia | 7 (3) | 1 (1) | 2 (2) | 2 (6) | 0.28 | |
| Other pregnancy complications | ||||||
| Gestational diabetes mellitus | 41 (18) | 27 (23) | 22 (24) | 3 (9) | 0.14 | |
| Prenatal ultrasound diagnosis of macrosomia | 16 (7) | 14 (11) | 9 (9) | 7 (20) | 0.08 | |
| Antenatal steroids | 44 (19) | 12 (10) | 19 (20) | 3 (8) | 0.04 | |
Pearson test or Fisher exact test as appropriate.
PPROM: Preterm premature rupture of membranes.
FGR: Fetal growth restriction, suspected if estimated fetal weight inferior to 10% of the CFEF national curves.
Macrosomia: estimated fetal weight over rating 95% of the national curves recommended by the French Fetal Ultrasound College - CFEF),.
No difference was found between variants for overall hospitalization rates (44% for Delta, vs 42%, 37% and 42% for WT, Alpha and Omicron, p = 0.75), nor for obstetrical complications such as preterm labor (equally, 5% vs 14%, 6% and 12%, p = 0.3) or premature preterm rupture of membrane (2% vs 6%, 10% and 6%, p = 0.51).
Fetal maturation with corticosteroids for any indication was administered more frequently in Wild Type and Delta variant than Alpha and Omicron (19% and 20% vs 10% and 8%, p<0.05).
SARS-CoV-2 variant was not associated with incidence of preeclampsia, gestational diabetes mellitus, or fetal macrosomia. There was a non-significant trend toward higher suspected fetal growth restriction risk in WT than Alpha, Delta and Omicron (9% vs 7%, 1% and 6%, p = 0.06).
Subgroup analysis (Table 5)
Results were similar in sensitivity analysis restricted to symptomatic patients.
Moreover, differences in postpartum hemorrhage were not significantly different in the sensitivity analysis (15% in WT vs 11%, 7% and 10% in Alpha, Delta and Omicron variant, p = 0.32).
Discussion
Main findings
Infection with the Delta variant was associated with a greater severity of COVID-19, but which did not lead to a significant difference regarding obstetrical and neonatal outcomes. Maternal severity was lowest with the Omicron variant, while there was a higher incidence of post-partum hemorrhage with the WT variant.
Results in the context of what is known
The greater severity of respiratory disease in case of the Delta variant in a pregnant population is consistent with existing literature on non-pregnant persons [8], [9], [10]. Adhikari et al. performed a multicenter cohort study including 1515 pregnant women in the USA, from May 2020 to September 2021, comparing maternal severity of the disease between the Delta variant surge from July to September with all other variants before this date. They found an increased severity for Delta variant and reported that over a quarter of pregnant patients diagnosed over one week were admitted for severe or critical illness. [18] In comparison, our hospitalization rate for the Delta variant was 63%.
Similarly, Seasely et al., in a retrospective monocenter cohort study comparing admission rates, neonatal and maternal outcomes between the pre-Delta period (March 2020 to May 2021) and the Delta period (July to August 2021), reported a higher proportion of severe or critical disease in the Delta period (36% vs 13%, aRR 2.76, 95% CI 1.73–4.40). They also found increased rates of cesarean delivery for maternal severity (71% vs 14%, aRR 4.94 95% CI 1.90–12.88), preterm birth (73% vs 32%, aRR 2.36 95% CI 1.68–3.32), and neonatal ICU admission (74% vs 44%, aRR 1.77 95% CI 1.25–2.51) [26]. More recently in France, a retrospective single-center study by Zayet et al. comparing 3 times periods (WT, Alpha and Delta) in 77 hospitalized pregnant women observed an increased risk of admission in ICU and need for oxygen support in the Alpha and mostly in the Delta variant period when compared to the WT period. [20]
To date, few studies have reported data on the Omicron period: a bicentric, binational retrospective study conducted in Turkey and United Kingdom, explored three time periods (pre-Delta, Delta and Omicron periods), and showed as previously that Delta was associated with more maternal severity. In this study, the Omicron wave was not associated with milder disease compared to the WT period [21]. A Japanese survey drawn from the national COVID-19 registry comparing respectively 111 and 119 hospitalized pregnant patients during the Delta and Omicron periods found different symptomatology and greater severity in the Delta cohort [27]. Adhikari et al. conducted a second cohort with similar design including the Omicron period and found greater severity in the Delta period and decreased severity of illness in the Omicron period, after adjustment for prior vaccination [19].
Concerning the trend toward a higher risk of stillbirth that we reported, this has been previously described for the Delta variant in a retrospective cohort study exploring the risk of stillbirth in women with COVID-19 compared to women without COVID-19. [28] The increased incidence of stillbirth had been primarily highlighted in few retrospective cohort studies without regards to variant identification, yet this study reported a higher magnitude of association during the Delta period when compared to the pre-Delta period (aRR 4.04, 95% CI 3.28–4.97 vs aRR 1.47, 95% CI 1.27–1.71). Stillbirth was also associated with maternal morbidity (ie, ICU admission aRR 2.74 95% CI 1.93–3.89) [29,30].
Fetal demise might be due to fetal hypoxia associated with maternal decreased oxygenation, although only 1/9 cases occurred during severe COVID pneumonia. Feto-placental infection is another possibility, as pathology analysis has shown placental positivity during mild maternal disease. Coagulopathy and microvascular inflammation are involved even in non-severe or mild cases of maternal Sars CoV-2 infection. In light of similar findings of stillbirths occurring during asymptomatic infection, a prospective study in French Guyana hypothesized an implication of vascular damage in the feto-placental unit [31].
Excessive local immune response and resulting placental inflammation may promote transplacental transmission or placental insufficiency possibly leading to stillbirth [32,33].
Interpretation
The lack of differences in obstetrical and neonatal outcomes despite a greater respiratory severity of the Delta variant may have several causes. Acquired immunity (past infections, vaccination) can modulate and lower virulence of emerging variants, most certainly with Delta wave. For example, according to Santé Publique France, seropositivity rate of SARS-CoV-2 infection grew from 60.8% in May 2021 to 83.3% in October 2021, during Delta wave, when it was measured at a level of 20.6% in the beginning of Alpha wave (2021, February) [34]. As evidence accumulated regarding safety and efficacy of vaccination of pregnant women [35], COVID mRNA vaccines were approval in France in December 2020, pregnant women were declared high-priority for vaccination in April 2021, and the recommendation was extended to pregnancy first trimester in July 2021. Our study covers the whole epidemic from January 2020 to March 2022. While pregnant women are still excluded from therapeutic and vaccine trials, safety data are now reassuring regarding SARS-CoV-2 vaccination during pregnancy, regarding adverse events [36], perinatal complications [37,38] or fetal malformations [39,40]. In addition to reducing the risk of severe disease, vaccination against SARS-CoV-2 can also reduce the risk of prematurity and stillbirths in the general population [41]. Although vaccination rate is unknown in our study population, it is most certainly greater in the Delta period rather than Alpha period and may have weakened variant impact in our study.
We can also hypothesize that growing progress in the management of SARS-CoV-2-infected pregnant women during this crisis allowed the health care providers to both maintain maternal health, without any maternal death in our series, and prolong their pregnancy thus minimizing cases of induced prematurity and its own neonatal complications. The introduction of corticosteroids in hospitalized patients has led to improvements in maternal and fetal outcomes. [[42], [43], [44]] Although at the beginning of the pandemic C-section was often performed at diagnosis, we are now able to treat maternal hypoxemia thus avoiding fetal hypoxic lesions, which may have contributed to avoiding adverse obstetrical outcomes with the Delta variant. [45] Another hypothesis is that obstetrical and neonatal outcomes may be independent from the severity of maternal lung disease, except for induced preterm birth and rare cases of fetal demise during extra corporeal oxygenation. COVID-19 has been shown to induce complex inflammatory phenomenon, with endothelial inflammation leading to microvascular complications [33,46]. COVID-19 might thus be considered as vascularitis, with specific complications when involving the placenta.
When compared to the outcomes in the French general pregnant population of the National Perinatal Study (Enquête Nationale Périnatale, ENP, 2016), our study highlights the obstetrical and neonatal impact of COVID regardless of the variant. Even with a study population slightly more comorbid than national benchmarks (diabetes, hypertension and overweight prevalence 2%, 2% and 50% in our study vs < 1%, <1% and 20% in the general population), there was a higher rate of prenatal hospitalization (40% vs 18%), need for fetal lung maturation (16% vs 5.9%), C-section (27% vs 20%, labor induction (27% vs 20% of deliveries), and preterm birth (14% vs 7.5%) [47].
Strengths and limitations
The main strength of our study is that it is the largest cohort to date comparing obstetrical and neonatal outcomes between variants among pregnant women to our knowledge. It is also one of the largest in literature regarding maternal severity between variants after Adhikari's and Zayet's studies [19,20]. Secondly, its multicenter design provides a better external validity than monocentric studies. Moreover, our study covers the pandemic until its main last surge. All SARS CoV-2 infections were diagnosed by biological testing. Although viral typing required recurrent sampling and was not systematically performed, variant identification by sequencing was available for more than 50% of the subjects in our study, and epidemiological extrapolation based on local data was conducted for the remainder, giving more accuracy to the identification than previous studies based only on the date of diagnosis. [18], [19], [20], [21]. Inclusion of all patients with a positive RT-PCR test, and not restricting the study to the hospitalized people, also gave us a less biased vision of this disease than studies conducted only in hospitalized populations. This also contributes to give our study a better external validity.
There are also limitations to this study. RT-PCR tests have imperfect sensitivity as well as the possibility of prolonged positivity. Thus, we cannot eliminate the possibility that we over-diagnosed this disease during pregnancy (in the few cases diagnosed during the first trimester) and cannot assure that we were accurate regarding the trimester of infection. However, false positives concern only weakly positive PCR with CT>33 in asymptomatic patients and rarely exceeds 4 weeks. Variant distribution differed between centers, with smaller proportions of Delta variants in center 3 and no Omicron in center 2. The retrospective design of this study may be responsible for some bias, with a significant number of missing outcomes in the Omicron cohort restricting our interpretation. Furthermore, COVID testing practices changed over time, leading to a likely selection bias. During the first pandemic wave (Wild Type variant), because RT-PCR reagents were rare, only symptomatic patients were tested. Systematic screening at admission, in particular for delivery, was adopted homogeneously thereafter. Thus, the higher incidence of symptoms in the Delta cohort occurred despite a higher rate of screening, which reinforces our findings.
Omicron variant surge being apparently less severe, it can explain that patients were more likely to have been lost to follow-up, but these results must still be interpreted with caution. Especially for this variant, lack of power may have prevented us from finding significant associations.
Lack of data concerning vaccination in our pregnant population is also a limit of this study. This data was not available in medical files during this retrospective analysis. Further stratification upon vaccine status would be required.
Implication for practice
The higher severity that we report for the Delta variant concerning respiratory disease may guide clinical teams toward specific surveillance and follow-up in these cases. The fact that it is not related to obstetrical and neonatal complications can help us deliver reassuring information to the patients and insist on the importance of vaccination in this high-risk population.
Implication for research
In the event of the emergence of new variants, which is to be expected, their potential association with adverse outcomes will be crucial to evaluate. Further characterization of endothelial and placental phenomena associated to COVID-19 should be performed by biological and pathological investigations. Pre-clinical research may be interesting to explore how neonatal and obstetrical specific severity may be independent from maternal ventilatory and general infection.
Conclusion
During pregnancy, although maternal respiratory morbidity was greater with the Delta variant as in the general population, SARS-CoV-2 variants did not appear to be associated with significant differences in obstetrical and neonatal outcomes, except for a possible association with the risk of stillbirth in non-wild-type variants. Further studies investigating the endothelial pathology should be conducted in order to understand the fetal and placental effects of COVID-19.
Declaration of Competing Interest
There are no conflicts of interest.
Acknowledgements
none
References
- 1.Wu Z., McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the chinese center for disease control and prevention. JAMA. 2020;323(13):1239. doi: 10.1001/jama.2020.2648. Apr 7. [DOI] [PubMed] [Google Scholar]
- 2.Connors J.M., Levy J.H. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020 4;135(23):2033-2040. [DOI] [PMC free article] [PubMed]
- 3.Schulman S. Coronavirus disease 2019, prothrombotic factors, and venous thromboembolism. Semin Thromb Hemost. 2020;46(07):772–776. doi: 10.1055/s-0040-1710337. Oct. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Miesbach W., Makris M. COVID-19: coagulopathy, risk of thrombosis, and the rationale for anticoagulation. Clin Appl Thromb. 2020;26 doi: 10.1177/1076029620938149. Jan 1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.WHO Coronavirus (COVID-19) Dashboard [Internet]. [cited 2022 Sep 22]. Available from: https://covid19.who.int
- 6.Perez-Gomez R. The development of SARS-CoV-2 variants: the gene makes the disease. J Dev Biol. 2021;9(4):58. doi: 10.3390/jdb9040058. Dec 15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Choi J.Y., Smith D.M. SARS-CoV-2 variants of concern. Yonsei Med J. 2021;62(11):961. doi: 10.3349/ymj.2021.62.11.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Lin L., Liu Y., Tang X., He D. The disease severity and clinical outcomes of the SARS-CoV-2 variants of concern. Front Public Health. 2021;9 doi: 10.3389/fpubh.2021.775224. Nov 30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Sheikh A., McMenamin J., Taylor B., Robertson C. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. The Lancet. 2021;397(10293):2461–2462. doi: 10.1016/S0140-6736(21)01358-1. Jun. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Ong S.W.X., Chiew C.J., Ang L.W., Mak T.M., Cui L., Toh M.P.H.S., et al. Clinical and virological features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern: a retrospective cohort study comparing B.1.1.7 (Alpha), B.1.351 (Beta), and B.1.617.2 (Delta) Clin Infect Dis. 2021:ciab721. doi: 10.1093/cid/ciab721. Aug 23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Maslo C., Friedland R., Toubkin M., Laubscher A., Akaloo T., Kama B. Characteristics and outcomes of hospitalized patients in south africa during the COVID-19 omicron wave compared with previous waves. JAMA. 2022;327(6):583–584. doi: 10.1001/jama.2021.24868. Feb 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Badr D.A., Mattern J., Carlin A., Cordier A.G., Maillart E., El Hachem L., et al. Are clinical outcomes worse for pregnant women at ≥20 weeks’ gestation infected with coronavirus disease 2019? A multicenter case-control study with propensity score matching. Am J Obstet Gynecol. 2020;223(5):764–768. doi: 10.1016/j.ajog.2020.07.045. Nov. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Allotey J., Fernandez S., Bonet M., Stallings E., Yap M., Kew T., et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2020:m3320. doi: 10.1136/bmj.m3320. Sep 1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Vivanti A.J., Vauloup-Fellous C., Prevot S., Zupan V., Suffee C., Do Cao J., et al. Transplacental transmission of SARS-CoV-2 infection. Nat Commun. 2020;11(1):3572. doi: 10.1038/s41467-020-17436-6. Dec. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Khalil A., Kalafat E., Benlioglu C., O'Brien P., Morris E., Draycott T., et al. SARS-CoV-2 infection in pregnancy: a systematic review and meta-analysis of clinical features and pregnancy outcomes. EClin Med. 2020;25 doi: 10.1016/j.eclinm.2020.100446. Aug. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Di Mascio D., Khalil A., Saccone G., Rizzo G., Buca D., Liberati M., et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2020;2(2) doi: 10.1016/j.ajogmf.2020.100107. May. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Interim guidelines for clinical specimens for COVID-19 | CDC [Internet]. [cited 2021 Jan 4]. Available from: https://www.cdc.gov/coronavirus/2019-ncov/lab/guidelines-clinical-specimens.html
- 18.Adhikari E.H., SoRelle J.A., McIntire D.D., Spong C.Y. Increasing severity of COVID-19 in pregnancy with Delta (B.1.617.2) variant surge. Am J Obstet Gynecol. 2022;226(1):149–151. doi: 10.1016/j.ajog.2021.09.008. Jan. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Adhikari E.H., MacDonald L., SoRelle J.A., Morse J., Pruszynski J., Spong C.Y. COVID-19 cases and disease severity in pregnancy and neonatal positivity associated with delta (b.1.617.2) and omicron (b.1.1.529) variant predominance. JAMA. 2022;327(15):1500–1502. doi: 10.1001/jama.2022.4356. Apr 19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zayet S., Gendrin V., Gay C., Selles P., Klopfenstein T. Increased COVID-19 severity among pregnant patients infected with SARS-CoV-2 delta variant, France. Emerg Infect Dis. 2022;28(5):1048–1050. doi: 10.3201/eid2805.212080. May. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Birol Ilter P., Prasad S., Mutlu M.A., Tekin A.B., O'Brien P., von Dadelszen P., et al. Maternal and perinatal outcomes of SARS-CoV-2 infection in unvaccinated pregnancies during Delta and Omicron waves. Ultrasound Obstet Gynecol. 2022 doi: 10.1002/uog.24916. Apr 20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Coronavirus : chiffres clés et évolution de la COVID-19 en France et dans le Monde [Internet]. [cited 2022 Aug 27]. Available from: https://www.santepubliquefrance.fr/dossiers/coronavirus-covid-19/coronavirus-chiffres-cles-et-evolution-de-la-covid-19-en-france-et-dans-le-monde
- 23.Clinical management of COVID-19 patients: living guideline [Internet]. [cited 2022 Sep 22]. Available from: https://app.magicapp.org/#/guideline/j1WBYn
- 24.Estimation of fetal weight: reference range at 20–36 weeks’ gestation and comparison with actual birth-weight reference range - Salomon - 2007 - Ultrasound in Obstetrics & Gynecology - Wiley Online Library [Internet]. [cited 2022 Aug 27]. Available from: https://obgyn.onlinelibrary.wiley.com/doi/10.1002/uog.4019 [DOI] [PubMed]
- 25.Badr D.A., Picone O., Bevilacqua E., Carlin A., Meli F., Sibiude J., et al. Severe acute respiratory syndrome coronavirus 2 and pregnancy outcomes according to gestational age at time of infection. Emerg Infect Dis. 2021;27(10):2535–2543. doi: 10.3201/eid2710.211394. Oct. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Seasely A.R., Blanchard C.T., Arora N., Battarbee A.N., Casey B.M., Dionne-Odom J., et al. Maternal and perinatal outcomes associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta (B.1.617.2) variant. Obstet Gynecol. 2021;138(6):842–844. doi: 10.1097/AOG.0000000000004607. Dec. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Shoji K., Tsuzuki S., Akiyama T., Matsunaga N., Asai Y., Suzuki S., et al. Comparison of clinical characteristics of COVID-19 in pregnant women between the Delta and Omicron variants of concern predominant periods. J Infect Chemother Off J Jpn Soc Chemother. 2022 doi: 10.1016/j.jiac.2022.09.005. Sep 11S1341-321X(22)00264-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.DeSisto C.L., Wallace B., Simeone R.M., Polen K., Ko J.Y., Meaney-Delman D., et al. Risk for stillbirth among women with and without COVID-19 at delivery hospitalization — United States, March 2020–September 2021. Morb Mortal Wkly Rep. 2021;70(47):1640–1645. doi: 10.15585/mmwr.mm7047e1. Nov 26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Khalil A., von Dadelszen P., Draycott T., Ugwumadu A., O'Brien P., Magee L. Change in the incidence of stillbirth and preterm delivery during the COVID-19 pandemic. JAMA. 2020 Jul 10 doi: 10.1001/jama.2020.12746. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.KC A., Gurung R., Kinney M.V., Sunny A.K., Moinuddin M., Basnet O., et al. Effect of the COVID-19 pandemic response on intrapartum care, stillbirth, and neonatal mortality outcomes in Nepal: a prospective observational study. Lancet Glob Health. 2020;8(10):e1273–e1281. doi: 10.1016/S2214-109X(20)30345-4. Oct. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Hcini N., Maamri F., Picone O., Carod J.F., Lambert V., Mathieu M., et al. Maternal, fetal and neonatal outcomes of large series of SARS-CoV-2 positive pregnancies in peripartum period: a single-center prospective comparative study. Eur J Obstet Gynecol Reprod Biol. 2021;257:11–18. doi: 10.1016/j.ejogrb.2020.11.068. Feb. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Vivanti A.J., Vauloup-Fellous C., Escourrou G., Rosenblatt J., Jouannic J.M., Laurent-Bellue A., et al. Factors associated with SARS-CoV-2 transplacental transmission. Am J Obstet Gynecol. 2022;227(3):541–543. doi: 10.1016/j.ajog.2022.05.015. Sepe11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Lu-Culligan A., Chavan A.R., Vijayakumar P., Irshaid L., Courchaine E.M., Milano K.M., et al. Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface. Med. 2021;2(5):591–610. doi: 10.1016/j.medj.2021.04.016. Maye10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Géodes - Santé publique France - Indicateurs : cartes, données et graphiques [Internet]. [cited 2022 Sep 12]. Available from: https://geodes.santepubliquefrance.fr/#bbox=112134,6339468,333003,236195&c=indicator&i=seroprev_sarscov_reg.seroprevalence_sarscov2&s=2021-42&selcodgeo=11&t=a01&view=map1
- 35.Harder T., Külper-Schiek W., Reda S., Treskova-Schwarzbach M., Koch J., Vygen-Bonnet S., et al. Effectiveness of COVID-19 vaccines against SARS-CoV-2 infection with the Delta (B.1.617.2) variant: second interim results of a living systematic review and meta-analysis, 1 January to 25 August 2021. Eurosurveillance [Internet] 2021;26(41) doi: 10.2807/1560-7917.ES.2021.26.41.2100920. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.41.2100920 Oct 14 [cited 2022 Mar 19]Available from: [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Fu W., Sivajohan B., McClymont E., Albert A., Elwood C., Ogilvie G., et al. Systematic review of the safety, immunogenicity, and effectiveness of COVID-19 vaccines in pregnant and lactating individuals and their infants. Int J Gynaecol Obstet. 2022;156:406–417. doi: 10.1002/ijgo.14008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Fell D.B., Dhinsa T., Alton G.D., Török E., Dimanlig-Cruz S., Regan A.K., et al. Association of COVID-19 vaccination in pregnancy with adverse peripartum outcomes. JAMA. 2022;327:1478–1487. doi: 10.1001/jama.2022.4255. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Magnus M.C., Örtqvist A.K., Dahlqwist E., Ljung R., Skår F., Oakley L., et al. Association of SARS-CoV-2 vaccination during pregnancy with pregnancy outcomes. JAMA. 2022;327:1469–1477. doi: 10.1001/jama.2022.3271. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Goldshtein I., Steinberg D.M., Kuint J., Chodick G., Segal Y., Shapiro Ben David S., et al. Association of BNT162b2 COVID-19 vaccination during pregnancy with neonatal and early infant outcomes. JAMA Pediatr. 2022;176:470–477. doi: 10.1001/jamapediatrics.2022.0001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Ruderman R.S., Mormol J., Trawick E., Perry M.F., Allen E.C., Millan D., et al. Association of COVID-19 vaccination during early pregnancy with risk of congenital fetal anomalies. JAMA Pediatr. 2022;176:717–719. doi: 10.1001/jamapediatrics.2022.0164. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Hui L., Marzan M.B., Rolnik D.L., Potenza S., Pritchard N., Said J.M., Palmer K.R., Whitehead C.L., Sheehan P.M., Ford J., Mol B.W., Walker S.P. Reductions in stillbirths and preterm birth inCOVID-19 vaccinated women: a multi-center cohort study of vaccination uptake and perinatal outcomes. Am J Obstet Gynecol. 2022 doi: 10.1016/j.ajog.2022.10.040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.RECOVERY Collaborative Group. Horby P., Lim W.S., Emberson J.R., Mafham M., Bell J.L., et al. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med. 2021;384(8):693–704. doi: 10.1056/NEJMoa2021436. Feb 25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Saad A.F., Chappell L., Saade G.R., Pacheco L.D. Corticosteroids in the management of pregnant patients with coronavirus disease (COVID-19) Obstet Gynecol. 2020;136(4):823–826. doi: 10.1097/AOG.0000000000004103. Oct. [DOI] [PubMed] [Google Scholar]
- 44.Magala Ssekandi A., Sserwanja Q., Olal E., Kawuki J., Bashir Adam M. Corticosteroids use in pregnant women with COVID-19: recommendations from available evidence. J Multidiscip Healthc. 2021;14:659–663. doi: 10.2147/JMDH.S301255. Mar 16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Huntley B.J.F., Huntley E.S., Di Mascio D., Chen T., Berghella V., Chauhan S.P. Rates of maternal and perinatal mortality and vertical transmission in pregnancies complicated by severe acute respiratory syndrome coronavirus 2 (SARS-Co-V-2) infection: a systematic review. Obstet Gynecol. 2020;136(2):303–312. doi: 10.1097/AOG.0000000000004010. Aug. [DOI] [PubMed] [Google Scholar]
- 46.Fajgenbaum D.C., June C.H. Cytokine Storm. N Engl J Med . 2020 Dec 3;383(23):2255-2273. [DOI] [PMC free article] [PubMed]
- 47.EPOPé; 2022. [:fr]Les enquêtes nationales périnatales[:en]french national perinatal surveys[:] [Internet]http://www.xn–epop-inserm-ebb.fr/grandes-enquetes/enquetes-nationales-perinatales [citedMay 28]. Available from: [Google Scholar]