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Extensive placental damage in some unvaccinated women causes stillbirths

In unvaccinated mothers with COVID-19, the placentas had a severe abnormality called SARS-CoV-2 placentitis, which killed the placental tissue and resulted in stillbirths or early neonatal deaths, found an international analysis of 68 cases.

During the pandemic, several studies have shown unvaccinated pregnant women run a higher risk of delivering stillborn babies when infected with COVID-19.  Although other viral infections have also been linked to stillbirths, this particular research suggests the coronavirus that causes COVID-19 may have a completely different impact on a developing foetus.

The researched concluded the COVID-19 infection destroyed the placenta, depriving the foetus of oxygen, according to the report published in Archives of Pathology & Laboratory Medicine. The researchers determined that the virus reaches the placenta and causes it to fail by passing through the motherʼs bloodstream, a process known as viremia.

“Our study identified placental insufficiency as the root cause for stillbirths in women with COVID-19 during pregnancy,” said Dr David Schwartz, an Atlanta-based pathologist who led the study. “Among the 68 cases, an average of 77% of the placenta had been destroyed and rendered useless for supporting critical foetal needs, resulting in stillbirth or early neonatal death.”

In all of the studied cases, researchers found the placentas from infected mothers had a severe abnormality called SARS-CoV-2 placentitis, Schwartz said. Researchers found viral-induced lesions in the placenta had blocked maternal and foetal blood flow and oxygen, killing placental tissues and causing “irreparable damage”.

In almost all of the cases, they also found that increased fibrin – a key protein involved with blood clotting – was so “massive” it blocked blood and oxygen flow to the placenta. All of the placentas also showed dead cells made up the major cell barrier between the mother and foetus, known as trophoblast necrosis.

Another placental complication that may have been caused by the virus was a rare accumulation of inflammatory cells called chronic histiocytic intervillositis, which was seen in 97% of cases studied by the international research team.

While the study may provide some insight into mechanisms of COVID-19 in a pregnant woman, it’s probably not the whole story, said Dr Catherine Spong, professor and chair of the department of obstetrics and gynaecology at the University of Texas Southwestern Medical Center.

The study did not include when the mothers had contracted COVID-19, the state, or size of the placenta before infection, or enough pre-existing conditions that could affect the vital organ. The study also did not compare stillbirth placentas with those of women who’d had live births and were also infected.

“It’s a piece of the puzzle,” she said of the study’s findings, “but it is just the beginning to really understand (COVID’s) impact on pregnancy.”

Researchers assumed many of the infections were from the Delta variant, not Omicron. While plenty of viral destruction was found in the placenta, post-mortem examinations showed a small number of foetuses had the virus in their internal organs. Despite this finding, researchers determined “there were no autopsy outcomes relating to the (virus) that would have accounted for their deaths.”

Other viral, bacterial and parasitic infections that occur in pregnancy and cause stillbirth travel through the placenta and damage the foetal organs, Schwartz said, but SARS-CoV-2 appears to stop at the placenta and do the most damage there.

“The placental destruction is so severe that whether or not the foetus becomes infected might be irrelevant,” he said.

While COVID-19 infection is associated with an increased risk of stillbirths, itʼs uncommon. A November study released by the Centers for Disease Control and Prevention found stillbirths were documented in about 1,26% of deliveries with COVID-19 from March 2020 to September 2021.

However, health experts say being unvaccinated is not worth the risk. Studies have shown the COVID-19 vaccine is safe and effective for both the expectant parent and baby. Health experts say antibodies from the vaccine can pass through to the foetus and protect the baby from COVID-19 after birth.

An observational study of more than 24,000 newborns in Israel found “no evident differences” between newborns of women who received the Pfizer-BioNTech vaccine during pregnancy and those of women who were not vaccinated. Study authors said the findings contributed to current evidence establishing the safety of prenatal vaccine exposure, according to the report published in JAMA Pediatrics.

“Women should get vaccinated in pregnancy, as well as (before) pregnancy,” Spong said. “COVID can cause severe disease so vaccination is very important.”

Study details 1
Placental Tissue Destruction and Insufficiency from COVID-19 Causes Stillbirth and Neonatal Death from Hypoxic-Ischemic Injury: A Study of 68 Cases with SARS-CoV-2 Placentitis from 12 Countries

David A. Schwartz, Elyzabeth Avvad-Portari, Pavel Babál, Marcella Baldewijns, Marie Blomberg, Amine Bouachba, Jessica Camacho, Sophie Collardeau-Frachon, Arthur Colson, Isabelle Dehaene, Joan Carles Ferreres, Brendan Fitzgerald, Marta Garrido-Pontnou, Hazem Gerges, Beata Hargitai, A. Cecilia Helguera-Repetto, Sandra Holmström, Claudine Liliane Irles, Åsa Leijonhfvud, Sasha Libbrecht,
Tamás Marton, Noel McEntagart, James T. Molina, Raffaella Morotti, Alfons Nadal, Alexandra Navarro, Maria Nelander, Angelica Oviedo, Andre Ricardo Oyamada Otani, Nikos Papadogiannakis.

Published in Archives of Pathology & Laboratory Medicine on 10 February 2022.

Abstract

Context
Perinatal death is an increasingly important problem as the COVID-19 pandemic continues, but the mechanism of death has been unclear.

Objective
To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for SARS-CoV-2.

Design
Case-based retrospective clinico-pathological analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19.

Results
All 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis, the three findings constituting SARS-CoV-2 placentitis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25/68) and chronic villitis (32%; 22/68). The majority (19, 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs.

Conclusions
The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

Study details 2
Association of BNT162b2 COVID-19 Vaccination During Pregnancy With Neonatal and Early Infant Outcomes

Inbal Goldshtein, David Steinberg, Jacob Kuint, et al.

Published in JAMA Pediatrics on 10 February 2022

Key Points
Question Is prenatal exposure to maternal BNT162b2 messenger RNA COVID-19 vaccine associated with adverse outcomes at birth or early childhood?
Findings In a population-based study including 24 288 singleton live births, the risks of preterm birth and small birth weight were similar between newborns prenatally exposed and unexposed to maternal vaccination.
Meaning Maternal BNT162b2 vaccination in pregnancy was not associated with detrimental outcomes to the offspring.

Abstract

Importance
Pregnant women were excluded from the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer-BioNTech) preauthorisation trial. Therefore, observational data on vaccine safety for prenatally exposed newborns are critical to inform recommendations on maternal immunisation.
Objective
To examine whether BNT162b2 mRNA vaccination during pregnancy is associated with adverse neonatal and early infant outcomes among the newborns.
Design, Setting, and Participants
Population-based cohort study comprising all singleton live births in March through September 2021, within a large state-mandated health care organisation in Israel, followed up until 31 October 2021.

Exposure
Maternal BNT162b2 mRNA vaccination during pregnancy.
Main Outcomes and Measures
Risk ratios (RR) of preterm birth, small birth weight for gestational age (SGA), congenital malformations, all-cause hospitalisations, and infant death. Stabilised inverse probability weighting was used to adjust for maternal age, timing of conception, parity, socioeconomic status, population subgroup, and maternal influenza immunisation status.

Results
The cohort included 24 288 eligible newborns (49% female, 96% born at ≥37 weeks’ gestation), of whom 16 697 were exposed (n = 2134 and n = 9364 in the first and second trimesters, respectively) to maternal vaccination in utero. Median (IQR) follow-up after birth was 126 days (76-179) among exposed and 152 days (88-209) among unexposed newborns. No substantial differences were observed in preterm birth rates between exposed and unexposed newborns (RR = 0.95; 95% CI, 0.83-1.10) or SGA (RR = 0.97; 95% CI, 0.87-1.08). No significant differences were observed in the incidence of all-cause neonatal hospitalisations (RR = 0.99; 95% CI, 0.88-1.12), postneonatal hospitalisations after birth (RR = 0.95; 95% CI, 0.84-1.07), congenital anomalies (RR = 0.69; 95% CI, 0.44-1.04), or infant mortality over the study period (RR = 0.84; 95% CI, 0.43-1.72).

Conclusions and Relevance
This large population-based study found no evident differences between newborns of women who received BNT162b2 mRNA vaccination during pregnancy, vs those of women who were not vaccinated, and contributes to current evidence in establishing the safety of prenatal vaccine exposure to the newborns. Interpretation of study findings is limited by the observational design.

 

USA Today article – How does COVID-19 cause stillbirths in some unvaccinated pregnant people? Study identifies 'a piece of the puzzle.' (Open access)

 

APLM article – Placental Tissue Destruction and Insufficiency from COVID-19 Causes Stillbirth and Neonatal Death from Hypoxic-Ischemic Injury: A Study of 68 Cases with SARS-CoV-2 Placentitis from 12 Countries (Open access)

 

JAMA Pediatrics article – Association of BNT162b2 COVID-19 Vaccination During Pregnancy With Neonatal and Early Infant Outcomes (Open access)

 

See more from MedicalBrief archives:

 

Maternal COVID infection increases preterm/low birth/stillbirth rate in unvaccinated women

 

COVID vaccination not linked to premature birth or unusually small babies – CDC study

 

COVID increases pregnancy and birth complications — French hospital study

 

Delta variant increases COVID-19 risks for pregnant women

 

Pfizer/Moderna vaccine side effects in breastfeeding women and infants

 

Effectiveness of Pfizer vaccine in pregnancy — Clalit Health Services study

 

 

 

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