Prenatal exposure to common infections and newborn DNA methylation: A prospective, population-based study.

BACKGROUND: Infections during pregnancy have been robustly associated with adverse mental and physical health outcomes in offspring, yet the underlying molecular pathways remain largely unknown. Here, we examined whether exposure to common infections in utero associates with DNA methylation (DNAm) patterns at birth and whether this in turn relates to offspring health outcomes in the general population. METHODS: Using data from 2,367 children from the Dutch population-based Generation R Study, we first performed an epigenome-wide association study to identify differentially methylated sites and regions at birth associated with prenatal infection exposure. We also examined the influence of infection timing by using self-reported cumulative infection scores for each trimester. Second, we sought to develop an aggregate methylation profile score (MPS) based on cord blood DNAm as an epigenetic proxy of prenatal infection exposure and tested whether this MPS prospectively associates with offspring health outcomes, including psychiatric symptoms, BMI, and asthma at ages 13-16 years. Third, we investigated whether prenatal infection exposure associates with offspring epigenetic age acceleration - a marker of biological aging. Across all analysis steps, we tested whether our findings replicate in 864 participants from an independent population-based cohort (ALSPAC, UK). RESULTS: We observed no differentially methylated sites or regions in cord blood in relation to prenatal infection exposure, after multiple testing correction. 33 DNAm sites showed suggestive associations (p < 5e10 - 5; of which one was also nominally associated in ALSPAC), indicating potential links to genes associated with immune, neurodevelopmental, and cardiovascular pathways. While the MPS of prenatal infections associated with maternal reports of infections in the internal hold out sample in the Generation R Study (R2incremental = 0.049), it did not replicate in ALSPAC (R2incremental = 0.001), and it did not prospectively associate with offspring health outcomes in either cohort. Moreover, we observed no association between prenatal exposure to infections and epigenetic age acceleration across cohorts and clocks. CONCLUSION: In contrast to prior studies, which reported DNAm differences in offspring exposed to severe infections in utero, we do not find evidence for associations between self-reported clinically evident common infections during pregnancy and DNAm or epigenetic aging in cord blood within the general pediatric population. Future studies are needed to establish whether associations exist but are too subtle to be statistically meaningful with present sample sizes, whether they replicate in a cohort with a more similar infection score as our discovery cohort, whether they occur in different tissues than cord blood, and whether other biological pathways may be more relevant for mediating the effect of prenatal common infection exposure on downstream offspring health outcomes.

The aetiology and antimicrobial resistance of bacterial maternal infections in Sub-Saharan Africa-a systematic review and meta-analysis.

BACKGROUND: Understanding the aetiological organisms causing maternal infections is crucial to inform antibiotic treatment guidelines, but such data are scarce from Sub-Saharan Africa (SSA). We performed this systematic review and meta-analysis to address this gap. METHODS: Microbiologically confirmed maternal infection data were collected from PubMed, Embase, and African Journals online databases. The search strategy combined terms related to bacterial infection, pregnancy, postnatal period, observational studies, SSA. Exclusion criteria included colonization, asymptomatic infection, and screening studies. Pooled proportions for bacterial isolates and antimicrobial resistance (AMR) were calculated. Quality and completeness of reporting were assessed using the Newcastle-Ottawa and STROBE checklists. FINDINGS: We included 14 papers comprising data from 2,575 women from four sources (blood, urine, surgical wound and endocervical). Mixed-growth was commonly reported at 17% (95% CI: 12%-23%), E. coli from 11%(CI:10%-12%), S. aureus from 5%(CI: 5%-6%), Klebsiella spp. at 5%(CI: 4%- 5%) and Streptococcus spp. at 2%(CI: 1%-2%). We observed intra-sample and inter-sample heterogeneity between 88-92% in all meta-analyses. AMR rates were between 19% -77%, the highest with first-line beta-lactam antibiotics. Convenience sampling, and limited reporting of laboratory techniques were areas of concern. INTERPRETATION: We provide a comprehensive summary of microbial aetiology of maternal infections in SSA and demonstrate the paucity of data available for this region. We flag the need to review the current local and international empirical treatment guidelines for maternal bacterial infections in SSA because there is high prevalence of AMR among common causative bacteria. FUNDING: This research was supported by the NIHR-Professorship/NIHR300808 and the Wellcome-Strategic-award /206545/Z/17/Z. TRIAL REGISTRATION: Prospero ID CRD42021238515.

Environmental Signals.

Environmental factors have long been known to play a role in the pathogenesis of congenital heart disease (CHD), but this has not been a major focus of research in the modern era. Studies of human exposures and animal models demonstrate that demographics (age, race, socioeconomic status), diseases (e.g., diabetes, hypertension, obesity, stress, infection, high altitude), recreational and therapeutic drug use, and chemical exposures are associated with an increased risk for CHD. Unfortunately, although studies suggest that exposures to these factors may cause CHD, in most cases, the data are not strong, are inconclusive, or are contradictory. Although most studies concentrate on the effects of maternal exposure, paternal exposure to some agents can also modify this risk. From a mechanistic standpoint, recent delineation of signaling and genetic controls of cardiac development has revealed molecular pathways that may explain the effects of environmental signals on cardiac morphogenesis and may provide further tools to study the effects of environmental stimuli on cardiac development. For example, environmental factors likely regulate cellular signaling pathways, transcriptional and epigenetic regulation, proliferation, and physiologic processes that can control the development of the heart and other organs. However, understanding of the epidemiology and risk of these exposures and the mechanistic basis for any effects on cardiac development remains incomplete. Further studies defining the relationship between environmental exposures and human CHD and the mechanisms involved should reveal strategies to prevent, diagnose, and treat CHD induced by environmental signals.

Maternal urogenital infection and fetal heart functional assessment - what is the missing link?

OBJECTIVES: Maternal urogenital infections during pregnancy are worldwide frequent problem. The aim was to analyze influence of maternal genitourinary infection on fetal cardiac function, pregnancy development and obstetrical outcomes. METHODS: This was a single-center cohort study on fetuses (average at 28th week) in two groups: with maternal urogenital infections (study group n=49) and control group with no infections (n=59). Parvovirus B19, toxoplasmosis, cytomegalovirus, herpes simplex infections, congenital malformations, fetal growth restriction, chronic maternal diseases, as well as patients with body mass index (BMI) >25 kg/m2 were excluded. We analyzed: maternal age, time of delivery, neonatal birth weight, Apgar scores, average time of hospitalization of newborns after birth and several fetal echocardiographic parameters. RESULTS: The only statistical differences was found for shorter isovolumetric relaxation time (IRT) (40 ± 10 vs. 45 ± 9; p=0.03) and longer ejection time (ET) [ms] for right ventricle (RV) (176 ± 24 vs. 164 ± 18; p=0.01). Thick placenta was observed more frequent in study group than in controls (36.7 vs. 16.9%; p= 0.02). CONCLUSIONS: The missing link for explanation of these findings was coincidence with thick placenta. This is probably the first observation suggesting that thick placenta (>5 cm) may affect fetal RV function in normal heart anatomy: prolongation of right ventricular ET and shortening of fetal right ventricular IVRT.

Factors associated with birth asphyxia among term singleton births at two referral hospitals in Northern Uganda: a cross sectional study.

BACKGROUND: Birth asphyxia is one of the leading causes of neonatal mortality worldwide. In Uganda, it accounts for 28.9% of all neonatal deaths. With a view to inform policy and practice interventions to reduce adverse neonatal outcomes, we aimed to determine the prevalence and factors associated with birth asphyxia at two referral hospitals in Northern Uganda. METHODS: This was a cross-sectional study, involving women who gave birth at two referral hospitals. Women in labour were consecutively enrolled by the research assistants, who also attended the births and determined Apgar scores. Data on socio-demographic characteristics, pregnancy history and care during labour, were obtained using a structured questionnaire. Participants were tested for; i) malaria (peripheral and placental blood samples), ii) syphilis, iii) white blood cell counts (WBC), and iv) haemoglobin levels. The prevalence of birth asphyxia was determined as the number of newborns with Apgar scores < 7 at 5 min out of the total population of study participants. Factors independently associated with birth asphyxia were determined using multivariable logistic regression analysis and a p-value < 0.05 was considered statistically significant. RESULTS: A total of 2,930 mother-newborn pairs were included, and the prevalence of birth asphyxia was 154 [5.3% (95% confidence interval: 4.5- 6.1)]. Factors associated with birth asphyxia were; maternal age ≤ 19 years [adjusted odds ratio (aOR) 1.92 (1.27-2.91)], syphilis infection [aOR 2.45(1.08-5.57)], and a high white blood cell count [aOR 2.26 (1.26-4.06)], while employment [aOR 0.43 (0.22-0.83)] was protective. Additionally, referral [aOR1.75 (1.10-2.79)], induction/augmentation of labour [aOR 2.70 (1.62-4.50)], prolonged labour [aOR 1.88 (1.25-2.83)], obstructed labour [aOR 3.40 (1.70-6.83)], malpresentation/ malposition [aOR 3.00 (1.44-6.27)] and assisted vaginal delivery [aOR 5.54 (2.30-13.30)] were associated with birth asphyxia. Male newborns [aOR 1.92 (1.28-2.88)] and those with a low birth weight [aOR 2.20 (1.07-4.50)], were also more likely to develop birth asphyxia. CONCLUSION: The prevalence of birth asphyxia was 5.3%. In addition to the known intrapartum complications, teenage motherhood, syphilis and a raised white blood cell count were associated with birth asphyxia. This indicates that for sustained reduction of birth asphyxia, appropriate management of maternal infections and improved intrapartum quality of care are essential.

[Recommendations and evidence synthesis: guidelines on antibiotic prophylaxis and choice of antiseptics for women in instrumental vaginal delivery or cesarean sectionSíntese de evidências e recomendações: diretrizes para a profilaxia antibiótica e a escolha de antissépticos em mulheres submetidas a parto vaginal operatório ou cesariana]. / Síntesis de evidencia y recomendaciones: directrices para la profilaxis antibiótica y la elección de antisépticos en las mujeres con parto vaginal instrumentado o cesárea.

Introduction: Maternal sepsis and infections during or after childbirth increase maternal mortality, leading to a high burden of disease in the Region of the Americas. The risk of infection after a cesarean section or instrumental vaginal delivery can be reduced with the appropriate skin antiseptic agents and antibiotic prophylaxis. Objectives: To synthesize World Health Organization (WHO) recommendations to improve the quality of care and health outcomes related to routine antibiotic prophylaxis in women during instrumental vaginal delivery; routine use of antibiotic prophylaxis in women having a cesarean section; the choice of antiseptics and skin preparation methods before a cesarean; and vaginal irrigation with antiseptics in women undergoing a cesarean. Methods: The WHO guidelines were based on the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology as described in the WHO Handbook for Guideline Development. Recommendations contained in four WHO guidelines were synthesized and a systematic search for studies carried out in the Region of the Americas was conducted in PubMed, Lilacs, Health Systems Evidence, Epistemonikos, and gray literature to identify barriers, facilitators, and implementation strategies. Results: Five recommendations were made on the routine use of antibiotic prophylaxis in women undergoing instrumental vaginal delivery, routine use of antibiotic prophylaxis in women having a cesarean section, the choice of antiseptics and skin preparation prior to a cesarean section, and vaginal irrigation with antiseptics during a cesarean section. Implementation barriers and facilitators were identified, and indicators were created to assess adherence and outcomes. Conclusions: The formulated recommendations aim to provide guidance on how to improve quality of care and outcomes related to antibiotic prophylaxis and the choice of antiseptics in women undergoing instrumental vaginal delivery or a cesarean section.

Introdução: As infecções maternas e a sepse durante ou após o parto aumentam a mortalidade materna e causam uma alta carga de doenças na Região das Américas. O risco de infecção após a cesariana e o parto operatório pode ser reduzido com o uso apropriado de antissépticos cutâneos e profilaxia antibiótica. Objetivos: Sintetizar as recomendações desenvolvidas pela Organização Mundial da Saúde (OMS) para melhorar a qualidade da assistência e os desfechos de saúde relacionados à profilaxia antibiótica de rotina em mulheres submetidas a parto vaginal operatório, à profilaxia antibiótica de rotina em mulheres submetidas a parto cesáreo, à escolha de antissépticos e ao método de aplicação para a preparação da pele antes de uma cesariana e à ducha vaginal com antissépticos em mulheres submetidas à cesariana. Métodos: As diretrizes desenvolvidas pela OMS seguiram os métodos de desenvolvimento da diretriz GRADE (Grading of Recommendations Assessment Development and Evaluation), do Manual para o desenvolvimento de diretrizes da OMS. Foi realizada uma síntese das recomendações de quatro diretrizes da OMS. Além disso, foi realizada uma busca sistemática nas bases de dados PubMed, Lilacs, Health Systems Evidence e Epistemonikos e na literatura cinzenta de estudos realizados nas Américas para identificar barreiras, facilitadores e estratégias de implementação, e para estabelecer indicadores. Resultados: Foram formuladas cinco recomendações para a profilaxia antibiótica de rotina em mulheres submetidas a parto vaginal operatório, a profilaxia antibiótica de rotina em mulheres submetidas a parto cesáreo, a escolha de antissépticos e o método de aplicação para a preparação da pele antes de uma cesariana e a ducha vaginal com antissépticos em mulheres submetidas a cesariana. Foram identificadas barreiras e facilitadores para a implementação e foram criados indicadores de adesão e resultados. Conclusões: As recomendações formuladas fornecem orientações para melhorar a qualidade da assistência e os desfechos de saúde relacionados à profilaxia antibiótica e à escolha de antissépticos em mulheres submetidas a parto vaginal operatório ou cesariana.

Adverse Outcomes in Pregnant Women Hospitalized With Respiratory Syncytial Virus Infection: A Case Series.

We identified 10 women hospitalized with respiratory syncytial virus infection during pregnancy. Diagnoses included pneumonia/atelectasis (5), respiratory failure (2), and sepsis (2). Six had obstetrical complications during hospitalization, including 1 induced preterm birth. One required intensive care unit admission and mechanical ventilation. Four infants had complications at birth.

The global burden and trends of maternal sepsis and other maternal infections in 204 countries and territories from 1990 to 2019.

BACKGROUND: Maternal sepsis and other maternal infections (MSMI) have considerable impacts on women's and neonatal health, but data on the global burden and trends of MSMI are limited. Comprehensive knowledge of the burden and trend patterns of MSMI is important to allocate resources, facilitate the establishment of tailored prevention strategies and implement effective clinical treatment measures. METHODS: Based on data from the Global Burden of Disease database, we analysed the global burden of MSMI by the incidence, death, disability-adjusted life year (DALY) and maternal mortality ratio (MMR) in the last 30 years. Then, the trends of MSMI were assessed by the estimated annual percentage change (EAPC) of MMR as well as the age-standardized rate (ASR) of incidence, death and DALY. Moreover, we determined the effect of sociodemographic index (SDI) on MSMI epidemiological parameters. RESULTS: Although incident cases almost stabilized from 1990 to 2015, the ASR of incidence, death, DALY and MMR steadily decreased globally from 1990 to 2019. The burden of MSMI was the highest in the low SDI region with the fastest downward trends. MSMI is still one of the most important causes of maternal death in the developed world. Substantial diversity of disease burden and trends occurred in different regions and individual countries, most of which had reduced burden and downward trends. The MMR and ASR were negatively correlated with corresponding SDI value in 2019 in 204 countries/territories and 21 regions. CONCLUSION: These findings highlight significant improvement in MSMI care in the past three decades, particularly in the low and low-middle SDI regions. However, the increased burden and upward trends of MSMI in a few countries and regions are raising concern, which poses a serious challenge to maternal health. More tailored prevention measures and additional resources for maternal health are urgently needed to resolve this problem.

Effects of maternal geohelminth infections on allergy in early childhood.

BACKGROUND: Maternal geohelminth infections during pregnancy may protect against allergy development in childhood. OBJECTIVE: We sought to investigate the effect of maternal geohelminths on the development of eczema, wheeze, and atopy during the first 3 years of life. METHODS: A cohort of 2404 neonates was followed to 3 years of age in a rural district in coastal Ecuador. Data on wheeze and eczema were collected by means of questionnaire and physical examination at 13, 24, and 36 months of age. Atopy was measured based on skin prick test (SPT) reactivity to 9 allergens at 36 months. Maternal stool samples were examined for geohelminths by microscopy. Data on potential confounders was collected after birth by questionnaire. RESULTS: Geohelminths were observed in 45.9% of mothers. Eczema and wheeze were reported for 17.7% and 25.9%, respectively, of 2069 (86.1%) children with complete follow-up to 3 years, and allergen SPT reactivity to any allergen was present in 17.2% and to house dust mite in 8.7%. Maternal geohelminth infections were not significantly associated with eczema (adjusted odds ratio [OR], 1.26; 95% CI, 0.98-1.61), wheeze (adjusted OR, 1.02; 95% CI, 0.82-1.27), and SPT reactivity to any allergen (adjusted OR, 0.79; 95% CI, 0.61-1.01). In subgroup analyses maternal geohelminths were associated with a significantly reduced risk of SPT reactivity to mite and other perennial allergens, and maternal ascariasis was associated with an increased risk of eczema and reduced risk of SPT reactivity to all allergens. CONCLUSION: Our data do not support a protective effect of maternal infections with geohelminth parasites during pregnancy against the development of eczema and wheeze in early childhood, although there was evidence in subgroup analyses for a reduction in SPT reactivity to house dust mites and perennial allergens.

Fever and antibiotic use in maternal urinary tract infections during pregnancy and risk of congenital heart defects: Findings from the National Birth Defects Prevention Study.

BACKGROUND: Previous studies report an association between prenatal maternal urinary tract infections (UTI) and specific congenital heart defects (CHDs); however, the role of fever and antibiotic use on this association is poorly understood. Using data from the National Birth Defects Prevention Study, we examined whether the relationship between maternal UTIs during the periconceptional period and occurrence of CHDs is modified by the presence of fever due to UTI and corresponding antibiotic use among 11,704 CHD case infants and 11,636 live-born control infants. METHODS: Information on UTIs, fever associated with UTI and antibiotic use (sulfonamides, nitrofurantoin, cephalosporins, penicillin, macrolides, and quinolones) during pregnancy were obtained using a computer-assisted telephone interview. Using unconditional multivariable logistic regression, we calculated adjusted odds ratios (ORs) to determine the association between maternal UTIs and subtypes of CHDs. Analyses were stratified by the presence of fever and medication use associated with UTI. RESULTS: The prevalence of UTIs during the periconceptional period was 7.6% in control mothers, and 8.7% in case mothers. In the absence of fever, UTI was associated with secundum atrial septal defects (ASD) (OR 1.3; 95% confidence interval [CI] 1.1-1.5) and in the absence of antibiotics, UTI was associated with conotruncal defects as a group and for four specific CHDs. When fever and UTI occurred concomitantly, no significantly elevated odds ratios were noticed for any subtypes of CHD. Among women with UTIs who used antibiotics, an elevated but statistically non-significant estimate was observed for secundum ASD (OR 1.4; 95% CI 1.0-2.0). CONCLUSION: Findings in the present study suggest that fever due to UTI and corresponding maternal antibiotic use do not substantially modify the association between maternal UTIs and specific CHDs in offspring. Further studies with larger sample sizes are warranted to guide clinical management of UTIs during the periconceptional period.

Congenital cerebral palsy and prenatal exposure to self-reported maternal infections, fever, or smoking.

OBJECTIVE: The objective of the study was to investigate the association between maternal self-reported infections, fever, and smoking in the prenatal period and the subsequent risk for congenital cerebral palsy (CP). STUDY DESIGN: We included the 81,066 mothers of singletons born between 1996 and 2003 who participated in the Danish National Birth Cohort. Children were followed up through December 2008. Information on maternal infections, fever, smoking, and other demographic and lifestyle factors during pregnancy were reported by mothers in computer-assisted telephone interviews in early and midgestation. We identified 139 CP cases including 121 cases of spastic CP (sCP) as confirmed by the Danish National Cerebral Palsy Register. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: Self-reported vaginal infections were associated with an increased risk of CP and sCP (aHR, 1.52; 95% CI, 1.04-2.24; and aHR, 1.73; 95% CI, 1.16-2.60, respectively) and particularly untreated vaginal infections were associated with an increased risk of sCP (aHR, 1.95; 95% CI, 1.16-3.26). Fever was associated with the risk of CP (aHR, 1.53; 95% CI, 1.06-2.21). Smoking 10 or more cigarettes per day during pregnancy was also associated with sCP (aHR, 1.80; 95% CI, 1.10-2.94). There was a modest excess in risk for children exposed to both heavy smoking and vaginal infections. No other self-reported infections were significantly associated with CP. CONCLUSION: Self-reported vaginal infections, fever, and smoking 10 or more cigarettes per day during pregnancy were associated with a higher risk of overall CP and/or sCP.

Maternal infections during pregnancy and cerebral palsy: a population-based cohort study.

BACKGROUND: Cerebral palsy (CP) is a common motor disability in childhood. We examined the association between maternal infections during pregnancy and the risk of congenital CP in the child. METHODS: Liveborn singletons in Denmark between 1997 and 2003 were identified from the Danish National Birth Registry and followed from 1 year of life until 2008. Redemption of antibiotics from the National Register of Medicinal Product Statistics and maternal infections reported by the National Hospital Register were used as markers of maternal infection during pregnancy. CP diagnoses were obtained from the Danish Cerebral Palsy Registry. Adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated by Cox proportional hazard models. RESULTS: Of the 440 564 singletons with follow-up data, 840 were diagnosed with congenital CP. Maternal genito-urinary tract infections (HR 2.1, 95% CI 1.4, 3.2) were associated with CP in all births, in term births (HR 1.9, 95% CI 1.1, 3.2), in children with spastic CP (HR 2.1, 95% CI 1.4, 3.3), and among first-born children (HR 1.9, 95% CI 1.4, 3.3). Overall, we found associations between redeemed nitrofurantoin (HR 1.7, 95% CI 1.1, 2.8) and CP. Among trimester-specific exposures, CP risk was associated with prescriptions redeemed in the first trimester for any antibacterials, beta-lactam antibacterials, and nitrofurantoin, an antibiotic commonly used to treat lower urinary tract infection, and genito-urinary tract infections in the third trimester. CONCLUSION: Genito-urinary tract infections and antibiotic use during pregnancy were associated with increased risks of CP, indicating that some maternal infections or causes of maternal infections present in prenatal life may be part of a causal pathway leading to CP.

Effect of Antimicrobial Exposure in Pregnancy on Adverse Pregnancy Outcomes and Admission Rate to the Neonatal Intensive Care Unit: A Multi-Center Cohort Study.

Purpose: Antimicrobial agents are frequently prescribed during pregnancy. This study aims to explore the association between antimicrobial exposure and pregnancy outcomes. Patients and Methods: A multi-center retrospective cohort study of pregnant patients (n=370) was conducted in 22 tertiary hospitals in China. Adverse pregnancy outcomes and admission of neonate to neonatal intensive care unit (NICU) were considered as outcomes. The effect of antimicrobial exposure on pregnancy outcomes was assessed using a multivariate logistic regression model. Results: Use of first-generation cephalosporins during pregnancy was associated with a significantly higher risk of adverse pregnancy outcomes (odds ratio [OR]: 3.64 [95% confidence interval, CI: 1.43-9.24], P = 0.007) and admission of neonate to the NICU (OR: 3.41, 95% CI: 1.37-8.53, P=0.009) compared with use of third-generation cephalosporins, after adjusting for gestational age of exposure to antimicrobial agents, cesarean section, and antimicrobial dose. Similarly, a higher risk of adverse pregnancy outcomes (OR: 14.76, 95% CI: 4.43-49.11) and neonatal NICU admission (OR: 11.74, 95% CI: 3.59-38.35) were observed among women with first-generation cephalosporins use compared with mothers with no antimicrobial use. Conclusion: Both first- and third-generation cephalosporins use was associated with an increased risk of adverse pregnancy and neonatal outcomes. In addition, first-generation cephalosporins were associated with an increased risk of those pregnant and neonatal outcomes, when compared with third-generation cephalosporins. We should require to determine the indications and contraindications for use of cephalosporins during pregnancy.

Antenatal interventions to reduce risk of low birth weight related to maternal infections during pregnancy.

BACKGROUND: Maternal infections during pregnancy have been linked to increased risk of adverse birth outcomes, including low birth weight (LBW), preterm birth (PTB), small for gestational age (SGA), and stillbirth (SB). OBJECTIVES: The purpose of this article was to summarize evidence from published literature on the effect of key interventions targeting maternal infections on adverse birth outcomes. METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and CINAHL Complete between March 2020 and May 2020 with an update to cover until August 2022. We included randomized controlled trials (RCTs) and reviews of RCTs of 15 antenatal interventions for pregnant women reporting LBW, PTB, SGA, or SB as outcomes. RESULTS: Of the 15 reviewed interventions, the administration of 3 or more doses of intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine [IPTp-SP; RR: 0.80 (95% CI: 0.69, 0.94)] can reduce risk of LBW compared with 2 doses. The provision of insecticide-treated bed nets, periodontal treatment, and screening and treatment of asymptomatic bacteriuria may reduce risk of LBW. Maternal viral influenza vaccination, treatment of bacterial vaginosis, intermittent preventive treatment with dihydroartemisinin-piperaquine compared with IPTp-SP, and intermittent screening and treatment of malaria during pregnancy compared with IPTp were deemed unlikely to reduce the prevalence of adverse birth outcomes. CONCLUSIONS: At present, there is limited evidence from RCTs available for some potentially relevant interventions targeting maternal infections, which could be prioritized for future research.

Maternal sepsis.

Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting from infection that can arise during pregnancy, childbirth, postabortion, or in the postpartum period. Validated diagnostic criteria of maternal sepsis and septic shock may reduce the impact of this condition on maternal health worldwide, but the lack of consensus on adequate tools due to the overlap between physiological adaptations that occur during pregnancy and signs and symptoms of infection and sepsis can delay both diagnosis and treatment. In the absence of evidence-based guidelines for obstetric populations, the WHO recommends the use of the "Surviving Sepsis Campaign" sepsis protocols for maternal care adapted to the local obstetric population. Interventions within the first hour from diagnosis have been proposed in 2021 to emphasize the state of emergency of a maternal sepsis. This review will highlight the utility of standardized diagnostic criteria, the implemented approaches for the prevention and treatment of maternal infections, and the strategies for early management of critically ill parturients.

Consequences of Viral Infection and Cytokine Production During Pregnancy on Brain Development in Offspring.

Infections during pregnancy can seriously damage fetal neurodevelopment by aberrantly activating the maternal immune system, directly impacting fetal neural cells. Increasing evidence suggests that these adverse impacts involve alterations in neural stem cell biology with long-term consequences for offspring, including neurodevelopmental disorders such as autism spectrum disorder, schizophrenia, and cognitive impairment. Here we review how maternal infection with viruses such as Influenza A, Cytomegalovirus, and Zika during pregnancy can affect the brain development of offspring by promoting the release of maternal pro-inflammatory cytokines, triggering neuroinflammation of the fetal brain, and/or directly infecting fetal neural cells. In addition, we review insights into how these infections impact human brain development from studies with animal models and brain organoids. Finally, we discuss how maternal infection with SARS-CoV-2 may have consequences for neurodevelopment of the offspring.

Maternal-Fetal Infections (Cytomegalovirus, Toxoplasma, Syphilis): Short-Term and Long-Term Neurodevelopmental Outcomes in Children Infected and Uninfected at Birth.

(1) Background: Infections in pregnancy can lead to miscarriage, premature birth, infections in newborns, and developmental disabilities in babies. Infected infants, symptomatic at birth, can have long-term sequelae, and asymptomatic babies are also at increased risk of developing long-term sensorineural outcomes. Targeted therapy of the pregnant mother can reduce fetal and neonatal harm. (2) Aim of the study: To explore the association between symptoms and time of onset of long-term sequelae in infected children born from mothers who contracted an infection during pregnancy, by a long-term multidisciplinary follow-up. (3) Methods: For up to 2−4 years, we evaluated cognitive, motor, audiological, visual, and language outcomes in infants with symptomatic and asymptomatic congenital infections and in uninfected infants. (4) Results: 186 infants born from women who acquired Cytomegalovirus infection (n = 103), Toxoplasma infection (n = 50), and Syphilis (n = 33) during pregnancy were observed. Among them, 119 infants acquired the infection in utero. Infected infants, symptomatic at birth, obtained lower scores on the Cognitive and Motor Scale on Bayley-III compared to asymptomatic and uninfected infants (p = 0.026; p = 0.049). Many severe or moderate sequelae rose up within the first year of life. At 24 months, we observed sequelae in 24.6% (14/57) of infected children classified as asymptomatic at birth, compared to 68.6% (24/35) of symptomatic ones (χ2 = 15.56; p < 0.001); (5) Conclusions: Infected babies symptomatic at birth have a worse prognosis than asymptomatic ones. Long-term sequelae may occur in infected children asymptomatic at birth after the first year of life. Multidisciplinary follow-up until 4−6 years of age should be performed in all infected children, regardless of the presence of symptoms at birth.

Methodological Considerations for Preterm Birth Research.

Complications from preterm birth are a leading cause of infant mortality, with long-term implications for morbidity and quality of life of preterm infants. There are many important risk factors for preterm births however in this article, we focus on the maternal infection etiological pathway, given its significance in low-to-middle income countries. In high preterm birth settings such as sub-Saharan Africa, maternal HIV infection and antiretroviral therapy (ART) use have been associated with an increased risk of preterm births. Consequently, we highlight methodological considerations related to selection and measurement bias in preterm birth research. We further illustrate the potential impact of these biases in studies investigating the relationship between HIV/ART and preterm births. We also briefly discuss issues related to population-level estimations based on routinely collected clinical or civil registration data. We conclude by emphasizing the importance of strengthening of antenatal care services to improve quality of population data as well as optimizing current and future study designs, by taking into account the important methodological considerations described in this article.

Association of Autism with Maternal Infections, Perinatal and Other Risk Factors: A Case-Control Study.

This case-control study explores the association between pregnancy/birth complications and other factors with Autism Spectrum Disorder (ASD) in Lebanese subjects aged 2-18 years. Researchers interviewed 136 ASD cases from the American University of Beirut Medical Center Special Kids Clinic, and 178 controls selected by systematic digit dialing in the Greater-Beirut area. Male gender (Adjusted Odds Ratio [95% CI]: 3.9 [2.2-7.0]); postpartum feeding difficulties (2.5 [1.2-5.4]); maternal infections/complications during pregnancy (2.9 [1.5-5.5], 2.1 [1.1-3.9]); consanguinity (2.5 [1.0-6.0]); family history of psychiatric disorders (2.2 [1.1-4.4]) were risk factors for ASD. Being born first/second (0.52 [0.28-0.95]) and maternal psychological support during pregnancy (0.49 [0.27-0.89]) were negatively associated with ASD. Identifying ASD correlates is crucial for instigating timely screening and subsequent early intervention.