SARS-CoV-2 infection elucidates unique features of pregnancy-specific immunity (preprint)

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8+ T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.

Maternal and perinatal outcomes associated with SARS-CoV-2 infection during pregnancy, Florida, 2020–2021: A retrospective cohort study (preprint)

Objective: To estimate risk of SARS-CoV-2 infection in pregnancy and assess adverse maternal and perinatal outcomes. Design: A population-based, retrospective cohort. Setting: Florida, USA. Population: All pregnancies with a live birth or fetal death from March 1, 2020 to April 30, 2021. Methods: COVID-19 case reports were matched to vital registries. Modified Poisson and multinomial logistic regression models were used to derive relative risk estimates. Main Outcome Measures: Infection in pregnancy, preterm birth, maternal or neonatal admission to and intensive care unit (ICU), fetal death. Results: Of 234,492 women with a live birth or fetal death during the study period, 12,976 (5.5%) were identified with COVID-19 during pregnancy. Risk factors for COVID-19 in pregnancy included Hispanic ethnicity (relative risk [RR]=1.89), Black race (RR=1.34), being unmarried (RR=1.04), and being overweight or obese pre-pregnancy (RR=1.08-1.32). COVID-19 during pregnancy was associated with preterm birth (RR=1.31), Cesarean delivery (RR=1.04), and neonatal (RR=1.17) and maternal (RR=3.10) ICU admission, but no association was found with increased risk of perinatal (RR=0.72) or fetal death (RR=0.86). Women infected during any trimester showed increased risk of preterm birth compared to women without COVID-19. Thirteen maternal deaths were identified among COVID-19 cases; of those who died, 11 were obese. The death rate was 20.53 per 10,000 among obese and 1.22 per 10,000 among non-obese gravida with COVID-19 during pregnancy (RR=16.88, P=0.001). Conclusions: Obesity is a risk factor for SARS-CoV-2 infection in pregnancy and for more severe COVID-19 illness among pregnant women. SARS-CoV-2 infection is associated with preterm birth.

Late miscarriage and stillbirth in asymptomatic and symptomatic hospitalised pregnant women in Belgium during the first and second waves of COVID-19: a prospective nationwide population-based study.

BACKGROUND: Stillbirth has been recognized as a possible complication of a SARS-CoV-2 infection during pregnancy, probably due to destructive placental lesions (SARS-CoV-2 placentitis). The aim of this work is to analyse stillbirth and late miscarriage cases in unvaccinated pregnant women infected with SARS-CoV-2 during the first two waves (wild-type period) in Belgium. METHODS: Stillbirths and late miscarriages in our prospective observational nationwide registry of SARS-CoV-2 infected pregnant women (n = 982) were classified by three authors using a modified WHO-UMC classification system for standardized case causality assessment. RESULTS: Our cohort included 982 hospitalised pregnant women infected with SARS-CoV-2, with 23 fetal demises (10 late miscarriages from 12 to 22 weeks of gestational age and 13 stillbirths). The stillbirth rate was 9.5‰ for singleton pregnancies and 83.3‰ for multiple pregnancies, which seems higher than for the background population (respectively 5.6‰ and 13.8‰). The agreement between assessors about the causal relationship with SARS-Cov-2 infection was fair (global weighted kappa value of 0.66). Among these demises, 17.4% (4/23) were "certainly" attributable to SARS-CoV-2 infection, 13.0% (3/23) "probably" and 30.4% (7/23) "possibly". Better agreement in the rating was noticed when pathological examination of the placenta and identification of the virus were available, underlining the importance of a thorough investigation in case of intra-uterine fetal demise. CONCLUSIONS: SARS-CoV-2 causality assessment of late miscarriage and stillbirth cases in our Belgian nationwide case series has shown that half of the fetal losses could be attributable to SARS-CoV-2. We must consider in future epidemic emergencies to rigorously investigate cases of intra-uterine fetal demise and to store placental tissue and other material for future analyses.

Fetal death as an outcome of acute respiratory distress in pregnancy, during the COVID-19 pandemic: a population-based cohort study in Bahia, Brazil.

BACKGROUND: Fetal loss is one of the most serious adverse outcomes of pregnancy. Since the onset of the COVID-19 pandemic, Brazil has recorded an unprecedented number of hospitalizations of pregnant women due to acute respiratory distress (ARD), thereby, we aimed to assess the risk of fetal deaths associated to ARD during pregnancy in Bahia state, Brazil, in the context of the COVID-19 pandemic. METHODS: This is an observational population-based retrospective cohort study, developed with women at or after 20 weeks of pregnancy, residents in Bahia, Brazil. Women who had acute respiratory distress (ARD) in pregnancy during the COVID-19 pandemic (Jan 2020 to Jun 2021) were considered 'exposed'. Women who did not have ARD in pregnancy, and whose pregnancy occurred before the onset of the COVID-19 pandemic (Jan 2019 to Dec 2019) were considered 'non-exposed'. The main outcome was fetal death. We linked administrative data (under mandatory registration) on live births, fetal deaths, and acute respiratory syndrome, using a probabilistic linkage method, and analyzed them with multivariable logistic regression models. RESULTS: 200,979 pregnant women participated in this study, 765 exposed and 200,214 unexposed. We found four times higher chance of fetal death in women with ARD during pregnancy, of all etiologies (adjusted odds ratio [aOR] 4.06 confidence interval [CI] 95% 2.66; 6.21), and due to SARS-CoV-2 (aOR 4.45 CI 95% 2.41; 8.20). The risk of fetal death increased more when ARD in pregnancy was accompanied by vaginal delivery (aOR 7.06 CI 95% 4.21; 11.83), or admission to Intensive Care Unit (aOR 8.79 CI 95% 4.96; 15.58), or use of invasive mechanical ventilation (aOR 21.22 CI 95% 9.93; 45.36). CONCLUSION: Our findings can contribute to expanding the understanding of health professionals and managers about the harmful effects of SARS-CoV-2 on maternal-fetal health and alerts the need to prioritize pregnant women in preventive actions against SARS-CoV-2 and other respiratory viruses. It also suggests that pregnant women, infected with SARS-CoV-2, need to be monitored to prevent complications of ARD, including a careful assessment of the risks and benefits of early delivery to prevent fetal death.

Predictive factors for severe placental damage in pregnant women with SARS-CoV-2 infection.

INTRODUCTION: SARS-Cov-2 infection during pregnancy can lead to severe placental lesions characterized by massive perivillous fibrin deposition, histiocytic intervillositis and trophoblast necrosis. Diffuse placental damage of this kind is rare, but can sometimes lead to obstetric complications, such as intrauterine fetal death (IUFD). The objectives of this study were to identify possible predictors of severe placental lesions. METHODS: We retrospectively studied 96 placentas from SARS-Cov-2 positive pregnant women who gave birth between March 2020 and March 2022. Cases with and without severe placental lesions were compared in terms of clinical and laboratory findings. RESULTS: Twelve of the 96 patients had severe placental lesions. There was no significant association with diabetes, obesity or severe clinical maternal disease. In contrast, presence of severe placental lesions was significantly associated with neonatal intensive care, cesarean section, prematurity, IUFD, intrauterine growth restriction (IUGR), gestational age, maternal hypofibrinogenemia and thrombocytopenia. No cases of severe placental lesions were observed in vaccinated patients or in those with the Omicron variant. DISCUSSION: In these patients, severe placental lesions due to SARS-Cov-2 were significantly associated with the presence of coagulation abnormalities (hypofibrinogenemia and thrombocytopenia), IUGR and gestational age. These results support laboratory and ultrasound monitoring of these parameters in pregnant women with SARS-Cov-2 infection, especially during the second trimester, to predict potential negative fetal outcomes.

The impact of COVID-19 vaccinations on stillbirth rates among pregnant women in the Metro-Detroit area.

Infection by COVID-19 increases maternal morbidity and mortality prompting both the American College of Obstetrics and Gynecology and the Society of Maternal Fetal Medicine to strongly recommend vaccination during pregnancy. Limited data exist assessing the risk of intrauterine fetal death (IUFD) associated with COVID vaccination during pregnancy. This was a retrospective chart review at a large multisite hospital system in Metro Detroit which reviewed data from 13,368 pregnancies. We compared IUFD rates between vaccinated and unvaccinated patients. The rate of stillbirths among unvaccinated women (0.75%) was not statistically different from those who were vaccinated (0.60%). Individuals with government insurance were less likely to be vaccinated and more likely to have IUFD in comparison to patients with private insurance. The rate of stillbirths among Black women was significantly higher than among White women at a rate of 1.1% compared to 0.53% (p=0.008) with no difference in stillbirth rates among vaccinated vs unvaccinated racial distribution. Lastly, it is worth noting that the overall vaccination rate at our healthcare system in pregnancy was very poor (0.26%). In conclusion, this is a large population of highly diverse patients which indicates that COVID-19 vaccination does not lead to IUFD. We plan to use this data to help drive an educational vaccination campaign to try to increase our COVID-19 vaccination rate in our pregnant patients. Systemic racism and social determinants of health have played a large factor in COVID-19 outcomes, and our data highlights that this is the case for IUFD in Black women. Improvements must be made to identify barriers for these women to allow for better pregnancy outcomes. We acknowledge that individuals with government insurance may also have other barriers to healthcare or face healthcare inequity which leaves room for improvement on getting these individuals vaccinated and getting the resources they need to have better pregnancy outcomes.

Home telemonitoring versus hospital care in complicated pregnancies in the Netherlands: a randomised, controlled non-inferiority trial (HoTeL).

BACKGROUND: Women with complicated pregnancies often require hospital admission. Telemonitoring at home is a promising alternative that fulfils a worldwide need in obstetric health care. Moreover, the COVID-19 pandemic has accelerated the transformation to digital care. The aim of this study was to evaluate safety, clinical effectiveness, patient satisfaction, and costs of home telemonitoring against hospital care in complicated pregnancies. METHODS: We did a multicentre, randomised, controlled, non-inferiority trial in six hospitals (four general teaching hospitals and two university hospitals) in the Netherlands (located in Utrecht, Amsterdam, and Groningen). Women aged 18 years and older with singleton pregnancies (>26 weeks gestation) requiring monitoring for pre-eclampsia, fetal growth restriction, fetal anomaly, preterm rupture of membranes, reduced fetal movements, or history of fetal death were included in the study. Participants were randomly assigned to either hospital admission or telemonitoring in (1:1), stratified for the six diagnoses for inclusion and the six centres of inclusion, using block randomisation (block sizes of four and six). When assigned to telemonitoring, participants went home with devices for cardiotocography and blood pressure measurements and had daily contact with their care providers after digitally sending their home measurements. When assigned to hospital admission, participants received care as usual on the ward until the postpartum period. The primary outcome was a composite of adverse perinatal outcomes assessed after delivery, including mortality; an Apgar score below 7 after 5 min or an umbilical arterial pH at birth below 7·05; maternal morbidity; admission of the newborn to the neonatal intensive care unit; and rate of caesarean section. The primary outcome was assessed in the intention-to-treat population. The non-inferiority margin for the primary outcome was a 10% absolute increase in composite primary endpoint based on baseline 20% incidence. The study was registered at the Dutch Trial Registration (NL5888) and is now closed to new participants. FINDINGS: From Dec 1, 2016, to Nov 30, 2019, 201 pregnant women were randomly assigned to an intervention procedure. 101 women were allocated to the telemonitoring group and 100 to the hospital admission group. One participant in the telemonitoring group withdrew consent before the intervention was initiated, and 100 participants were analysed for the primary outcome. In the hospital admission group, four participants did not receive the allocated intervention because they did not accept hospital admission. 100 participants in each group were analysed for the primary outcome according to the intention-to-treat principal. No participants were lost to follow-up. The primary outcome occurred in 31 (31%) of 100 participants in the telemonitoring group and in 40 (40%) of 100 participants in the hospital admission group. Adjusted for centre of inclusion, diagnosis, and nulliparity, the risk difference in primary outcome between both groups was 10·3% (95% CI -22·4 to 2·2) lower in the telemonitoring group, below the pre-defined non-inferiority margin of 10% absolute increase. A similar distribution for each of the individual components within the composite primary outcome was seen between groups. Five serious adverse events were reported: one neonatal death in the hospital admission group, in addition to one intra-uterine fetal death, two neonatal deaths, and one case of eclampsia in the telemonitoring group, all unrelated to the study. INTERPRETATION: This non-inferiority trial shows the first evidence that telemonitoring might be as safe as hospital admission for monitoring complicated pregnancies. FUNDING: Stichting Achmea Gezondheidszorg and ICT Healthcare Technology Solutions.

Cytomegalovirus reactivation in a SARS-CoV-2 infected woman experiencing fetal demise in the first trimester with fetal trisomy 21: A case report.

Cytomegalovirus (CMV) is the most common cause of congenital viral infections. Women seropositive for CMV prior to pregnancy can develop a non-primary CMV infection. Here, we present a case of first trimester pregnancy loss during active SARS-CoV-2 infection. There was no evidence of SARS-CoV-2 RNA in placenta and fetal tissue, but there was presence of congenital cytomegalovirus infection by nested PCR. To the best of our knowledge, this is the first report demonstrating association of early congenital CMV infection due to reactivation and fetal demise in a SARS-CoV-2 positive woman with fetal trisomy 21.

Maternal and Perinatal Outcomes Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection During Pregnancy, Florida, 2020-2021: A Retrospective Cohort Study.

BACKGROUND: The objective was to estimate risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy and assess adverse maternal and perinatal outcomes. METHODS: We used a population-based, retrospective cohort of all pregnancies with a live birth or fetal death in Florida from 1 March 2020 to 30 April 2021. Coronavirus disease 2019 (COVID-19) case reports were matched to vital registries. Outcomes assessed were risk of infection in pregnancy, preterm birth, maternal or neonatal admission to an intensive care unit (ICU), perinatal or fetal death, and maternal death. Modified Poisson and multinomial logistic regression models were used to derive relative risk estimates. RESULTS: Of 234 492 women with a live birth or fetal death during the study period, 12 976 (5.5%) were identified with COVID-19 during pregnancy. Risk factors for COVID-19 in pregnancy included Hispanic ethnicity (relative risk [RR] = 1.89), Black race (RR = 1.34), being unmarried (RR = 1.04), and being overweight or obese pre-pregnancy (RR = 1.08-1.32). COVID-19 during pregnancy was associated with preterm birth (RR = 1.31), Cesarean delivery (RR = 1.04), and neonatal (RR = 1.17) and maternal (RR = 3.10) ICU admission; no association was found with increased risk of perinatal (RR = 0.72) or fetal death (RR = 0.86). Women infected during any trimester showed increased risk of preterm birth. Fourteen maternal deaths were identified among COVID-19 cases; of those who died, 12 were obese. The death rate per 10 000 was 22.09 among obese and 1.22 among non-obese gravida with COVID-19 during pregnancy (RR = 18.99, P = .001). CONCLUSIONS: Obesity is a risk factor for SARS-CoV-2 infection in pregnancy and for more severe COVID-19 illness among pregnant women. SARS-CoV-2 infection is associated with preterm birth.

The influence of COVID-19 pandemic on intrauterine fetal demise and possible vertical transmission of SARS-CoV-2.

OBJECTIVE: The impact of COVID-19 on intrauterine fetal demise (IUFD) and vertical transmission of the SARS-CoV-2 from the mother to the fetus are crucial issues of the COVID-19 pandemic. In the current study, we aimed to detect the pandemic's influence on the IUFD and evaluate the vertical transmission of the SARS-CoV-2 through analysis of placental tissues collected from PCR positive women with IUFD above 20 weeks of gestation. MATERIALS AND METHODS: The pregnant women above 20 weeks of gestation and had a fetus intrauterine demised during pandemic were included in the study. The pregnant women screened for COVID-19. Vertical transmission searched from placental tissues of COVID-19 positive women by RT-PCR tests for the presence of SARS-CoV-2 RNA. The number of IUFD before the pandemic and during the pandemic compared to assess the influence of the COVID-19 pandemic on the IUFD ratio. RESULTS: Among 138 pregnant women with IUFD, 100 of them could screen for COVID-19 status. RT-PCR test results of 6 of the screened pregnant women were positive for SARS-CoV-2. Placental tissues of these six women were analyzed, and one test result was positive for SARS-CoV-2 RNA. The IUFD ratio was significantly increased during the pandemic. CONCLUSION: It is clear that COVID-19 increases the IUFD ratio. Previous data for vertical transmission of SARS-CoV-2 during the second trimester is limited. We present the third case of literature that has positive placental results for SARS-CoV-2 RNA in the second trimester of pregnancy.

Congenital Infection of Severe Acute Respiratory Syndrome Coronavirus 2 With Intrauterine Fetal Death: A Clinicopathological Study With Molecular Analysis.

BACKGROUND: Observations of vertical transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from mother to fetus have recently been described in the literature. However, the consequences of such transmission, whether fetal or neonatal, are poorly understood. METHODS: From a case of in utero fetal death at 24+2 weeks of gestation that occurred 7 days after the diagnosis of symptomatic SARS-CoV-2 infection in the mother, we isolated the incriminating virus by immunochemistry and molecular techniques in several fetal tissues, with a variant analysis of the SARS-CoV-2 genome. RESULTS: The fetal demise could be explained by the presence of placental histological lesions, such as histiocytic intervillositis and trophoblastic necrosis, in addition to fetal tissue damage. We observed mild fetal growth retardation and visceral damage to the liver, causing hepatocellular damage and hemosiderosis. To the best of our knowledge, this is the first report in the literature of fetal demise secondary to maternal-fetal transmission of SARSCoV- 2 with a congenital infection and a pathological description of placental and fetal tissue damage. CONCLUSIONS: SARS-CoV-2 was identified in both specimens using 3 independent techniques (immunochemistry, real-time quantitative polymerase chain reaction, and realtime digital polymerase chain reaction). Furthermore, the incriminating variant has been identified.

COVID-19 and Burkholderia cepacia co-infection in pregnancy associated with fetal demise: a case report.

Since the global pandemic of the 2019 coronavirus disease (COVID-19), few studies have reported on the relevance of bacteria co-infection on outcome of COVID-19 patients. Little is known about the clinical presentation among pregnant women, mother-to-child transmission, and fetal outcomes. This report shows a 24-year-old nulliparous woman who was 32 weeks pregnant and was admitted to the University Hospital, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi Ghana with symptoms of fever (40.3°C), cough and breathlessness of two weeks duration. Her nasopharyngeal sample tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and blood culture isolated Burkholderia cepacia. She was given medications but went into pre-term labour and delivered a stillborn baby. This rare case of COVID-19 and Burkholderia cepacia co-infection emphasizes the need for a thorough assessment and appropriate treatment of patients presenting with fever and respiratory symptoms in order to mitigate poor outcome.

Intrauterine fetal death during COVID-19 pregnancy: Typical fetal heart rate changes, coagulopathy, and placentitis.

Although various perinatal outcomes in coronavirus disease 2019 (COVID-19) pregnancies have been reported, the fetal and neonatal consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain unclear. Several reports of miscarriages and stillbirths have been recorded, but vertical transmission by SARS-CoV-2 is considered very rare, and the cause remains unknown. We report a case of a 22-year-old uncomplicated Japanese woman infected with SARS-CoV-2 during the second trimester, resulting in intrauterine fetal death due to placental insufficiency associated with COVID-19 placentitis. This report emphasizes the importance of longitudinal assessment of fetal well-being by fetal heart rate monitoring and early detection of maternal coagulation dysfunction representing SARS-CoV-2 inflammation to manage COVID-19 in pregnancy.

Chronic Inflammatory Placental Disorders Associated With Recurrent Adverse Pregnancy Outcome.

Chronic inflammatory placental disorders are a group of rare but devastating gestational syndromes associated with adverse pregnancy outcome. This review focuses on three related conditions: villitis of unknown etiology (VUE), chronic histiocytic intervillositis (CHI) and massive perivillous fibrin deposition (MPFD). The hallmark of these disorders is infiltration of the placental architecture by maternal immune cells and disruption of the intervillous space, where gas exchange between the mother and fetus occurs. Currently, they can only be detected through histopathological examination of the placenta after a pregnancy has ended. All three are associated with a significant risk of recurrence in subsequent pregnancies. Villitis of unknown etiology is characterised by a destructive infiltrate of maternal CD8+ T lymphocytes invading into the chorionic villi, combined with activation of fetal villous macrophages. The diagnosis can only be made when an infectious aetiology has been excluded. VUE becomes more common as pregnancy progresses and is frequently seen with normal pregnancy outcome. However, severe early-onset villitis is usually associated with fetal growth restriction and recurrent pregnancy loss. Chronic histiocytic intervillositis is characterised by excessive accumulation of maternal CD68+ histiocytes in the intervillous space. It is associated with a wide spectrum of adverse pregnancy outcomes including high rates of first-trimester miscarriage, severe fetal growth restriction and late intrauterine fetal death. Intervillous histiocytes can also accumulate due to infection, including SARS-CoV-2, although this infection-induced intervillositis does not appear to recur. As with VUE, the diagnosis of CHI requires exclusion of an infectious cause. Women with recurrent CHI and their families are predisposed to autoimmune diseases, suggesting CHI may have an alloimmune pathology. This observation has driven attempts to prevent CHI with a wide range of maternal immunosuppression. Massive perivillous fibrin deposition is diagnosed when >25% of the intervillous space is occupied by fibrin, and is associated with fetal growth restriction and late intrauterine fetal death. Although not an inflammatory disorder per se, MPFD is frequently seen in association with both VUE and CHI. This review summarises current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology and potential prophylaxis against recurrence in these three chronic inflammatory placental syndromes.

Pregnancy outcomes in Italy during COVID-19 pandemic: a population-based cohort study. (preprint)

Objective: To compare the estimates of preterm birth (PTB; 22-36 weeks gestational age, GA) and stillbirth rates during COVID-19 pandemic in Italy with those recorded in the three previous years. Design. A population-based cohort study of liveborn and stillborn infants was conducted using data from Regional Health Systems and comparing the pandemic period (March 1st, 2020-March 31st, 2021, N= 362,129) to an historical period (January 2017- February 2020, N=1,117,172). The cohort covered 84.3% of the births in Italy. Methods. Logistic regressions were run in each Region and meta-analyses were performed centrally. We used an interrupted time series regression analysis to study the trend of preterm births from 2017 to 2021. Main Outcome Measures. The primary outcomes were PTB and stillbirths. Secondary outcomes were late PTB (32-36 weeks’ GA), very PTB (<32 weeks’ GA), and extreme PTB (<28 weeks’ GA), overall and stratified into singleton and multiples. Results. The pandemic period compared with the historical one was associated with a reduced risk for PTB (Odds Ratio: 0.90; 95% Confidence Interval, CI: 0.87, 0.93), late PTB (0.91; 0.87, 0.94), very PTB (0.87; 0.84, 0.91), and extreme PTB (0.88; 0.82, 0.94). In multiples, point estimates were not very different, but had wider CIs. No association was found for stillbirths (1.01; 0.90, 1.13). A linear decreasing trend in PTB rate was present in the historical period, with a further reduction after the lockdown. Conclusions We demonstrated a decrease in PTB rate after the introduction of COVID-19 restriction measures, without an increase in stillbirths.

Stillbirth due to SARS-CoV-2 placentitis without evidence of intrauterine transmission to fetus: association with maternal risk factors.

OBJECTIVES: To describe the placental pathology, fetal autopsy findings and clinical characteristics of pregnancies that resulted in stillbirth owing to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) placentitis, and to identify potential risk factors. METHODS: This was a prospective multicenter study of non-vaccinated pregnant women affected by coronavirus disease 2019 (COVID-19) in Greece from April 2020 to August 2021. A total of 165 placentas were examined histologically and six cases of stillbirth associated with SARS-CoV-2 placentitis were retrieved. Complete fetal autopsy was performed in three of these cases. Gross, histopathological, immunohistochemical, molecular and electron microscopy examinations were carried out in the stillbirth placentas and fetal organs. The histological findings of cases with SARS-CoV-2 placentitis were compared with those in 159 cases with maternal COVID-19 which resulted in a live birth. Regression analysis was used to identify predisposing risk factors for SARS-CoV-2 placentitis. RESULTS: The placentas of all six stillborn cases showed severe and extensive histological changes typical of SARS-CoV-2 placentitis, characterized by a combination of marked intervillositis with a mixed inflammatory infiltrate and massive perivillous fibrinoid deposition with trophoblast damage, associated with intensely positive immunostaining for SARS-CoV-2 spike protein, the presence of virions on electron microscopy and positive reverse-transcription polymerase chain reaction test of placental tissues. The histological lesions obliterated over 75% of the maternal intervillous space, accounting for intrauterine fetal death. Similar histological lesions affecting less than 25% of the placenta were observed in seven liveborn neonates, while the remaining 152 placentas of COVID-19-affected pregnancies with a live birth did not show these findings. Complete fetal autopsy showed evidence of an asphyctic mode of death without evidence of viral transmission to the fetus. The mothers had mild clinical symptoms or were asymptomatic, and the interval between maternal COVID-19 diagnosis and fetal death ranged from 3 to 15 days. Statistically significant predisposing factors for SARS-CoV-2 placentitis included thrombophilia and prenatally diagnosed fetal growth restriction (FGR). Multiple sclerosis was seen in one case. CONCLUSIONS: SARS-CoV-2 placentitis occurred uncommonly in COVID-19-affected pregnancies of non-vaccinated mothers and, when extensive, caused fetal demise, with no evidence of transplacental fetal infection. Thrombophilia and prenatally detected FGR emerged as independent predisposing factors for the potentially lethal SARS-CoV-2 placentitis. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal thrombocytopenia precedes fetal death associated with COVID-19.

Acute coagulopathy, specific placental pathology, and an increased risk of fetal death have been reported in pregnant women with COVID-19; however, the association between coagulopathy and fetal death remains unknown. We report two pregnant women with COVID-19 who showed acute coagulopathy prior to fetal death. Both pregnant women presented with thrombocytopenia after testing positive for SARS-CoV-2 (days 5 and 7). They had mild symptoms, but coagulopathy progressed, and their fetuses died on day 9 at 27 and 22 weeks of pregnancy. Their coagulability improved after delivery. Placental histology in both cases showed intervillous infiltration of histiocytes, necrosis of trophoblasts, and intervillous fibrin deposition, which were consistent with previously reported pathological findings related to SARS-CoV-2. In the management of pregnant women with COVID-19, thrombocytopenia may be a predictive marker of fetal death following coagulopathy and placental inflammatory changes due to SARS-CoV-2 infection.