Hypertensive disorders of pregnancy and the risk of maternal dementia: a systematic review and meta-analysis.

OBJECTIVE: Hypertensive disorders of pregnancy, including preeclampsia, are associated with an increased risk for maternal cardiovascular disease, stroke, and chronic kidney disease. However, their association with subsequent maternal dementia or cognitive impairment is less well understood. This study aimed to review and synthesize the published literature on hypertensive disorders of pregnancy and the subsequent risk for maternal dementia or cognitive impairment. DATA SOURCES: PubMed, Web of Science, Pyschinfo, and CINAHL were searched from database inception until July 31, 2022, for observational studies of hypertensive disorders of pregnancy and maternal dementia or cognitive impairment. STUDY ELIGIBILITY CRITERIA: Selected studies included the following: a population of pregnant women, exposure to a hypertensive disorder of pregnancy of interest, and at least 1 primary outcome (dementia) or secondary outcome (cognitive impairment). Two reviewers were involved in study selection. METHODS: We followed the Meta-analyses of Observational Studies in Epidemiology guidelines throughout. Random-effects meta-analyses were used to calculate the overall pooled estimates. Bias was assessed using an adapted version of the validated Newcastle-Ottawa Quality Assessment tool. RESULTS: A total of 25 eligible studies were identified and included 2,501,673 women. Preeclampsia was associated with a significantly increased risk for vascular dementia (adjusted hazard ratio, 1.89; 95% confidence interval, 1.47-2.43), whereas no clear association was noted between preeclampsia and Alzheimer's disease (adjusted hazard ratio, 1.27; 95% confidence interval, 0.95-1.70), nor between preeclampsia and any (undifferentiated) dementia (adjusted hazard ratio, 1.18; 95% confidence interval, 0.95-1.47). However, in an analysis restricted to women aged 65 years and older, preeclampsia was associated with an increased risk for Alzheimer's disease (adjusted hazard ratio, 1.92; 95% confidence interval, 1.35-2.73) and any dementia (adjusted hazard ratio, 1.87; 95% confidence interval, 1.21-2.91). CONCLUSION: Women whose pregnancies were complicated by preeclampsia seem to be at a substantially increased future risk for vascular dementia. The longer-term risks among these women with regards to Alzheimer's disease and other forms of dementia are less clear.

Pregnancy and birth complications and long-term maternal mental health outcomes: A systematic review and meta-analysis.

BACKGROUND: Few studies have examined the associations between pregnancy and birth complications and long-term (>12 months) maternal mental health outcomes. OBJECTIVES: To review the published literature on pregnancy and birth complications and long-term maternal mental health outcomes. SEARCH STRATEGY: Systematic search of Cumulative Index to Nursing and Allied Health Literature (CINAHL), Excerpta Medica Database (Embase), PsycInfo®, PubMed® and Web of Science from inception until August 2022. SELECTION CRITERIA: Three reviewers independently reviewed titles, abstracts and full texts. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and appraised study quality. Random-effects meta-analyses were used to calculate pooled estimates. The Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines were followed. The protocol was prospectively registered on the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022359017). MAIN RESULTS: Of the 16 310 articles identified, 33 studies were included (3 973 631 participants). Termination of pregnancy was associated with depression (pooled adjusted odds ratio, aOR 1.49, 95% CI 1.20-1.83) and anxiety disorder (pooled aOR 1.43, 95% CI 1.20-1.71). Miscarriage was associated with depression (pooled aOR 1.97, 95% CI 1.38-2.82) and anxiety disorder (pooled aOR 1.24, 95% CI 1.11-1.39). Sensitivity analyses excluding early pregnancy loss and termination reported similar results. Preterm birth was associated with depression (pooled aOR 1.37, 95% CI 1.32-1.42), anxiety disorder (pooled aOR 0.97, 95% CI 0.41-2.27) and post-traumatic stress disorder (PTSD) (pooled aOR 1.75, 95% CI 0.52-5.89). Caesarean section was not significantly associated with PTSD (pooled aOR 2.51, 95% CI 0.75-8.37). There were few studies on other mental disorders and therefore it was not possible to perform meta-analyses. CONCLUSIONS: Exposure to complications during pregnancy and birth increases the odds of long-term depression, anxiety disorder and PTSD.

Access to nutrition advice and knowledge, attitudes and practices of pregnant women in Ireland: A cross-sectional study.

BACKGROUND: Healthy nutritional status, appropriate gestational weight gain and a balanced diet are important predictors of perinatal health outcomes. However, gaps exist in the translation of nutrition recommendations into dietary practices of women before and during pregnancy. The present study explored the relationship between access to nutrition advice, nutrition knowledge, attitudes and practices among pregnant women. METHODS: Pregnant women aged > 18 years in Ireland were eligible to complete a self-administered survey consisting of four subsections (demographics, nutrition knowledge, attitudes and practices) delivered online through Qualtrics. RESULTS: In this convenience sample (n = 334, median [interquartile range] gestation, 25.0 [16.0, 34.0] weeks), 85% had at least an honours bachelor degree and 88.9% planned their pregnancy. Two out of five women received nutrition advice during their pregnancy, mostly from a midwife. Based on the percentage of correct answers (of 15 questions), women with previous nutrition education (e.g., school home economics) had better median [interquartile range] nutrition knowledge than those with none (80.0% [66.7, 86.7%] vs. 73.3% [60.0, 80.0%], p < 0.001). Those who received nutrition advice during pregnancy did not score higher than those who did not (73.3% [66.7, 80.0%] vs. 73.3% [66.7, 80.0%], p = 0.6). Over three-quarters of participants considered nutritional supplement use to be very or extremely important. Although 73.6% and 92.4% took supplements prior to and during pregnancy, only 25.7% reported compliance with periconceptional folic acid supplementation guidelines. Half of respondents considered healthy eating during pregnancy as very or extremely important. CONCLUSIONS: Access to nutrition advice during pregnancy was inadequate with poor nutrition knowledge, attitudes and practices observed. Accessible, evidence-based nutrition education for women prior to and during pregnancy is required.

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis.

AIMS: To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. METHODS AND RESULTS: Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. CONCLUSION: These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

A proteomic profile of the healthy human placenta.

BACKGROUND: The placenta remains one of the least studied organs within the human body. Yet, placental dysfunction has been associated with various pregnancy complications leading to both maternal and fetal death and long-term health consequences. The aim of this study was to characterise the protein networks of healthy term placental sub-anatomical regions using label free quantification mass spectrometry. METHODS: Three healthy placentae were sampled at five sample sites and each biopsy was dissected into maternal-, middle-, and fetal- sub-anatomical regions. Quadrupole-orbitrap mass spectrometer was used in data dependant analysis mode to identify 1859 unique proteins before detailed differential expression between regions. RESULTS: Protein profiling identified 1081, 1086, and 1101 proteins in maternal, middle, and fetal sub-anatomical regions respectively. Differentially expressed proteins were identified considering the effect between sample site location and sub-anatomical region on protein expression. Of these, 374 differentially expressed proteins (Two-way ANOVA adjusted p-value < 0.05, HSD Tukey adjusted p-value 0.05) were identified between sample site locations and sub-anatomical regions. The placenta specific disease map NaviCenta ( https://www.sbi.uni-rostock.de/minerva/index.xhtml?id=NaviCenta ) was used to focus functional analysis results to the placenta specific context. Subsequently, functional analysis with a focus on senescence, and mitochondrial function were performed. Significant differences were observed between sub-anatomical regions in protein intensity and composition. A decrease in anti-senescent proteins within the maternal sub-anatomical region, and an increase in proteins associated with a switch from ATP to fatty acid consumption as a source of energy between middle and fetal sub-anatomical regions were observed. CONCLUSION: These results suggest that normal proteomic variations exist within the anatomical structure of the placenta, thus recommending serial sectioning methodology for consistent placental research.

Hypertensive disorders of pregnancy and long-term risk of maternal stroke-a systematic review and meta-analysis.

OBJECTIVE: Hypertensive disorders of pregnancy are associated with a long-term risk for cardiovascular disease among parous patients later in life. However, relatively little is known about whether hypertensive disorders of pregnancy are associated with an increased risk for ischemic stroke or hemorrhagic stroke in later life. This systematic review aimed to synthesize the available literature on the association between hypertensive disorders of pregnancy and the long-term risk for maternal stroke. DATA SOURCES: PubMed, Web of Science, and CINAHL were searched from inception to December 19, 2022. STUDY ELIGIBILITY CRITERIA: Studies were only included if the following criteria were met: case-control or cohort studies that were conducted with human participants, were available in English, and that measured the exposure of a history of hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, chronic hypertension, or superimposed preeclampsia) and the outcome of maternal ischemic stroke or hemorrhagic stroke. METHODS: Three reviewers extracted the data and appraised the study quality following the Meta-analyses of Observational Studies in Epidemiology guidelines and using the Newcastle-Ottawa scale for risk of bias assessment. RESULTS: The primary outcome was any stroke (undifferentiated) and secondary outcomes included ischemic stroke and hemorrhagic stroke. The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews under identifier CRD42021254660. Of 24 studies included (10,632,808 study participants), 8 studies examined more than 1 outcome of interest. Hypertensive disorders of pregnancy were significantly associated with any stroke (adjusted risk ratio, 1.74; 95% confidence interval, 1.45-2.10). Preeclampsia was significantly associated with any stroke (adjusted risk ratio, 1.75; 95% confidence interval, 1.56-1.97), ischemic stroke (adjusted risk ratio, 1.74; 95% confidence interval, 1.46-2.06), and hemorrhagic stroke (adjusted risk ratio, 2.77; 95% confidence interval, 2.04-3.75). Gestational hypertension was significantly associated with any stroke (adjusted risk ratio, 1.23; 95% confidence interval, 1.20-1.26), ischemic stroke (adjusted risk ratio, 1.35; 95% confidence interval, 1.19-1.53), and hemorrhagic stroke (adjusted risk ratio, 2.66; 95% confidence interval, 1.02-6.98). Chronic hypertension was associated with ischemic stroke (adjusted risk ratio, 1.49; 95% confidence interval, 1.01-2.19). CONCLUSION: In this meta-analysis, exposure to hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, seems to be associated with an increased risk for any stroke and ischemic stroke among parous patients in later life. Preventive interventions may be warranted for patients who experience hypertensive disorders of pregnancy to reduce their long-term risk for stroke.

Maternal and perinatal outcomes following a diagnosis of Hodgkin lymphoma during or prior to pregnancy: A systematic review.

BACKGROUND: The initial peak incidence of Hodgkin lymphoma (HL) occurs during reproductive years. OBJECTIVES: Synthesise published literature on the relationship between HL and maternal and perinatal outcomes. SEARCH STRATEGY: Systematic search of PubMed/Medline, Cochrane Library, Scopus, Embase and Science Direct from inception to June 2022, supplemented by hand-searching reference lists. SELECTION CRITERIA: Two reviewers independently reviewed titles, abstracts and full-text articles. Published studies containing original data were eligible. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and appraised study quality. Outcomes for pregnant women with a previous/current diagnosis of HL were compared separately with women never diagnosed with HL. Where data permitted, meta-analyses of odds ratios and proportions were performed. Certainty of evidence was determined using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. MAIN RESULTS: Of the 5527 studies identified, 33 met the inclusion criteria. In the groups with HL before pregnancy and HL during pregnancy, adjusted odds ratios were not statistically significant for congenital malformation (aOR 1.7, 95% CI 0.9-3.1, and aOR 1.84, 95% CI 0.81-4.15, respectively), preterm birth (PTB) (aOR 0.99, 95% CI 0.65-1.51, and aOR 6.74, 95% CI 0.52-88.03, respectively) and miscarriage (aOR 0.78, 95% CI 0.55-1.10, and aOR 0.38, 95% CI 0.05-2.72, respectively). The aORs for all other outcomes were not statistically significant, except for blood transfusion (aOR 1.38, 95% CI 1.05-1.82) and venous thromboembolism (VTE) (aOR 7.93, 95% CI 2.97-21.22) in the group for HL during pregnancy. The proportion of anaemia was also increased in this group (69%, 95% CI 57%-80% vs 4%, 95% CI 4%-5%, respectively). The GRADE certainty of findings ranged from low to very low. CONCLUSIONS: Rates of most adverse pregnancy outcomes among women with a previous/current HL diagnosis are not increased significantly compared with the general pregnant population. Women with HL diagnosed during pregnancy may have a higher PTB rate and increased likelihood of VTE, anaemia and blood transfusion; however, small study numbers and the low to very low GRADE certainty of findings preclude firm conclusions.

Association between socioeconomic status with pregnancy and neonatal outcomes: An international multicenter cohort.

INTRODUCTION: Previous evidence examining the association between socioeconomic status and pregnancy complications are conflicted and often limited to using area-based measures of socioeconomic status. In this study, we aimed to examine the association between individual-level socioeconomic factors and a wide range of adverse pregnancy and neonatal outcomes using data from the IMPROvED birth cohort conducted in Sweden, the Netherlands and Republic of Ireland. MATERIAL AND METHODS: The study cohort consisted of women who participated in the IMPROvED birth cohort between 2013 and 2017. Data on socioeconomic factors were self-reported and obtained at 15 weeks' gestation, and included level of education, employment status, relationship status, and income. Data on pregnancy and neonatal outcomes included gestational hypertension, pre-eclampsia, gestational diabetes mellitus, emergency cesarean section, preterm birth, post term delivery, small for gestational age and Apgar score at 1 min. These data were obtained within 72 h following delivery and confirmed using medical records. Multivariable logistic regression examined the association between each socioeconomic variable and each outcome separately adjusting for maternal age, maternal body mass index, maternal smoking, maternal alcohol consumption and cohort center. We also examined the effect of exposure to any ≥2 risk factors compared to none. RESULTS: A total of 2879 participants were included. Adjusted results suggested that those with less than third level of education had an increased odds of gestational hypertension (OR: 1.74, 95% CI: 1.23-2.46), while those on a middle level of income had a reduced odds of emergency cesarean section (OR: 0.59, 95% CI: 0.42-0.84). No significant associations were observed between socioeconomic variables and neonatal outcomes. Exposure to any ≥2 socioeconomic risk factors was associated with an increased risk of preterm birth (OR: 1.75, 95% CI: 1.06-2.89). CONCLUSIONS: We did not find strong evidence of associations between individual-level socioeconomic factors and pregnancy and neonatal outcomes in high-income settings overall, with only few significant associations observed among pregnancy outcomes.

Heterogenous Differences in Cellular Senescent Phenotypes in Pre-Eclampsia and IUGR following Quantitative Assessment of Multiple Biomarkers of Senescence.

Premature ageing of the placenta in pregnancy outcomes is associated with the persistent presence of oxidative stress and placental insufficiency reducing its functional capacity. In this study, we investigated cellular senescence phenotypes of pre-eclampsia and IUGR pregnancies by simultaneously measuring several biomarkers of senescence. Maternal plasma and placental samples were collected at term gestation from nulliparous women undergoing pre-labour elective caesarean section with pre-eclampsia without intrauterine growth restriction (PE; n = 5), pre-eclampsia associated with intrauterine growth restriction (n = 8), intrauterine growth restriction (IUGR < 10th centile; n = 6), and age-matched controls (n = 20). Placental absolute telomere length and senescence gene analysis was performed by RTqPCR. The expression of cyclin-dependent kinase inhibitors (p21 and p16) was determined by Western blot. Senescence-associated secretory phenotypes (SASPs) were evaluated in maternal plasma by multiplex ELISA assay. Placental expression of senescence-associated genes showed significant increases in CHEK1, PCNA, PTEN, CDKN2A, and CCNB-1 (p < 0.05) in pre-eclampsia, while TBX-2, PCNA, ATM, and CCNB-1 expression were evident (p < 0.05) and were significantly decreased in IUGR compared with controls. Placental p16 protein expression was significantly decreased in pre-eclampsia only compared with controls (p = 0.028). IL-6 was significantly increased in pre-eclampsia (0.54 pg/mL ± 0.271 vs. 0.3 pg/mL ± 0.102; p = 0.017) while IFN-γ was significantly increased in IUGR (4.6 pg/mL ± 2.2 vs. 2.17 pg/mL ± 0.8; p = 0.002) compared with controls. These results provide evidence of premature senescence in IUGR pregnancies, and while cell cycle checkpoint regulators are activated in pre-eclampsia, the cellular phenotype is one of cell repair and subsequent proliferation rather than progression to senescence. The heterogeneity of these cellular phenotypes highlights the complexity of characterising cellular senescence and may equally be indicative of the differing pathophysiological insults unique to each obstetric complication.

Prenatal maternal cortisol, stress and anxiety, and childhood obesity at 5 years: a nested case-control study.

BACKGROUND: Paediatric obesity is a global public health issue. Prenatal maternal mental health is potentially implicated in the development of childhood obesity. This study examined associations between prenatal maternal cortisol, self-reported stress, anxiety and depression in the second trimester, and childhood overweight and obesity at 5 years of age. METHODS: A nested case-control study was conducted using data from the Irish prospective longitudinal birth cohort SCOPE BASELINE. Cases were children with overweight or obesity, operationalised as having a BMI z-score above +2 standard deviations. Controls were children with a BMI z-score between -0.5 and 0.5 standard deviations at 5 years of age. Two to one matching by sex was conducted. Thirty-eight cases and 83 sex-matched controls were included. Maternal serum cortisol concentration and self-reported stress, anxiety and depression were measured at 15 ± 1 and 20 ± 1 weeks gestation. Conditional logistic regression analyses were conducted to examine associations between prenatal maternal cortisol and self-reported stress, anxiety and depression, and childhood overweight and obesity. RESULTS: Despite some evidence for associations between anxiety and depression, and child BMI z-scores in univariate analyses, adjusted models indicated no associations between prenatal maternal stress (OR: 1.02, 95% CI: 0.94-1.12), anxiety (OR: 1.03, 95% CI: 0.97-1.09), depression (OR: 1.04, 95% CI: 0.91-1.19), or cortisol concentration (OR: 0.99, 95% CI: 0.99-1.00) and child BMI z-score. CONCLUSION: Our findings do not provide support for associations between foetal exposure during the second trimester of pregnancy and maternal cortisol, stress and anxiety, and childhood overweight or obesity at 5 years of age.

Chronic kidney disease and adverse pregnancy outcomes: a systematic review and meta-analysis.

OBJECTIVE: Limited evidence exists on the role that the cause of chronic kidney disease plays in determining pregnancy outcomes. The aim of this systematic review and meta-analysis was to examine the association between chronic kidney disease and adverse pregnancy outcomes by the cause and severity of chronic kidney disease where reported. The protocol was registered under the International Prospective Register of Systematic Reviews (CRD42020211925). DATA SOURCES: PubMed, Embase, and Web of Science were searched until May 24, 2021, supplemented with reference list checking. STUDY ELIGIBILITY CRITERIA: Studies that compared the pregnancy outcomes in women with or without chronic kidney disease were included. Two reviewers independently screened titles, abstracts, and full-text articles according to a priori defined inclusion criteria. METHODS: Data extraction and quality appraisal were performed independently by 3 reviewers. The grading of recommendations, assessment, development, and evaluation approach was used to assess the overall certainty of the evidence. Random-effects meta-analyses were used to calculate the pooled estimates using the generic inverse variance method. The primary outcomes included preeclampsia, cesarean delivery, preterm birth (<37 weeks' gestation), and small for gestational age babies. RESULTS: Of 4076 citations, 31 studies were included. Prepregnancy chronic kidney disease was significantly associated with a higher odds of preeclampsia (pooled crude odds ratio, 8.13; [95% confidence interval, 4.41-15], and adjusted odds ratio, 2.58; [1.33-5.01]), cesarean delivery (adjusted odds ratio, 1.65; [1.21-2.25]), preterm birth (adjusted odds ratio, 1.73; [1.31-2.27]), and small for gestational age babies (adjusted odds ratio, 1.93; [1.06-3.52]). The association with stillbirth was not statistically significant (adjusted odds ratio, 1.67; [0.96-2.92]). Subgroup analyses indicated that different causes of chronic kidney disease might confer different risks and that the severity of chronic kidney disease is associated with a risk of adverse pregnancy outcomes, as pregnancies with later stages of chronic kidney disease had higher odds of preeclampsia, preterm birth, and small for gestational age babies than those at earlier stages. The grading of recommendations, assessment, development, and evaluation certainty of the evidence overall was "very low". CONCLUSION: This meta-analysis quantified the associations between prepregnancy chronic kidney disease and adverse pregnancy outcomes, both overall and according to the cause and severity of the disease. These findings might support the clinicians aiming to counsel women having chronic kidney disease by allowing them to tailor their advice according to cause and severity of the chronic kidney disease. We identified the gaps in the literature, and further studies examining the effect of specific kidney diseases and other clinical characteristics (eg, proteinuria, hypertension) on adverse pregnancy outcomes are warranted.

The association between hypertensive disorders of pregnancy and childhood asthma.

BACKGROUND: Asthma is a chronic long-term inflammatory disease of the airways and is a major global health challenge. The primary aim of this study was to investigate the association between hypertensive disorders of pregnancy (HDP) and the risk of asthma at or before the age of seven years using the UK Millennium Cohort Study (MCS). METHODS: Overall, 18,552 families were recruited for wave one of the MCS when the child was 9 months old, and subsequently participated in waves two, three and four when they were three, five and seven years respectively. HDP were self-reported by mothers in wave one. The primary outcome was a parent-reported diagnosis of "ever asthma" at seven years, based on responses to a validated questionnaire. RESULTS: Following adjustment for a range of potential confounding factors, HDP was found to be associated with asthma in the offspring (adjusted odds ratio (AOR 1.35; 95% CI: 1.15-1.59)). A larger effect estimate was observed amongst children exposed to HDP and born preterm (AOR 1.81; 95% CI: 1.25-2.61) or small for gestational age (SGA) (AOR = 1.58; (95% CI: 1.15-2.18)). CONCLUSIONS: In conclusion, children exposed to HDP may be at increased odds of asthma diagnosis by age seven, particularly if they were born preterm or SGA. IMPACT: There is a paucity of data investigating the relationship between hypertensive disorders of pregnancy and childhood asthma, with recent studies showing conflicting results. Our study investigated this relationship using a large cohort with ample information on a wide range of confounding factors. Our study showed that individuals exposed to HDP may be at increased odds of asthma diagnosis by age seven years, particularly if they were also born SGA or preterm.

Fetal and maternal outcomes after maternal biologic use during conception and pregnancy: A systematic review and meta-analysis.

BACKGROUND: Biologic medications, specifically tumour necrosis factor-α (TNF-α) inhibitors, have become increasingly prevalent in the treatment of chronic inflammatory disease (CID) in pregnancy. OBJECTIVE: To determine pregnancy outcomes in women with CID exposed to biologics during pregnancy. SEARCH STRATEGY: PubMed and EMBASE databases were searched through January 1998-July 2021. SELECTION CRITERIA: Peer-reviewed, English-language cohort, case-control, cross-sectional studies, and case series that contained original data. DATA COLLECTION AND ANALYSIS: Two authors independently conducted data extraction. A meta-analysis of proportions using a random-effects model was used to pool outcomes. Linear regression analysis was used to compare the mean of proportions of outcomes across exposure groups using the 'treated' group as the reference category. All studies were evaluated using an appropriate quality assessment tool. The GRADE approach was used to assess the overall certainty of evidence. MAIN RESULTS: Thirty-five studies, describing 11 172 pregnancies, were eligible for inclusion. Analysis showed pooled proportions for congenital malformations as follows: treated 0.04 (95% CI 0.03-0.04; I2  = 77) versus disease-matched 0.04 (95% CI 0.03-0.05. I2  = 86; p = 0.238); preterm delivery treated 0.04 (95% CI 0.10-0.14; I2  = 88) versus disease-matched 0.10 (95% CI 0.09-0.12; I2  = 87; p = 0.250); severe neonatal infection: treated 0.05 (95% CI 0.03-0.07; I2  = 88) versus disease-matched 0.05 (95% CI 0.02-0.07; I2  = 94; p = 0.970); low birthweight: treated 0.10 (95% CI 0.07-0.12; I2  = 93) versus disease-matched 0.08 (95% CI 0.07-0.09; I2  = 0; p = 0.241); pooled miscarriage: treated 0.13 (95% CI 0.10-0.15; I2  = 77) versus disease-matched 0.08 (95% CI 0.04-0.11; I2  = 5; p = 0.078); pre-eclampsia; treated 0.01 (95% CI 0.01-0.02; I2  = 0) versus disease-matched 0.01 (95% CI 0.00-0.01; I2  = 0; p = 0.193). No statistical differences in proportions were observed. GRADE certainty of findings was low to very low. CONCLUSION: We demonstrated comparable pregnancy outcomes in pregnancies exposed to biologics, disease-matched controls and CID-free pregnancies using the GRADE approach.

Obstetrical mode of delivery and behavioural outcomes in childhood and adolescence: findings from the Millennium Cohort Study.

PURPOSE: To examine the association between mode of delivery (in particular caesarean section) and behavioural outcomes in offspring at six time-points between age 3 and 17 years. METHODS: Similar to previous work examining the association between mode of delivery and behavioural outcomes in offspring at age 7, we used maternal-reported data from the Millennium Cohort Study. Data on mode of delivery were collected when children were 9 months and categorised as spontaneous vaginal delivery, assisted vaginal delivery, induced vaginal delivery, emergency caesarean section, planned caesarean section and caesarean section after induction of labor. Data on behavioural outcomes were collected at ages 3, 5, 7, 11, 14 and 17 years using the Strengths and Difficulties Questionnaire (SDQ). Crude and adjusted logistic regression examined mode of delivery-behavioural difficulties relationship, using validated SDQ cut-off points (total SDQ ≥ 17, emotional ≥ 5, conduct ≥ 4, hyperactivity ≥ 7, peer problems ≥ 4 and prosocial behaviour ≤ 4). Multilevel models with linear splines examined the association between mode of delivery and repeated measures of SDQ. RESULTS: There were 18,213 singleton mother-child pairs included at baseline, 13,600 at age 3; 13,831 at age 5; 12,687 at age 7; 11,055 at age 11; 10,745 at age 14 and 8839 at age 17. Adjusted logistic regression suggested few associations between mode of delivery and behavioural outcomes at ages 3, 5, 11, 14 and 17 years using validated SDQ cut-off points. After correction for multiple testing, only the protective association between planned caesarean section-Conduct difficulties at age 5 years (OR 0.63, 95% CI 0.46, 0.85) and positive association between caesarean section after induction-Emotional difficulties at age 11 years (OR 1.57, 95% CI 1.19, 2.07) remained statistically significant. Multilevel modelling suggested mean SDQ scores were similar in each mode of delivery group at each time point. CONCLUSIONS: Results of this study indicate that mode of delivery is unlikely to have a major impact on behavioural outcomes.

Puberty timing and markers of cardiovascular structure and function at 25 years: a prospective cohort study.

BACKGROUND: Whether earlier onset of puberty is associated with higher cardiovascular risk in early adulthood is not well understood. Our objective was to examine the association between puberty timing and markers of cardiovascular structure and function at age 25 years. METHODS: We conducted a prospective birth cohort study using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were born between April 1, 1991, and December 31, 1992. Exposure of interest was age at peak height velocity (aPHV), an objective and validated growth-based measure of puberty onset. Outcome measures included cardiovascular structure and function at age 25 years: carotid intima-media thickness (CIMT), left ventricular mass index (LVMI) and relative wall thickness (RWT), pulse wave velocity (PWV) and systolic blood pressure (SBP). Multiple imputation was used to impute missing data on covariates and outcomes. Linear regression was used to examine the association between aPHV and each measure of cardiac structure and function, adjusting for maternal age, gestational age, household social class, maternal education, mother's partner's education, breastfeeding, parity, birthweight, maternal body mass index, maternal marital status, maternal prenatal smoking status and height and fat mass at age 9. All analyses were stratified by sex. RESULTS: A total of 2752-4571 participants were included in the imputed analyses. A 1-year older aPHV was not strongly associated with markers of cardiac structure and function in males and females at 25 years and most results spanned the null value. In adjusted analyses, a 1-year older aPHV was associated with 0.003 mm (95% confidence interval (CI) 0.00001, 0.006) and 0.0008 mm (95% CI - 0.002, 0.003) higher CIMT; 0.02 m/s (95% CI - 0.05, 0.09) and 0.02 m/s (95% CI - 0.04, 0.09) higher PWV; and 0.003 mmHg (95% CI - 0.60, 0.60) and 0.13 mmHg (95% CI - 0.44, 0.70) higher SBP, among males and females, respectively. A 1-year older aPHV was associated with - 0.55 g/m2.7 (95% CI - 0.03, - 1.08) and - 0.89 g/m2.7 (95% CI - 0.45, - 1.34) lower LVMI and - 0.001 (95% CI - 0.006, 0.002) and - 0.002 (95% CI - 0.006, 0.002) lower RWT among males and females. CONCLUSIONS: Earlier puberty is unlikely to have a major impact on pre-clinical cardiovascular risk in early adulthood.

Association between hypertensive disorders of pregnancy and the risk of asthma, eczema and allergies in offspring: A systematic review and meta-analysis.

OBJECTIVE: Conduct a systematic review and meta-analysis examining the association between hypertensive disorders of pregnancy (HDP) and risk of asthma, eczema, food allergies and allergic rhinitis in the offspring. DESIGN: A systematic review and random-effects meta-analyses were used to synthesize the published literature. PRISMA guidelines were followed throughout. Two independent reviewers carried out data extraction and quality assessment of included studies. Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess certainty of findings. DATA SOURCES: A systematic search of PubMed, Embase, Web of Science and CINAHL was performed from inception of databases-21 April 2020, supplemented by hand-searching reference lists of included articles. ELIGIBILITY CRITERIA: Two reviewers independently reviewed titles, abstracts and full-text articles. English language, cohort, case-control and cross-sectional published studies examining the association between HDP (primary exposure: pre-eclampsia; secondary exposures: all other HDP) and asthma, eczema, food allergies and allergic rhinitis were included. RESULTS: Of the 2833 studies retrieved, 14 studies met inclusion criteria. Of these, 11 studies reported evidence of association between HDP and atopic disorders. Thirteen studies reported estimates for asthma. Seven of these included adjusted estimates (including 3 645 773 participants) for a pre-eclampsia-asthma relationship resulting in a pooled odds ratio (OR) of 1.14 (95% CI: 1.04, 1.26) (I2  = 62%). However, this OR was reduced to 1.08 (95% CI: (0.78, 1.48) when the large registry-based cohort studies were excluded, and only studies using parent-reported measures to determine a diagnosis of asthma were included. Four studies included adjusted estimates (including 254 998 participants) for other HDP and asthma (pooled OR: 1.02, 95% CI: 0.96, 1.09) (I2  = 0%). Two studies provided adjusted estimates (including 1 699 663 participants) for a pre-eclampsia-eczema relationship (pooled OR: 1.06, 95% CI: 0.98, 1.14) (I2  = 0%). One study including pre-eclampsia-food allergies was identified (OR: 1.28, 95% CI: 1.11, 1.46). Three studies examined a HDP (including pre-eclampsia) and allergic rhinitis relationship, with effect estimates ranging from 1.14 to 2.10. Studies were classified as low or low-moderate risk of bias, while GRADE certainty of findings were low to very low. CONCLUSIONS: While pre-eclampsia was associated with a possible increased risk of asthma in offspring, there was no evidence for a relationship between other HDP and asthma. There is a lack of published literature examining the association between HDP and eczema, food allergy and allergic rhinitis. Further primary research is warranted to gain a better understanding of the association between HDP and the risk of childhood atopic disease. SYSTEMATIC REVIEW REGISTRATION: Review protocol in appendix.

Glycerophospholipid and detoxification pathways associated with small for gestation age pathophysiology: discovery metabolomics analysis in the SCOPE cohort.

INTRODUCTION: Small for gestational age (SGA) may be associated with neonatal morbidity and mortality. Our understanding of the molecular pathways implicated is poor. OBJECTIVES: Our aim was to determine the metabolic pathways involved in the pathophysiology of SGA and examine their variation between maternal biofluid samples. METHODS: Plasma (Cork) and urine (Cork, Auckland) samples were collected at 20 weeks' gestation from nulliparous low-risk pregnant women participating in the SCOPE study. Women who delivered an SGA infant (birthweight < 10th percentile) were matched to controls (uncomplicated pregnancies). Metabolomics (urine) and lipidomics (plasma) analyses were performed using ultra performance liquid chromatography-mass spectrometry. Features were ranked based on FDR adjusted p-values from empirical Bayes analysis, and significant features putatively identified. RESULTS: Lipidomics plasma analysis revealed that 22 out of the 33 significantly altered lipids annotated were glycerophospholipids; all were detected in higher levels in SGA. Metabolomic analysis identified reduced expression of metabolites associated with detoxification (D-Glucuronic acid, Estriol-16-glucuronide), nutrient absorption and transport (Sulfolithocholic acid) pathways. CONCLUSIONS: This study suggests higher levels of glycerophospholipids, and lower levels of specific urine metabolites are implicated in the pathophysiology of SGA. Further research is needed to confirm these findings in independent samples.

Pregnancy outcomes in women with chronic kidney disease and chronic hypertension: a National cohort study.

BACKGROUND: Maternal chronic kidney disease and chronic hypertension have been linked with adverse pregnancy outcomes. We aimed to examine the association between these conditions and adverse pregnancy outcomes over the last 3 decades. OBJECTIVE: We conducted this national cohort study to assess the association between maternal chronic disease (CH, CKD or both conditions) and adverse pregnancy outcomes with an emphasis on the effect of parity, maternal age, and BMI on these associations over the last three decades. We further investigated whether different subtypes of CKD had differing effects. STUDY DESIGN: We used data from the Swedish Medical Birth Register, including 2,788,490 singleton births between 1982 and 2012. Women with chronic kidney disease and chronic hypertension were identified from the Medical Birth Register and National Patient Register. Logistic regression models were performed to assess the associations between maternal chronic disease (chronic hypertension, chronic kidney disease, or both conditions) and pregnancy outcomes, including preeclampsia, in-labor and prelabor cesarean delivery, preterm birth, small for gestational age, and stillbirth. RESULTS: During the 30-year study period, 22,397 babies (0.8%) were born to women with chronic kidney disease, 13,279 (0.48%) to women with chronic hypertension and 1079 (0.04%) to women with both conditions. Associations with chronic hypertension were strongest for preeclampsia (adjusted odds ratio, 4.57; 95% confidence interval, 4.33-4.84) and stillbirth (adjusted odds ratio, 1.65; 95% confidence interval, 1.35-2.03) and weakest for spontaneous preterm birth (adjusted odds ratio, 1.07; 95% confidence interval, 0.96-1.20). The effect of chronic kidney disease varied from (adjusted odds ratio, 2.05; 95% confidence interval, 1.92-2.19) for indicated preterm birth to no effect for stillbirth (adjusted odds ratio, 1.16; 95% confidence interval, 0.95-1.43). Women with both conditions had the strongest associations for in-labor cesarean delivery (adjusted odds ratio, 1.86; 95% confidence interval, 1.49-2.32), prelabor cesarean delivery (adjusted odds ratio, 2.68; 95% confidence interval, 2.18-3.28), indicated preterm birth (adjusted odds ratio, 9.09; 95% confidence interval, 7.61-10.7), and small for gestational age (adjusted odds ratio, 4.52; 95% confidence interval, 3.68-5.57). The results remained constant over the last 3 decades. Stratified analyses of the associations by parity, maternal age, and body mass index showed that adverse outcomes remained independently higher in women with these conditions, with worse outcomes in multiparous women. All chronic kidney disease subtypes were associated with higher odds of preeclampsia, in-labor cesarean delivery, and medically indicated preterm birth. Different subtypes of chronic kidney disease had differing risks; strongest associations of preeclampsia (adjusted odds ratio, 3.98; 95% confidence interval, 2.98-5.31) and stillbirth (adjusted odds ratio, 2.73; 95% confidence interval, 1.13-6.59) were observed in women with congenital kidney disease, whereas women with diabetic nephropathy had the most pronounced increase odds of in-labor cesarean delivery (adjusted odds ratio, 3.54; 95% confidence interval, 2.06-6.09), prelabor cesarean delivery (adjusted odds ratio, 7.50; 95% confidence interval, 4.74-11.9), and small for gestational age (adjusted odds ratio, 4.50; 95% confidence interval, 2.92-6.94). In addition, women with renovascular disease had the highest increased risk of preterm birth in both spontaneous preterm birth (adjusted odds ratio, 3.01; 95% confidence interval, 1.57-5.76) and indicated preterm birth (adjusted odds ratio, 8.09; 95% confidence interval, 5.73-11.4). CONCLUSION: Women with chronic hypertension, chronic kidney disease, or both conditions are at an increased risk of adverse pregnancy outcomes which were independent of maternal age, body mass index, and parity. Multidisciplinary management should be provided with intensive clinical follow-up to support these women during pregnancy, particularly multiparous women. Further research is needed to evaluate the effect of disease severity on adverse pregnancy outcomes.

Eating behaviour, physical activity, TV exposure and sleeping habits in five year olds: a latent class analysis.

BACKGROUND: Diet, physical activity, sedentary behaviours, and sleep time are considered major contributory factors of the increased prevalence of childhood overweight and obesity. The aims of this study were to (1) identify behavioural clusters of 5 year old children based on lifestyle behaviours, (2) explore potential determinants of class membership, and (3) to determine if class membership was associated with body measure outcomes at 5 years of age. METHODS: Data on eating behaviour, engagement in active play, TV watching, and sleep duration in 1229 5 year old children from the Cork BASELINE birth cohort study was obtained through in-person interviews with parent. Latent class analysis was used to identify behavioural clusters. Potential determinants of cluster membership were investigated using multinomial logistic regression. Associations between the identified classes and cardio metabolic body measures were examined using multivariate logistic and linear regression, with cluster membership used as the independent variable. RESULTS: 51% of children belonged to a normative class, while 28% of children were in a class characterised by high scores on food avoidance scales in combination with low enjoyment of food, and 20% experienced high scores on the food approach scales. Children in both these classes had lower conditional probabilities of engaging in active play for at least 1 hour per day and sleeping for a minimum of 10 h, and higher probability of watching TV for 2 hours or more, compared to the normative class. Low socioeconomic index (SEI) and no breastfeeding at 2 months were found to be associated with membership of the class associated with high scores on the food avoidance scale, while lower maternal education was associated with the class defined by high food approach scores. Children in the class with high scores on the food approach scales had higher fat mass index (FMI), lean mass index (LMI), and waist-to-height ratio (WtHR) compared to the normative class, and were at greater risk of overweight and obesity. CONCLUSION: Findings suggest that eating behaviour appeared to influence overweight and obesity risk to a greater degree than activity levels at 5 years old. Further research of how potentially obesogenic behaviours in early life track over time and influence adiposity and other cardio metabolic outcomes is crucial to inform the timing of interventions.

Gestational Diabetes Mellitus and Maternal Immune Dysregulation: What We Know So Far.

Gestational diabetes mellitus (GDM) is an obstetric complication that affects approximately 5-10% of all pregnancies worldwide. GDM is defined as any degree of glucose intolerance with onset or first recognition during pregnancy, and is characterized by exaggerated insulin resistance, a condition which is already pronounced in healthy pregnancies. Maternal hyperglycaemia ensues, instigating a 'glucose stress' response and concurrent systemic inflammation. Previous findings have proposed that both placental and visceral adipose tissue play a part in instigating and mediating this low-grade inflammatory response which involves altered infiltration, differentiation and activation of maternal innate and adaptive immune cells. The resulting maternal immune dysregulation is responsible for exacerbation of the condition and a further reduction in maternal insulin sensitivity. GDM pathology results in maternal and foetal adverse outcomes such as increased susceptibility to diabetes mellitus development and foetal neurological conditions. A clearer understanding of how these pathways originate and evolve will improve therapeutic targeting. In this review, we will explore the existing findings describing maternal immunological adaption in GDM in an attempt to highlight our current understanding of GDM-mediated immune dysregulation and identify areas where further research is required.