3816 babies died after mothers vaccinated - Vaers

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Thu, Jun 23 2022, 3:33 am

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3,816 Babies Died After Their Mothers Were Vaccinated – Report
June 8, 2022 • by Maria Ziminsky and Linnea Wahl

Unborn Babies Are More At Risk From Covid Vaccines Than Any Other Vaccine.
In a shocking new finding, according to VAERS – the U.S. Vaccine Adverse Event Reporting System – 57% of all the vaccinations that resulted in a baby or fetus dying in the past 25 years occurred when pregnant women started receiving COVID-19 vaccines.

The 3,816 babies who died after their mothers were vaccinated between December 2020 and March 2022 are likely only a fraction of the actual number of adverse events such as spontaneous abortions and fetal deaths.

Risks to Babies of Vaccinated Mothers as Reported in VAERS
Team 5: Maria Ziminsky and Linnea Wahl
6/7/22
If you are pregnant, your baby is more likely to die at or before birth if you receive a COVID-19 vaccine than if you receive measles, mumps, flu, tetanus, or any other vaccine. This and other alarming facts about risks to babies of vaccinated mothers comes from the U.S. government’s own Vaccine Adverse Event Reporting System (VAERS).

According to VAERS, between 1998 (the earliest VAERS reporting date) and May 2022, the total number of pregnant women who were vaccinated for all diseases and then lost their babies was 6,695. These babies died in spontaneous abortions and fetal disorders such as cardiac arrest and cystic hygroma (a tumor that forms on a newborn’s neck). But just in the past couple years, 3,816 babies died after their mothers received a COVID-19 vaccine manufactured by Moderna, Pfizer/BioNTech, or Janssen (Table 1). These women were vaccinated between December 2020 and March 2022. That means 57% of all the vaccinations that resulted in a baby or fetus dying in the past 25 years or so occurred when pregnant women started receiving COVID-19 vaccines.

Also according to VAERS, we know that very soon—within the first 10 days—after these mothers were vaccinated against COVID-19, 1,559 of their babies or fetuses died. The remaining 2,257 babies died from day 10 on. Of the pregnant women who had spontaneous abortions or their babies died of other fetal disorders, 20% lost their babies on the same day the mothers were vaccinated, and 21% lost their babies in the following 9 days (Table 2). Could it be a coincidence that a COVID-19-vaccinated woman loses her baby, and 41% of the time the baby dies within 10 days of the mother’s vaccination?

In spite of this unusual “coincidence,” many pregnant women go ahead with COVID-19 vaccination as recommended by the Centers for Disease Control. Does VAERS suggest which vaccine is safest for an unborn baby? Indeed, for women vaccinated between December 2020 and March 2022, VAERS reports that of the 3,816 pregnant women whose babies died after COVID-19 vaccination, 2,819 women—nearly 74%—received the Pfizer/BioNTech vaccine (Table 1). About 21% received Moderna’s vaccine and less than 5% received Janssen’s vaccine. Babies’ deaths were roughly equal after the mothers’ first and second shots. These figures are rough; they would be more accurate if we knew how many pregnant women were vaccinated with each of the three vaccines. Still as we have reported before, the Pfizer/BioNTech vaccine appears to be putting unborn babies at increased risk of death.

These are alarming figures, and they are even more so when we understand what VAERS data represent. The U.S. government’s guide to VAERS states that “‘Underreporting’ is one of the main limitations of passive surveillance systems, including VAERS. The term, underreporting refers to the fact that VAERS receives reports for only a small fraction of actual adverse events.” So we must keep in mind the 3,816 babies who died after their mothers were vaccinated between December 2020 and March 2022 are probably only a fraction of the actual number of adverse events such as spontaneous abortions and fetal deaths.

There are other limitations to data gathered in VAERS. The total count of unborn babies who died after their mothers were vaccinated (6,695) varies depending on the data selection criteria, such as symptoms, vaccine manufacturer, and vaccine products (Fig. 1). In addition, VAERS has data integrity issues; for example, some time intervals have no data associated with them, the system doesn’t collect information on how old a fetus was at death (how far along the woman’s pregnancy was), and followup health records are not available (from the VAERS website: “amended [followup] data are not available to the public”), making it difficult to verify cause and effect. Usefulness of the VAERS data also suffers because VAERS does not tell us the total number of doses given to pregnant women for each vaccine.

Nonetheless, the VAERS data suggest, as do Pfizer sources, grave danger to pregnant women and their babies from COVID-19 vaccines. When will the U.S. Centers for Disease Control and the Food and Drug Administration acknowledge and act on these alarming safety signals?

Table 1. VAERS Fetal Deaths After COVID-19 Vaccination
COVID-19 vaccine manufacturer VAERS symptom resulting in fetal death Number of cases % of total cases
Moderna Fetal exposure during pregnancy 32
Spontaneous abortion 693
Fetal death 73
Fetal disorder 18
Fetal cardiac disorder 4
Fetal distress syndrome 1
Subtotal 821 21.5%
Pfizer/BioNTech Fetal exposure during pregnancy 89
Spontaneous abortion 2418
Fetal death 236
Fetal cystic hygroma 9
Fetal cardiac arrest 20
Fetal disorder 16
Fetal cardiac disorder 15
Fetal distress syndrome 15
Fetal damage 1
Subtotal 2819 73.9%
Janssen Fetal exposure during pregnancy 43
Spontaneous abortion 115
Fetal death 11
Fetal cystic hygroma 1
Fetal cardiac arrest 2
Fetal disorder 1
Fetal cardiac disorder 2
Fetal distress syndrome 1
Subtotal 176 4.6%
Total cases 3816

Table 2. VAERS Days After Mother’s COVID-19 Vaccination of Reported Fetal Death

VAERS symptom resulting in fetal death Day 0 Day 1—9 Day 10—14 Day 15—30 Day 31—60 Day 61—120 > 121 Days Not known Total cases
Fetal exposure during pregnancy 64 7 4 8 7 2 6 66 164
Spontaneous abortion 601 707 233 455 396 218 112 504 3226
Fetal death 71 70 25 44 30 20 14 46 320
Fetal cystic hygroma 2 1 1 1 1 2 0 2 10
Fetal cardiac arrest 10 4 0 1 1 0 0 6 22
Fetal disorder 3 5 4 1 5 8 5 4 35
Fetal cardiac disorder 3 4 1 2 1 2 3 5 21
Fetal distress syndrome 3 4 0 0 1 3 2 4 17
Fetal damage 0 0 0 0 1 0 0 0 1
Total cases 757 802 268 512 443 255 142 637 3816
% of total cases 20% 21% 7% 13% 12% 7% 4% 17%

[b]

amother

Periwinkle ↓

Thu, Jun 23 2022, 5:13 am

COVID-19 starkly increases pregnancy complications, including stillbirths, among the unvaccinated, Scottish study shows
Separate study finds timing of infection during pregnancy predicts prematurity

Two studies released yesterday delivered dire news about the dangers of COVID-19 to unvaccinated pregnant women and their babies. Perhaps the most disturbing data came from a first-of-its-kind analysis that tracked the tens of thousands of pregnancies in Scotland since vaccination against SARS-CoV-2 became available. It found that unvaccinated, coronavirus-infected women were far more likely than the general pregnant population to have a stillborn infant or one that dies in the first month of life. Among the infected women in the study, every one of the perinatal deaths occurred in the pregnancy of someone who was unvaccinated.

The unvaccinated mothers themselves were also more endangered: Nearly every pregnant person with a SARS-CoV-2 infection who required critical care was unvaccinated. Unvaccinated women also had a far higher rate of hospitalization than their vaccinated counterparts in the study of nearly 88,000 pregnant women.

Yet the study found that in October 2021, months after COVID-19 vaccines became widely available, fewer than one-third of pregnant Scots delivering babies had been fully vaccinated. By contrast, more than 77% of adult women of childbearing age in the general Scottish population were, highlighting a disturbing vaccine hesitancy among the pregnant that is mirrored in many places around the world. “This should shake us up and really be a call to action,” says Yalda Afshar, a high-risk obstetrician at Ronald Reagan UCLA Medical Center who was not involved with the study. “Vaccination is the clear action item to improve health for pregnant people and their babies.”

Using data from an ongoing population study called COVID-19 In Pregnancy in Scotland, researchers at the University of Edinburgh and colleagues elsewhere tracked pregnant women in Scotland between December 2020, when COVID-19 vaccines first became available, and October 2021. The scientists report in Nature Medicine that although the risk of poor outcomes was generally elevated for unvaccinated pregnant women who got COVID-19 at any point in their babies’ gestation, it was starkly worse if that happened late in pregnancy.

In the 620 mothers who contracted COVID-19 in the 28 days before they delivered their babies, the study recorded 14 fetal or infant deaths, 10 of them stillbirths. All of the deaths occurred in unvaccinated pregnancies. That amounts to 22.5 deaths per 1000 births, compared with 5.6 perinatal deaths per 1000 births among all Scottish pregnancies from March 2020 through October 2021.

A mother’s COVID-19 infection also increased the risk of premature births, confirming earlier work. Scots infected at any point in pregnancy were likelier than the general pregnant population, surveyed from March 2020 through October 2021, to have premature babies: 10.2% versus 8%. Those who delivered their babies within 28 days of being infected saw the rate jump to 16.6%.

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The pregnancy study also highlighted risks to the unvaccinated women’s own health: Ninety-eight percent of critical care admissions that occurred during the study and 91% of hospitalizations were in unvaccinated women. “My colleagues should not be doing ward rounds in critical care units,” says Sarah Stock, a maternal and fetal medicine specialist at the University of Edinburgh who is the first author of the paper. A pregnant woman critically ill with COVID-19 “should be an anomaly [and] not a daily occurrence.”

Worldwide, many pregnant women have been reluctant to get COVID-19 vaccines, with some citing the decision by vaccine companies to exclude pregnant women from initial trials and others swayed by misinformation, such as claims that the shots themselves cause perinatal deaths. To address safety concerns about taking the vaccine during pregnancy, the scientists also examined birth outcomes in more than 18,000 people who were vaccinated during their pregnancies. They found no indication that vaccination during pregnancy, including receiving a shot within 28 days of giving birth, increased preterm births or deaths of infants in the weeks before and after birth. The rates of these events matched those in the general pregnant population.

That finding “is really important” says Sarah Mulkey, a fetal and neonatal neurologist who studies congenital viral infections at Children’s National Hospital who was not involved in the research. “Other [recent] studies too … showed there is not an increased risk of preterm delivery or stillbirth or other abnormal pregnancy outcomes because of vaccination.”

A U.S. study published in The Lancet Digital Health yesterday underscored the risk of even mild COVID-19 infection to pregnancy outcomes. In the retrospective study, researchers at the Institute for Systems Biology (ISB) in Seattle examined electronic health records from more than 18,000 pregnant women at hospitals and clinics in five U.S. states who were tested for COVID-19 between March 2020 and February 2021.

They matched 882 unvaccinated women who had a confirmed infection and mild to moderate symptoms with other pregnant women who tested negative. After controlling for factors likely to influence birth outcomes, like maternal age, race, ethnicity, and smoking status, the study found infected women were significantly more likely to have preterm births or stillborn infants.

The scientists also found that time of the infection was a very strong predictor of how close to term a woman would carry her pregnancy: The earlier in pregnancy a mother was infected with SARS-CoV-2, the earlier a baby was likely to be born. Perhaps surprisingly, the severity of COVID-19 symptoms didn’t worsen the outcome. “Even mild COVID-19 infections put pregnant people at increased risk for preterm delivery,” says Samantha Piekos, a systems biologist at ISB who is the paper’s first author.

Because of the increased risk to women who were even mildly ill early in pregnancy, Mulkey says another major take-home message “is that it’s very important for obstetricians, maternal and fetal medicine doctors, and pediatricians to be asking a mother if she had infection early in pregnancy. When she does, that requires additional monitoring of the pregnancy and of the baby.”

Correction, 18 January, 12:30 p.m.: This article originally reported that birth outcomes of nearly 26,000 people who were vaccinated while pregnant were analyzed. In fact, the scientists studied birth outcomes in more than 18,000 women who received nearly 26,000 vaccinations while pregnant.
doi: 10.1126/science.ada0212
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amother

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Thu, Jun 23 2022, 5:15 am

J Glob Health. 2020 Dec; 10(2): 020378.
Published online 2020 Nov 23. doi: 10.7189/jogh.10.020378
PMCID: PMC7690649
PMID: 33274057
Risk of congenital birth defects during COVID-19 pandemic: Draw attention to the physicians and policymakers
Md Sakirul Islam Khan,1 Hiroaki Nabeka,1 Sheikh Mohammad Fazle Akbar,2 Mamun Al Mahtab,3 Tetsuya Shimokawa,1 Farzana Islam,1 and Seiji Matsuda1
Author information Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
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Photo: COVID-19 in pregnant women and possible risk to develop congenital birth defects.

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents a global public health emergency with considerable morbidity and mortality. Since its first description in late 2019, SARS-CoV-2 has already spread worldwide. As of mid-May 2020, over 4.5 million people have already been infected globally by SARS-CoV-2 with more than 300 000 deaths [1]. It is almost clear that SARS-CoV-2 has infected both male and female in almost same proportions. Although every human is susceptible to the infection, data show that relatively more female has been infected at their active reproductive age (between 20 years to 49 years) [2]. Therefore, it is likely that numerous females during their pregnancy have already been infected with SARS-CoV-2. As the world is in the middle of a pandemic, the majority efforts have been attributed to innovation of anti-COVID therapy for management of patients and development of prophylactic vaccines for SARS-CoV-2 so that transmission cycle of the virus can be contained. However, little has been explored about SARS-CoV-2 infection and the implications of anti-COVID-19 drugs on pregnancy.

Members of the coronavirus family are known to be responsible for severe complications during pregnancy, such as miscarriage, fetal growth restriction and congenital anomalies [3]. Only few studies to date have reported, relatively higher rates of adverse birth outcomes in women affected by SARS-CoV-2 at late pregnancy [3]. Considering the possible adverse effects of SARS-CoV-2 infection in early pregnancy, the American Society of Reproductive Medicine as well as other similar professional organizations recommend individuals with confirmed or presumed COVID-19 patients should avoid pregnancy or not to have fertility treatments during outbreak of COVID-19. However, this seems to be unrealistic as most of the scientific information will not reach the huge population of developing and resource-constrained countries. On the other hand, there is potential chance of increased conception due to stay home and other approaches such as lockdown situation in many countries as people have been confined to their houses. These realities indicate that the medical community should have a clear conception about the implications of SARS-CoV-2, COVID-19 and the anti-COVID drugs on early pregnancy when some intractable neurological complications develop. In this perspective, we would intend to provide an outline of the role of SARS-CoV-2, COVID-19 and the role of antiviral drugs (using for containment of COVID-19) on neural tube defects (NTDs), one of the severe congenital malformations develop in early pregnancy, to draw attention of physicians and policymakers to this formidable challenge.

Published literatures have indicated that viral illness during early pregnancy and several antiviral drugs are associated with an increased risk for neurodevelopmental congenital anomalies of newborn [4]. These include NTDs, the most common and severe malformations of spinal cord (spina bifida) or brain (anencephaly, encephalocele, hydrocephalus), which develop within 6 weeks of pregnancy with an incidence of one in 1000 neonates worldwide and cause lifelong neurological complications [5]. NTDs are leading causes of pediatric hospitalization, medical expenditure, and infant mortality. In fact, it is estimated that NTDs resulting approximately 88 000 neonatal deaths (29% in low-income countries) and 8.6 million disability adjusted life years [6]. In addition to enormous suffering of the patient, the public health and social impact of these diseases are also extremely notable as an estimated lifetime medical costs exceeds US$81.00 million per year for children born with spina bifida [5]. Since viral illness and its therapeutic approaches are associated with NTDs in infants [4], there may be some long-lasting health burden related to SARS-CoV-2 infection during pregnancy, and these have remained unnoticed till now.

Scientific evidences indicate that the causative agent of COVID-19, SARS-CoV-2 seem to cross both placental barrier (viral IgM detected in infants hours after birth) [7] and blood brain barrier (virus detected in cerebrospinal fluid) [8]. As the virus can enter placenta and nervous system, the virus itself may have some adverse effects on the pathogenesis of NTDs, if pregnant mothers suffer from COVID-19. Also, it appears that coronavirus, SARS-CoV-2, may be transmitted to fetus from mother as the virus use entry receptor, angiotensin-converting enzyme 2 (ACE2) and S protein proteases expressed in developing human embryo. Notably, ACE2 and S protein proteases are expressed in early gametes, zygotes, and 4-cell embryos [9]. Thus, direct transmission of infection of blast cells by SARS-CoV-2 may be possible, but remains to be confirmed. In developing embryos, the health of these cells of the epiblast is crucial as these cells undergo organogenesis. Any functionally alterations in early embryonic cells by the viral infection may lead to adverse birth defects. With much still unknown about COVID-19 and neurodevelopmental complications, there is an increased risk to develop congenital birth defects, if SARS-CoV-2 infection occurs during early pregnancy. However, the severity of COVID-19 pandemic has disrupted the normal process of patient counseling, case compilation and data processing at present. There is, therefore, an urgent need to continue collecting data on clinical cases of COVID-19 infection in pregnancy particularly during first or early second trimester, and to improve our understanding regarding the role of COVID-19 on NTDs.

Next, there are several concerns about the usage of antiviral drugs to contain SARS-CoV-2, and control virus-related complications, such as pneumonia. Although no effective drug has been developed to contain SARS-CoV-2, some antiviral drugs as well as anti-inflammatory agents developed for other viral infections and pathologies are widely used in COVID-19 patients around the world. Many of these drugs have been used for COVID-19 without undergoing proper safety and efficacy tests as we are now facing a serious pandemic. The usage of hydroxychloroquine is a controversial issue at present as this drug has been reported to cause many complications including death. Although chloroquine is classified as class C in the US Food and Drug Administration (FDA) for pregnancy, this drug is now widely used for COVID-19 treatment around the world.

Similarly, drugs like favipiravir, a drug developed to treat influenza virus disease; remdesivir to treat Ebola virus disease; and dolutegravir/lamivudine/tenofovir to treat human immunodeficiency viruses (HIV) have been used for COVID-19 treatment around the world on the basis of their availability. In fact, some of these drugs have been given emergency licensing and approval by US FDA. As the effects of these drugs have not been checked in pregnancy particularly in early trimester, there is growing fear suggesting that antiviral drugs may cause adverse birth outcomes. Favipiravir is contraindicated in women who might be or are pregnant because of its association with birth defects [10], however, this drug is now widely being used to treat COVID-19 in about 40 countries with the assistance of Japanese government and also in several developing countries including Bangladesh as a trial drug received from their own source. The drug has not been recommended by US FDA or Japanese Pharmaceuticals and Medical Devices Agency (PMDA), however, the availability of the drug and possible effects in COVID-19 has made a drug of choice or a golden bullet. Dolutegravir, an effective antiretroviral therapy for HIV treatment, is promising choice in low-income and middle-income countries, is also used for COVID-19 treatment. However, recent findings reveal that dolutegravir increases number of NTDs; the prevalence of NTDs is 3 times higher with dolutegravir [11]. Also, the effect of dolutegravir on external structural abnormalities of infants has been documented at high percentage (9 per 1000 births) if this drug is used during conception [11].

Taken together, as of today, the speed of designing and initiating trials to evaluate potential COVID-19 therapeutics is really impressing, as expected. However, less impressive is the fact that due importance and consideration has not been given about one of the most important fact; the effects of the virus and management strategy on pregnant women particularly those are in early pregnancy. Now, world is in middle of pandemic and COVID-19 would prevail for at least one or more years. Thus, abstinence from being pregnant is not a practical option. Rather, it is needed to check the pregnancy state of COVID-19 patients with an eye regarding adverse pregnancy outcomes including NTDs. Also, use of antiviral drugs should be regulated in COVID-19 pregnant patients, particularly those are in early pregnancy, until its safety and potential efficacy is not ascertained for neonates by randomized clinical trial.

In conclusion, it seems that COVID-19 may results in long-lasting congenital anomalies of infants either by infection or by therapeutic maneuver. These realities become more relevant in developing and resource-constrained countries where the screening before birth particularly at early pregnancy is almost non-existing. However, the incidence and prevalence of COVID-19 is not low in these countries. Also, another spectrum should be considered at this time. Pregnancy is monitored by obstetrician and gynecologists, whereas COVID-19 is managed by virologists and infectious disease specialists. Therefore, intradepartmental collaboration and exchange of information about management and treatment of COVID-19 and NTDs are required for avoiding disastrous complications in neonates.

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https://www.ncbi.nlm.nih.gov/p.....0649/

amother

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Thu, Jun 23 2022, 9:04 am

Review Article
Open Access
Published: 06 June 2022
Deleterious effects of nervous system in the offspring following maternal SARS-CoV-2 infection during the COVID-19 pandemic
Ruting Wang, Zifeng Wu, Chaoli Huang, Kenji Hashimoto, Ling Yang & Chun Yang
Translational Psychiatry volume 12, Article number: 232 (2022) Cite this article

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Abstract
During the Coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is universally susceptible to all types of populations. In addition to the elderly and children becoming the groups of great concern, pregnant women carrying new lives need to be even more alert to SARS-CoV-2 infection. Studies have shown that pregnant women infected with SARS-CoV-2 can lead to brain damage and post-birth psychiatric disorders in offspring. It has been widely recognized that SARS-CoV-2 can affect the development of the fetal nervous system directly or indirectly. Pregnant women are recommended to mitigate the effects of COVID-19 on the fetus through vaccination, nutritional supplements, and psychological support. This review summarizes the possible mechanisms of the nervous system effects of SARS-CoV-2 infection on their offspring during the pregnancy and analyzes the available prophylactic and treatment strategies to improve the prognosis of fetal-related neuropsychiatric diseases after birth.

Introduction
Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The World Health Organization (WHO) declared COVID-19 as a global pandemic in March 2020. It has since been called “the most critical global health disaster of the century and the greatest challenge facing humanity since World War II” [1, 2]. COVID-19 has spread rapidly across the globe, posing enormous health, economic and social challenges to humanity. As a respiratory infectious disease, SARS-CoV-2 is transmitted mainly through droplets, respiratory secretions, and direct contact [3]. However, recent studies have shown that SARS-CoV-2 can also affect the health of the next generation through vertical transmission from mother to child [4, 5]. Although COVID-19 is considered as a respiratory disease with the main clinical manifestations of fever, cough, and malaise, SARS-CoV-2 still causes damage to other organs, including the central nervous system (CNS) with symptoms such as dizziness, headache, and impaired consciousness [6]. Current human autopsy studies have determined that patients who died from COVID-19 had detectable viral RNA transcription products in brain tissue, viral proteins in endothelial cells of the olfactory bulb, and genetic sequencing of the cerebrospinal fluid showed the presence of SARS-CoV-2, suggesting that SARS-CoV-2 has the ability to invade the nervous system [7,8,9]. During the COVID-19 pandemic, the number of pregnant women infected with SARS-CoV-2 worldwide has been steadily increasing, and we have to consider whether maternal infection may have adverse effects on their offspring. The fetal nervous system is in a state of development from the third week of gestation and this process continues until adulthood [10]. During this period, any deviation can lead to nervous system developmental defects and cognitive impairment [11]. Considering the risk of maternal infection on neuropsychiatric disorders in the offspring, this review summarizes the mechanisms of nervous system effects of SARS-CoV-2 infection in pregnant women on their offspring and analyzes feasible treatment modalities.

Mechanisms
Maternal immune activation (MIA)
Since the COVID-19 epidemic, several studies have reported that the clinical symptoms and laboratory findings of patients with combined SARS-CoV-2 infection in pregnancy are consistent with those of the general population, with patients showing increased C-reactive protein (CRP) and decreased lymphocytes in their hemogram [12]. Tanacan et al. found that pregnant women with COVID-19 had significantly increased pregnancy complications and inflammatory markers [13]. In addition, the inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-6 were significantly increased, while IL-10 and IL-17 were decreased [13]. Since the fetus is a semi-allograft to the maternal body, pregnancy is also a specific immune adaptation process [14]. On the one hand, increased production of inflammatory cytokines such as IL-4 and IL-10 provides a suitable microenvironment of immunologic tolerance. On the other hand, altered expression of inflammatory cytokines such as IL-1 and tumor necrosis factor (TNF)-α is associated with increased pregnancy complications, such as miscarriage, and preterm delivery [15, 16]. Thus, homeostasis of inflammatory cytokines is essential to a healthy pregnancy, while elevated levels of inflammatory cytokines suggest a state of MIA.

Fetal nervous system injury
Maternal trophoblasts, specific natural killer cells, and meconium leukocytes secrete IFN-γ during the pregnancy and are involved in the differentiation of meconium natural killer cells, placenta formation, and meconium maintenance [17]. However, congenital infection causes miscarriage and reduced IFN-γ levels. IFN-γ levels have been reported to be lower in patients with severe COVID-19 infection than in healthy pregnant women and in patients with mild to moderate infection [18]. Similarly, a significant increase in IL-6 levels is observed in patients with severe COVID-19 [19]. Excessive production of IL-6 is associated with adverse pregnancy outcomes, such as preterm birth, premature rupture of membranes, and chorioamnionitis [20]. On the contrary, IL-10 is involved in the immune tolerance process during the pregnancy due to its anti-inflammatory effects and is mainly produced by placental chorionic trophoblasts, uterine natural killer cells, and metaphase mononuclear cells [21]. The decreased IL-10 levels in pregnant women with COVID-19 may be a factor in the impaired immune tolerance in this population and is associated with miscarriage [22]. Adverse pregnancy outcomes such as preterm birth, premature rupture of membranes, and chorioamnionitis can cause neonatal brain damage and even lifelong nervous system disorders [23]. In addition, increased secretion of inflammatory cytokines such as IL-8, IL-1β, and CRP, were found to be associated with microcephaly, ventricular enlargement, and low intelligent quotient [24], suggesting that inflammatory cytokines can cross the placenta and blood-brain barrier (BBB) and directly affect fetal neurodevelopment.

Vulnerability to psychiatric disorders in offspring
There is a study that reported that pregnant women during the influenza pandemics had a high incidence of psychiatric disorders in their offspring, including schizophrenia, autism spectrum disorder (ASD), and attention-deficit hyperactivity disorder (ADHD) [25]. Similar results have been obtained in animal experiments, where an animal model of maternal immune activation was constructed by administering polyinosinic- polycytidylic acid [Poly (I:C)] to pregnant mice, and it was found that exposure of mice on days 10–12 of embryonic life resulted in damage to the developing basal ganglia and offspring with defects in prepulse inhibition and latent inhibition that are similar to those found in ASD and schizophrenia individuals [26]. A study of Chinese mothers during the COVID-19 epidemic showed that most mothers were infected with SARS-CoV-2 around the third trimester, and their offspring had reduced motor, communication, and social performance compared to normal levels at 3 months of age [27]. The occurrence of infection in mothers during the first trimester may be a risk factor for ASD and schizophrenia in their offspring [28]. Given that IL-6 has the potential to alter cognitive behavior in offspring [29] and that elevated levels of IL-8, TNF-α, and CRP are associated with an increased risk of schizophrenia in offspring [30, 31], the effects of immune activation responses induced by maternal SARS-CoV-2 infection on fetal brain development may make the offspring more susceptible to neuropsychiatric disorders.

Direct effects of SARS-CoV-2
Past epidemiological studies have shown that a large number of viral infections during maternal pregnancy can lead to abnormalities in the nervous system in the fetus [32]. Although studies show that the probability of mother-to-child transmission of COVID-19 is extremely low, the possibility of vertical transmission has been reported in several cases [5, 33]. In a study from Wuhan, China, a primigravida was diagnosed with SARS-CoV-2 infection at 34 weeks of gestation and delivered a baby by cesarean section in a negative pressure isolation room at 38 weeks of gestation, during which she wore an N95 mask without contact with the newborn [4]. However, the levels of IgM and IgG antibodies were significantly elevated 2 h after birth, suggesting the possibility of intrauterine infection. It is known that IgM antibodies cannot pass through the placenta, while IgG antibodies can be transmitted through the placenta, and IgM antibodies usually appear 3–7 days after infection, suggesting that SARS-CoV-2 may cause indirect infection of the fetus through vertical transmission from mother to child.

During fetal brain development, genetic defects, environmental disturbances or pathogens can lead to defective mitosis or apoptosis of neural stem cells, which can disrupt the stem cell homeostasis and affect the differentiation of stem cells to other neural cells, manifesting as neurodevelopmental disorders, such as microcephaly and multiple sclerosis [34]. And the formation of neural circuits and changes in their function can lead to other mental disorders, such as ASD and schizophrenia [31]. It was found that SARS-CoV-2 may invade the CNS through blood circulation and peripheral nerve via the olfactory nerve [35].

The immune system plays an important role in nervous system injury caused by viral infection [36]. Persistent infection with SARS-CoV-2 and its infection of macrophages, microglia, and astrocytes in the CNS activates the inflammatory response of the body, causing immune system damage and brain injury [37]. At the same time, immune system damage and peripheral lymphocytopenia caused by SARS-CoV-2 increase the risk of secondary bacterial infections and exacerbate neurological damage [38]. A large number of deaths caused by COVID-19, most of which are due to multiple organ failures caused by viral-induced systemic inflammatory response syndrome (SIRS) or SIRS-like immune disorders [39].

Angiotensin-converting enzyme 2 (ACE2), a cardiovascular and cerebrovascular protective factor, is also abundantly expressed in glial cells, and SARS-CoV-2 has a high affinity for ACE2, and its spine protein interacts with ACE2 to disrupt the BBB and attack the nervous system. Children complete myelin development by the age of 2 years, and SARS-CoV-2 infection of oligodendrocytes causes demyelinating lesions, such as multiple sclerosis [40]. Patients with COVID-19 often present with severe hypoxia, and that hypoxia injury in the fetus can cause secondary damage to the nervous system [41].

Increased mental stress in the general environment
The form of COVID-19 remains severe and people are inevitably affected and prone to stress and anxiety, and depression [42]. A meta-analysis study enrolling 27475 subjects showed ~25% of anxiety and 28% of depression in patients with COVID-19 [43]. Another cross-national study during the COVID-19 pandemic showed that 43% of the 6894 pregnant women and mothers felt elevated stress, 31% felt anxious or depressed, and 53% felt lonely [44]. It is suggested that pregnant women, as a more vulnerable group, are more emotionally vulnerable during their pregnancy and suffer from higher levels of psychological stress. In turn, excessive maternal stress during pregnancy produces prenatal stress damage that increases the risk of fetal neurodevelopmental disorders [45]. Animal studies have shown that prenatal stress leads to shorter and less complex dendrites, reduced myelin, and altered synapses [46]. To determine whether changes in brain function occur in the offspring of women with high maternal stress, Thomason et al. performed functional magnetic resonance imaging on 118 fetuses at a mean gestational age of 32.9 weeks and found that increased maternal prenatal stress and negative emotions were associated with alterations in fetal frontoparietal, striatal, and temporoparietal neural connectivity (β = 0.82, P < 0.001), suggesting that high maternal stress and negative emotions during the pregnancy can have an unwanted impact on the nervous system of the offspring [47].

Deoni et al. found that children born after the COVID-19 pandemic were found to have lower developmental scores and these children had significantly lower language, motor, and overall cognitive skills [48]. Anti-epidemic measures may block parent-child emotional interactions and negatively affect children’s brains and behavior [49]. What’s more, this may be related to maternal stress and negative emotions during pregnancy affecting the structure and connectivity of the developing brain of the fetus, leading to potential delays in its motor, cognitive, and behavioral development [50]. The fetal brain is born with a strong capacity to learn and adapt, but is also very fragile and vulnerable to environmental exposures [51]. Maternal-fetal interaction and “kangaroo” care facilitate neurodevelopmental processes, including myelin formation and synaptogenesis [52]. On the other hand, exposure of the fetus to stress-related hormones such as cortisol might affect the structural and functional changes of the brain [53]. This is likely that higher cortisol levels in the mother during the pregnancy lead to lower cortisol levels in the infant at birth, which can dysregulate the hypothalamic-pituitary-adrenal axis and affect neurological development in the newborn [54] (Fig. 1).

Fig. 1
figure 1
Potential mechanisms of SARS-Cov-2 infection on the nervous system in the offspring during the pregnancy. MIA maternal immune activation.

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Prophylactic and treatment strategies
There is still no specific medicine for COVID-19, and the most common treatments for infection in pregnant women are antibiotics, antivirals, and oxygen support. However, both the public and the scientific community pay great attention to the safety and impacts of these treatment measures on the fetus. A meta-study analysis showed that the use of antibiotics and antivirals is higher in Asian countries than in other countries, suggesting a possibility of antibiotic abuse [55]. The use of immunosuppressive drugs is associated with the occurrence of adverse outcomes and potentially serious complications, and their use should be minimized, and improved therapeutic approaches through risk stratification are recommended. Therefore, effective prophylactic is important for disease management in pregnant women. Given that current studies have not reported serious adverse reactions in pregnant women after receiving the COVID-19 vaccine [56], a vaccine with nutritional support seems to be an effective approach. For pregnant women who have already developed psychological problems, appropriate use of drug medication and psychological treatment are recommended and prescribed under the guidance of physicians (Fig. 2).

Fig. 2
figure 2
Prophylactic and treatment strategies. Effective prophylactic and treatment strategies for potential risks of offspring’s neuropsychiatric disorders in pregnant women during the COVID-19 pandemic.

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Vaccination
Vaccination against infectious pathogens is one of the most influential public health interventions to reduce infection-related morbidity and mortality worldwide [57]. Theoretically, anti-SARS-CoV-2 immunoglobulins (IgG and IgA) are transmitted to the newborn through the placenta and breast milk after vaccination of pregnant women, providing humoral immunity. Regarding the safety of the vaccine in pregnant women, several studies have shown that no serious adverse events occurred in pregnant and lactating women who received the Pfizer/BioNTech vaccine, and no vaccine-associated mRNA was detected in breast milk collected 4 to 48 hours after vaccination, indicating that the vaccine is safe, although more studies are needed to analyze its effectiveness and impact on the offspring in the future [58,59,60]. Societies such as the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) continue to advocate for the availability of COVID-19 vaccine to pregnant and breastfeeding women [61]. WHO revised its statement on January 29, 2021, to allow vaccination of pregnant women at high risk of SARS-CoV-2 exposure (e.g., health workers) or with comorbidities that increase their risk of serious illness after consultation with their health care providers [56].

Nutrition
Based on previous experience with disease pandemics and experience with other respiratory viruses and animal models, increasing maternal choline levels and other nutrient levels may reduce the effects of infection on fetal brain development [25]. Choline supplementation may reduce the increase in fetal IL-6 levels caused by RNA virus stimulation and may decrease anxiety [62]. Maternal choline levels are associated with the development of attention and orienting regulation in early childhood [63]. Maternal vitamin D deficiency was found to lead to altered placental pathology and increased risk of bacterial vaginitis, but excessive vitamin D levels were associated with increased IL-6 levels [64, 65]. Therefore, it is recommended that pregnant women consume vitamin D with folic acid according to a standard prenatal vitamin formula and moderate choline supplementation from beef, egg yolk, and soy.

Antidepressants
The use of antidepressants such as selective serotonin reuptake inhibitor (SSRI) may be associated with a reduced risk of clinical deterioration in patients with SARS-CoV-2 infection. It may benefit depression patients with COVID-19 infection, since SSRIs exert anti-inflammatory effects on the damaged striatal neurons [28, 66]. Although using antidepressants during the pregnancy may increase the risk of ASD in offspring [67], a subsequent systematic review did not show an absolute contraindication to antidepressants and there was insufficient evidence of an association between antidepressants and adverse events [68]. Therefore, considering the safety of medication use in pregnant women, clinicians should balance the risks and benefits to develop an optimal treatment strategy on the basis of the actual situation.

Psychological intervention
Psychotherapy is a safer strategy with less adverse effects than pharmacological treatments. Cognitive behavior therapy (CBT) is currently the most well-studied and popular treatment modality [69]. In view of the fact that maternal stress and hair cortisol levels are associated with motor and cognitive neurodevelopment of the fetus at 6 months of age [70]. A recent randomized controlled trial showed that CBT reduced cortisol levels in the hair of pregnant women and improved psychological stress and psychiatric symptoms [71]. The decreased cortisol levels in the hair are beneficial to the physical and mental health of pregnant women and their fetuses, so the use of CBT for stress and negative emotions could be greatly encouraged.

Conclusion
COVID-19 affects fetal neurological development through multiple pathways during the pregnancy, although most newborns born in a COVID-19 pandemic setting are not directly infected with SARS-CoV-2. We need to pay attention not only to the neurological symptoms of neonatal impairment at birth, but also to the neuropsychiatric symptoms during the growth, and therefore improving the prognosis by early intervention. There is still a need for extensive follow-up studies to determine whether the fetal damage will be continued in adulthood, and new-onset psychiatric symptoms will be developed in adulthood. Most importantly, it is essential to create a safer environment and provide great support for pregnant women and their offspring.

https://www.nature.com/article.....985-z

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Thu, Jun 23 2022, 9:10 am

COVID-19 tied to higher risk of stillbirth, maternal death
Filed Under: COVID-19
Mary Van Beusekom | News Writer | CIDRAP News | Nov 22, 2021
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A pair of new US studies highlight the increased risks faced by pregnant women infected by SARS-CoV-2—particularly after the emergence of the Delta (B1617.2) variant—one finding nearly double the risk of stillbirth and the other showing five times the risk of death.

The studies were published late last week in Morbidity and Mortality Weekly Report.

Stillbirths rare but more of a risk with COVID
In the first study, the Centers for Disease Control and Prevention (CDC) COVID-19 Response Team analyzed data from the Premier Healthcare Database Special COVID-19 Release, a large, hospital-based database from March 2020 to September 2021, a period that included the emergence and eventual dominance of Delta.

Of all pregnant women in the database, 53.7% were White, 50.6% had private health insurance, 15.4% were obese, 11.2% had diabetes, 17.2% had high blood pressure, 1.8% had multiple-gestation pregnancy, 4.9% smoked, and 1.73% had COVID-19. The study authors noted that most of the women who tested positive for COVID-19 at delivery were likely unvaccinated.

Among 1,249,634 deliveries at 736 hospitals, stillbirths were rare, at 0.65%, but the rate was 1.26% among 21,653 deliveries to pregnant COVID-19 patients, compared with 0.64% among 1,227,981 deliveries to non–COVID-19 patients. Stillbirths were defined as fetal deaths at 20 weeks' gestation or later.

The risk of stillbirth among COVID-19 patients was almost twice as high among uninfected patients (adjusted relative risk [aRR], 1.90; 95% confidence interval [CI], 1.69 to 2.15). But the increased risk before Delta was around 50% (aRR, 1.47; 95% CI, 1.27 to 1.71), compared with quadruple the risk after the variant began circulating widely (aRR, 4.04; 95% CI, 3.28 to 4.97).

Risk factors for stillbirth among pregnant COVID-19 patients included chronic high blood pressure, multiple-gestation pregnancy, adverse cardiac events, placental abruption, sepsis, shock, acute respiratory distress syndrome, the need for mechanical ventilation, and admission to an intensive care unit (ICU). The link between adverse cardiac events and ICU admissions was stronger after Delta became dominant.

"Implementing evidence-based COVID-19 prevention strategies, including vaccination before or during pregnancy, is critical to reducing the impact of COVID-19 on stillbirths," the researchers wrote.

They also called for prospective studies to identify the biological mechanism for the increased risk for stillbirth in pregnant COVID-19 patients and evaluate differences in risks related to the timing and severity of illness and the contribution of maternal risk factors.

"In addition, further investigation of vaccine effectiveness during pregnancy, including prevention of stillbirth, is warranted," the authors concluded. "Most importantly, these findings underscore the importance of COVID-19 prevention strategies, including vaccination before or during pregnancy."

From 5 to 25 deaths per 1,000 after Delta
The second study, led by Mississippi State Department of Health researchers, evaluated the deaths of pregnant women diagnosed as having COVID-19 in Mississippi from Mar 1, 2020, to Oct 6, 2021.

During this period, 1,637 COVID-19 cases were identified among pregnant women, and 15 (0.92%) died of their infections (9 per 1,000 cases, or a 0.9% death rate). In comparison, 2.5 COVID-19 deaths occurred among 1,000 infections in nonpregnant women of reproductive age.

Six of those deaths (5 per 1,000 cases during pregnancy, or 0.5%) occurred before Delta became the dominant SARS-CoV-2 strain in July 2021, and nine occurred after (25 per 1,000, or 2.5%). For reference, 2.1 per 1,000 died among nonpregnant women of reproductive age before Delta, while 3.3 per 1,000 died after it became dominant.

All patients had been admitted to an ICU, 14 needed invasive mechanical ventilation, and 7 had an emergency cesarean delivery, including 2 at the patients' bedside. Three patients died during pregnancy, resulting in 1 miscarriage at 9 weeks and 2 stillbirths at 22 and 23 weeks' gestation, and 12 died after a live birth (median time from delivery to death, 5 days).

Median age at death was 30 years, 9 were Black, 3 were White, and 3 were Hispanic; during the study period, about 43% and 5% of births in Mississippi were to Black and Hispanic women, respectively. Median time from symptom onset to death was 18 days, both before and during Delta dominance.

Fourteen decedents had chronic medical conditions, and none had been fully vaccinated against COVID-19; 5 deaths occurred before vaccination became available, 1 decedent was partially vaccinated, and 9 were unvaccinated. None of the women had received monoclonal antibodies as treatment.

The authors noted that the CDC recommends that pregnant women get vaccinated against COVID-19 to prevent severe illness, death, and adverse pregnancy outcomes. They added that Mississippi maternal mortality review committees will review all COVID-19–related and -unrelated deaths among pregnant women in the state to determine their relationship to pregnancy, identify risk factors such as health inequities, and develop recommendations to prevent deaths in this population.

"Given existing disparities in vaccination rates among pregnant women, partnerships to address vaccine access, hesitancy, or other concerns about vaccination can enhance fair and just access to COVID-19 vaccination, including among Black persons and Hispanic persons," the researchers concluded.

https://www.cidrap.umn.edu/new.....death