The impact of the COVID-19 pandemic on adverse fetal outcomes: A cross-sectional study.

The coronavirus disease 2019 (COVID-19) pandemic has been one of the most damaging pandemics in all of human history. Some of the most vulnerable groups within society such as pregnant women and children have also been affected. This observational research, cross-sectional study was conducted to investigate if there was any difference in the incidence of unfavorable outcomes in pregnancy such as miscarriage, intrauterine fetal demise, and early neonatal death during the year prior to the pandemic and the year of the COVID-19 pandemic. This retrospective study was conducted at the University Hospital of Split at the Department of Pathology, Forensic and Cytology and Department of Obstetrics and Gynecology of the same hospital. All data was collected in the time period from March 1st, 2019, to March 1st, 2021. The study included all pregnant women who had an unfavorable pregnancy outcome such as miscarriage and intrauterine fetal demise, as well as early neonatal death at the University Hospital of Split within the time frame mentioned previously. There was no statistically significant difference in the incidence of adverse pregnancy outcomes in the year prior to the pandemic and during the year of the COVID-19 pandemic. Our study showed that the pandemic did not have a negative effect on pregnant women and their fetuses; there was no increase in miscarriage, intrauterine fetal demise, or perinatal death during the year of the pandemic.

Fetal effects of mild maternal COVID-19 infection: metabolomic profiling of cord blood.

INTRODUCTION: The impact of maternal coronavirus disease 2019 (COVID-19) infection on fetal health remains to be precisely characterized. OBJECTIVES: Using metabolomic profiling of newborn umbilical cord blood, we aimed to investigate the potential fetal biological consequences of maternal COVID-19 infection. METHODS: Cord blood plasma samples from 23 mild COVID-19 cases (mother infected/newborn negative) and 23 gestational age-matched controls were analyzed using nuclear magnetic spectroscopy and liquid chromatography coupled with mass spectrometry. Metabolite set enrichment analysis (MSEA) was used to evaluate altered biochemical pathways due to COVID-19 intrauterine exposure. Logistic regression models were developed using metabolites to predict intrauterine exposure. RESULTS: Significant concentration differences between groups (p-value < 0.05) were observed in 19 metabolites. Elevated levels of glucocorticoids, pyruvate, lactate, purine metabolites, phenylalanine, and branched-chain amino acids of valine and isoleucine were discovered in cases while ceramide subclasses were decreased. The top metabolite model including cortisol and ceramide (d18:1/23:0) achieved an Area under the Receiver Operating Characteristics curve (95% CI) = 0.841 (0.725-0.957) for detecting fetal exposure to maternal COVID-19 infection. MSEA highlighted steroidogenesis, pyruvate metabolism, gluconeogenesis, and the Warburg effect as the major perturbed metabolic pathways (p-value < 0.05). These changes indicate fetal increased oxidative metabolism, hyperinsulinemia, and inflammatory response. CONCLUSION: We present fetal biochemical changes related to intrauterine inflammation and altered energy metabolism in cases of mild maternal COVID-19 infection despite the absence of viral infection. Elucidation of the long-term consequences of these findings is imperative considering the large number of exposures in the population.

Entry, egress and vertical transmission of SARS-CoV-2.

The high infectivity and pathogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused the COVID-19 outbreak, one of the most devastating pandemics in more than a century. This pandemic has already left a trail of destruction, including enormous loss of life, a global economic slump, and widespread psychological damage. Despite assiduous world-wide endeavors, an effective cure for COVID-19 is still lacking. Surprisingly, infected neonates and children have relatively mild clinical manifestations and a much lower fatality rate than elderly adults. Recent studies have unambiguously demonstrated the vertical transmission of SARS-CoV-2 from infected pregnant women to fetuses, which creates yet another challenge for disease prevention. In this review, we will summarize the molecular mechanism for entry of SARS-CoV-2 into host cells, the basis for the failure of the lungs and other organs in severe acute cases, and the evidence for congenital transmission.

Impact of Endogenic and Exogenic Oxidative Stress Triggers on Pregnant Woman, Fetus, and Child.

In all living organisms, there is a delicate balance between oxidation caused by reactive species (RS, also called free radicals) and antioxidant defence [...].

Transmission of SARS-CoV-2 from mother to fetus or neonate: What to know and what to do?

SARS-CoV-2 can be vertically transmitted from the mother to the fetus and the neonate. This transmission route is rare compared to the environmental or horizontal spread and therefore, the risk can be deemed inconsequential by some medical providers. However, severe, although just as rare, feto-neonatal consequences are possible: fetal demise, severe/critical neonatal COVID-19 and multi-inflammatory syndrome (MIS-N) have been described. Therefore, it is important for the clinicians to know the mechanism of vertical transmission, how to recognize this, and how to deal with neonatal COVID-19 and MIS-N. Our knowledge about this field has significantly increased in the last three years. This is a summary of the pathophysiology, diagnostics, and therapeutics of vertical SARS-CoV-2 transmission that clinicians apply in their clinical practice.

Safety, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons: A protocol for systematic review and meta analysis.

INTRODUCTION: Numerous vaccines have been evaluated and approved for coronavirus disease 2019 (COVID-19). Since pregnant persons have been excluded from most clinical trials of COVID-19 vaccines, sufficient data regarding the safety of these vaccines for the pregnant person and their fetus have rarely been available at the time of product licensure. However, as COVID-19 vaccines have been deployed, data on the safety, reactogenicity, immunogenicity, and efficacy of COVID-19 vaccines for pregnant persons and neonates are becoming increasingly available. A living systematic review and meta-analysis of the safety and effectiveness of COVID-19 vaccines for pregnant persons and newborns could provide the information necessary to help guide vaccine policy decisions. METHODS AND ANALYSIS: We aim to conduct a living systematic review and meta-analysis based on biweekly searches of medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries to systematically identify relevant studies of COVID-19 vaccines for pregnant persons. Pairs of reviewers will independently select, extract data, and conduct risk of bias assessments. We will include randomized clinical trials, quasi-experimental studies, cohort, case-control, cross-sectional studies, and case reports. Primary outcomes will be the safety, efficacy, and effectiveness of COVID-19 vaccines in pregnant persons, including neonatal outcomes. Secondary outcomes will be immunogenicity and reactogenicity. We will conduct paired meta-analyses, including prespecified subgroup and sensitivity analyses. We will use the grading of recommendations assessment, development, and evaluation approach to evaluate the certainty of evidence.

Foetal Intrapartum Compromise at Term: Could COVID-19 Infection Be Involved? A Case Report.

The impact of the SARS-CoV-2 infection on pregnancy has been studied and many reports have been published, mainly focussing on complications and in utero transmission with neonatal consequences. Although the effects of other viruses on foetuses are well known, the impact of maternal COVID-19 during pregnancy is not completely understood. We report a case of acute foetal intrapartum hypoxia without other risk factors than maternal COVID-19 disease 2 weeks previous to birth at term. Placental histological changes suggested that the viral infection could have been the culprit for the unfavourable outcome during labour. The neonate was promptly delivered by Caesarean section. Neonatal intensive care was started, including therapeutic hypothermia. The procedure was successful, the evolution of the neonate was favourable, and she was discharged after 10 days. Follow-up at 2 months of life indicated a normal neurological development but a drop in head growth. The case raises the idea that pregnancies with even mild COVID-19 symptoms may represent the cause of neonate compromise in a low-risk pregnancy. An important follow-up in the neonatal period and infancy is required to identify and treat any subsequent conditions. Further long-term studies are necessary to identify a cause-effect relationship between COVID-19 pregnancies and the whole spectrum of neonatal and infant consequences.

Impact of perinatal COVID on fetal and neonatal brain and neurodevelopmental outcomes.

After three years of the COVID-19 pandemic, we have learned many aspects of the disease and the virus: its molecular structure, how it infects human cells, the clinical picture at different ages, potential therapies, and the effectiveness of prophylaxis. Research is currently focused on the short- and long-term consequences of COVID-19. We review the available information on the neurodevelopmental outcome of infants born during the pandemic from infected and non-infected mothers, as well as the neurological impact of neonatal SARS-CoV-2 infection. We also discuss the mechanisms that could potentially affect the fetal or neonatal brain including direct impact after vertical transmission, maternal immune activation with a proinflammatory cytokine storm, and finally the consequences of complications of pregnancy secondary to maternal infection that could affect the fetus. Several follow-up studies have noted a variety of neurodevelopmental sequelae among infants born during the pandemic. There is controversy as to the exact etiopathogenesis of these neurodevelopmental effects: from the infection itself or as a result of parental emotional stress during that period. We summarize case reports of acute neonatal SARS-CoV-2 infections associated with neurological signs and neuroimaging changes. Many infants born during previous pandemics caused by other respiratory viruses demonstrated serious neurodevelopmental and psychological sequelae that were only recognized after several years of follow-up. It is essential to warn health authorities about the need for very long-term continuous follow up of infants born during the SARS-CoV-2 pandemic for early detection and treatment that could help mitigate the neurodevelopmental consequences of perinatal COVID-19.

Techniques for managing an impacted fetal head at caesarean section: A systematic review.

A complication arising at caesarean birth when the baby's head is deeply engaged in the pelvis and may be difficult to deliver, is known as an 'impacted fetal head'. This obstetric emergency occurs in 16% of second stage caesarean sections. Multiple techniques are described in the literature to manage the complication but there is no consensus regarding which technique results in the best maternal and neonatal outcomes. The objective of this review is to determine which technique for managing impacted fetal head at caesarean section has the best maternal and neonatal outcomes. A literature search of three electronic databases was conducted in November 2021. Studies directly comparing two methods for the management of impacted fetal head at caesarean section in the second stage were included. Systematic reviews, meta-analyses, case-control studies, and studies not fitting the search criteria were excluded. Data was extracted in Covidence and meta-analysis of the six most commonly reported outcomes was conducted using RevMan 5.4. In total, 16 studies (3344women) were included. 13 studies (2506women) compared the push method with reverse breech extraction. meta-analysis showed that risk of extension of the uterine incision, blood transfusion, bladder injury, postpartum haemorrhage, NICU admission and Apgar score <7 at 5 min were significantly higher with the push method compared with reverse breech extraction. Three studies (838women) compared the push method with Patwardhan's technique. meta-analysis of studies comparing the push method with Patwardhan's technique found no significant differences between the two groups in any of the six maternal or neonatal outcomes. Evidence derived from small, inadequately powered studies suggests reverse breech extraction is associated with better outcomes than the push method. The method which produces the best outcomes is still unknown as not all methods have been tested. Further high quality, adequately powered RCTs are warranted for definitive conclusions to be drawn and to ameliorate the paucity of evidence on how best to manage this complication.

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.

SARS-CoV-2 placentitis as a cause of intrauterine death of a fetus in a patient with covid-19 infection and ongoing HELLP syndrome.

OBJECTIVE: We hereby present a case of intrauterine death of a fetus due to placental damage by placentitis caused by SARS-CoV-2 infection in ongoing covid-19 disease and HELLP syndrome. CASE REPORT: In this case report, we describe a patient who experienced intrauterine death of a fetus and the development of HELLP syndrome in ongoing covid-19 infection. Placentitis caused by SARS-CoV-2 infection was identified as the cause of intrauterine death of a fetus. After the end of pregnancy, a patient experienced an improvement in the symptoms of covid-19 and also a gradual improvement and adjustment of laboratory and coagulation parameters. CONCLUSION: SARS-CoV-2 infection in pregnancy can be complicated by the development of SARS-CoV-2 placenitis, which can cause intrauterine death of a fetus. Covid-19 infection can even have similar signs to HELLP syndrome and therefore careful monitoring of pregnant women with covid-19 is recommended.

Investigation of developmental toxicity of favipiravir on fetal bone and embryonic development.

BACKGROUND: Favipiravir is one of the essential antiviral drugs used for the treatment of coronavirus disease (COVID-19) in some countries. However, there is not enough information about used, especially in pregnancy. Therefore, in this study, it was aimed to determine the developmental toxicity of favipiravir on fetal bone development and embryonic development. METHODS: In this study, 16 pregnant wistar albino rats were used. The rats were divided into four groups: Control (saline) and Group A (50 mg/kg × 5 days), Group B (50 mg/kg × 1 days + 20 mg/kg × 4 days), Group C (20 mg/kg × 5 days). Solutions were administered to the rats by oral gavage from the 10th to 14th days of pregnancy, twice a day. The skeletal system development of fetuses was examined with double skeletal staining and immunohistochemical staining methods. RESULTS: A total of 72 fetuses from pregnant rats, 18 in each group, were included in the study. As a result, depending on favipiravir dose increase, in experimental groups, it was determined that the statistically significant decrease on the ossification rates of anterior and posterior extremity bones, and length and weight of fetuses. CONCLUSION: Exposure to favipiravir during pregnancy impairs bone metabolism and bone formation-resorption stages and may cause developmental delay.

Limb ischaemia at birth in a new-born whose mother tested positive for COVID-19 one month before delivery.

We report a case of right upper limb ischaemia diagnosed at birth in a neonate whose mother had presented with paucisymptomatic COVID-19 four weeks previously. Typical causes were investigated and excluded. Maternal morbidity and mortality resulting from COVID-19 during pregnancy is well recognised and documented, however, foetal and neonatal complications are increasingly being reported. Our case sheds further light on the diverse nature of such complications, and in particular this type of possible association related to their delayed onset.

Biotransformation and transplacental transfer of the anti-viral remdesivir and predominant metabolite, GS-441524 in pregnant rats.

BACKGROUND: Remdesivir was the first prodrug approved to treat coronavirus disease 2019 (COVID-19) and has the potential to be used during pregnancy. However, it is not known whether remdesivir and its main metabolite, GS-441524 have the potential to cross the blood-placental barrier. We hypothesize that remdesivir and predominant metabolite GS-441524may cross the blood-placental barrier to reach the embryo tissues. METHODS: To test this hypothesis, ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) coupled with multisite microdialysis was used to monitor the levels of remdesivir and the nucleoside analogue GS-441524 in the maternal blood, fetus, placenta, and amniotic fluid of pregnant Sprague-Dawley rats. The transplacental transfer was evaluated using the pharmacokinetic parameters of AUC and mother-to-fetus transfer ratio (AUCfetus/AUCmother). FINDINGS: Our in-vivo results show that remdesivir is rapidly biotransformed into GS-441524 in the maternal blood, which then readily crossed the placenta with a mother-to-fetus transfer ratio of 0.51 ± 0.18. The Cmax and AUClast values of GS-441524 followed the order: maternal blood > amniotic fluid > fetus > placenta in rats. INTERPRETATION: While remdesivir does not directly cross into the fetus, however, its main metabolite, GS-441524 readily crosses the placenta and can reside there for at least 4 hours as shown in the pregnant Sprague-Dawley rat model. These findings suggest that careful consideration should be taken for the use of remdesivir in the treatment of COVID-19 in pregnancy. FUNDING: Ministry of Science and Technology of Taiwan.

Does Maternal SARS-CoV-2 Infection or SARS-CoV-2 Vaccination Trigger an Inflammatory Response in the Fetus? A Prospective Cohort Study.

OBJECTIVES: SARS-CoV-2 infection triggers a significant maternal inflammatory response. There is a dearth of information regarding whether maternal SARS-CoV-2 infection at admission for delivery or SARS-CoV-2 vaccination triggers an inflammatory response in the fetus. This study aims at evaluating fetal inflammatory response to maternal SARS-CoV-2 infection or SARS-CoV-2 vaccination compared to control group. Design, Participants, Setting, and Methods: A prospective cohort study was performed with a total of 61 pregnant women who presented for delivery at a single medical center (William Beaumont Hospital, Royal Oak, MI). All mothers were tested for SARS-CoV-2 infection using polymerase chain reaction (PCR) on admission to labor and delivery unit. Three groups were evaluated: 22 pregnant with a positive SARS-CoV-2 test (case group), 23 pregnant women with a negative SARS-CoV-2 test (control group), and 16 pregnant women who had recent SAR-CoV-2 vaccination and a negative SARS-CoV-2 test (vaccine group). At delivery, cord blood was collected to determine the levels of IL-6, C-reactive protein (CRP), and SARS-CoV-2 nucleocapsid IgG and IgM antibodies. In all cases, the newborn had a negative PCR test or showed no clinical findings consistent with SARS-CoV-2 infection. RESULTS: Mean (SD) IL-6 level was not significantly different for the three groups: case group 9.00 ± 3.340 pg/mL, control group 5.19 ± 0.759 pg/mL, and vaccine group 7.11 ± 2.468 pg/mL (p value 0.855). Pairwise comparison also revealed no statistical difference for IL-6 concentrations with p values for case versus control, case versus vaccine, and control versus vaccine = 0.57, 0.91, and 0.74, respectively. Similarly, there was no statistically significant difference in the frequency of elevated IL-6 (>11 pg/mL) between groups (p value 0.89). CRP levels across the three groups were not statistically significant different (p value 0.634). Pairwise comparison of CRP levels among the different groups was also not statistically different. SARS-CoV-2 nucleocapsid IgG was positive in 12 out of 22 cord blood samples in the case group, 2 out of 23 of the control group (indicating old resolved maternal infection), and 0 out of 16 of the vaccine group. SARS-CoV-2 nucleocapsid IgM was negative in all cord blood samples of the case group, control group, and vaccine group. LIMITATIONS: A total number of 61 mothers enrolled in the study which represents a relatively small number of patients. Most patients with positive SARS-CoV-2 PCR were mainly asymptomatic. In addition, our vaccine group received the mRNA-based vaccines (mRNA1273 and BNT162b2). We did not study fetal response to other SARS-CoV-2 vaccines. CONCLUSION: In our prospective cohort, neither IL-6 nor CRP indicated increased inflammation in the cord blood of newborns of SARS-CoV-2-infected or vaccinated mothers.

Parvovirus (B19) Infection during Pregnancy: Possible Effect on the Course of Pregnancy and Rare Fetal Outcomes. A Case Report and Literature Review.

Infection caused by human parvovirus B19 (B19) often has mild yet wide-ranging clinical signs, with the course of disease usually defined as benign. Particularly prevalent in the population of young children, the virus is commonly transmitted to the parents, especially to susceptible mothers. During pregnancy, particularly the first and second trimesters, parvovirus infection can lead to pathology of the fetus: anemia, heart failure, hydrops, and disorders of physical and neurological development. In severe cases, the disease can result in fetal demise. This article presents a rare case of manifestation of B19 infection during pregnancy. At the 27th week of gestation, a sudden change in fetal movement occurred in a previously healthy pregnancy. The examination of both fetus and the mother revealed newly formed fetal subdural hematoma of unknown etiology and ventriculomegaly. Following extensive examination to ascertain the origin of fetal pathology, a maternal B19 infection was detected. Due to worsening fetal condition, a planned cesarean section was performed to terminate the pregnancy at 31 weeks of gestation. A preterm male newborn was delivered in a critical condition with congenital B19 infection, hydrocephalus, and severe progressive encephalopathy. The manifestation and the origin of the fetal condition remain partially unclear. The transplacental transmission of maternal B19 infection to the fetus occurs in approximately 30% of cases. The main method for diagnosing B19 infection is Polymerase Chain Reaction (PCR) performed on blood serum. In the absence of clinical manifestations, the early diagnosis of B19 infection is rarely achieved. As a result, the disease left untreated can progress inconspicuously and cause serious complications. Treatment strategies are limited and depend on the condition of the pregnant woman and the fetus. When applicable, intrauterine blood transfusion reduces the risk of fetal mortality. It is crucial to assess the predisposing factors of the infection and evaluate signs of early manifestation, as this may help prevent the progression and poor outcomes of the disease.

No evidence of fetal defects or anti-syncytin-1 antibody induction following COVID-19 mRNA vaccination.

The impact of Coronavirus Disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated 2 of the most widely propagated claims to determine (1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities; and (2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from these murine pregnancies vaccinated prior to the formation of the definitive placenta exhibit high circulating levels of anti-spike and anti-receptor-binding domain (anti-RBD) antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) consistent with maternal antibody status, indicating transplacental transfer in the later stages of pregnancy after early immunization. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes.