The association between hypertensive disorders of pregnancy and neurodevelopmental disorders in the offspring

Background and aims: Hypertensive disorders of pregnancy (HDP) are one of the most common gestational complications. HDP may be chronic (pre-dating pregnancy or diagnosed before 20 weeks’ gestation) or arise de novo (either preeclampsia or gestational hypertension). Of these, preeclampsia is one of the leading cause of maternal mortality and morbidity. Evidence suggests an association between HDP and neurodevelopmental outcomes; however, results are limited and inconsistent. The aim of the current thesis was to examine the association between HDP (in particular, preeclampsia) and neurodevelopmental disorders in the offspring, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), child development and behavioural outcomes. This would be achieved by systematically reviewing existing literature, and conducting a range of robust analyses using Swedish National Registry data, and data from a nationally representative study of children living in Ireland. Structure and methods: This thesis includes a brief introductory chapter (Chapter 1), and a detailed methods chapter describing study designs, data sources, exposure and outcome variables, statistical modelling, and the role of bias, confounding and chance in epidemiology (Chapter 2). Published literature on the relationship between HDP and neurodevelopmental disorders in the offspring were synthesised using a systematic review and meta-analysis, based on a pre-prepared protocol (Chapters 3 and 4). This was followed by a narrative literature review to provide a perspective on how maternal inflammation may lead to altered neurodevelopmental outcomes in preeclampsia-exposed offspring (Chapter 5). Data from Swedish National Registers were analysed to examine the association between preeclampsia and ASD and ADHD, using Cox proportional hazards regression analysis, adjusting for several perinatal and sociodemographic factors. Sibling-matched analysis was used to also control for shared genetic and familial confounding (Chapters 6 and 7). These associations were further explored by examining the intergenerational association between preeclampsia and ASD and ADHD (Chapter 8). Data from Growing Up in Ireland (GUI), a nationally representative study of children living in Ireland, were analysed to examine the association between preeclampsia and child development using the Ages and Stages Questionnaire (ASQ) at age 9-months, and behavioural outcomes using the Strengths and Difficulties Questionnaire (SDQ) at age 3 years, 5 years and 7-8 years. Multivariate logistic regression, linear regression and linear spline multilevel modelling were applied for this analysis (Chapter 9). Finally, the systematic review and meta-analysis was updated and included in this thesis (Chapter 10), along with discussion of findings, strengths and limitations of the thesis, and recommendations for future research (Chapter 11). Results: Updated systematic review and meta-analysis: Among ASD studies, adjusted pooled results indicated that exposure to HDP is associated with a 33% increased odds of ASD when compared to those unexposed (OR: 1.33, 95% CI: 1.17, 1.52). Results of a subgroup analysis, examining a preeclampsia-ASD relationship in isolation provided an OR of 1.36 (95% CI: 1.18, 1.58), while the other HDP-ASD relationship was statistically non-significant with an OR of 1.29 (95% CI: 0.97, 1.71). Among ADHD studies, adjusted pooled results suggested that offspring exposed to HDP are 26% more likely to have ADHD compared to those unexposed (OR: 1.26, 95% CI: 1.15, 1.38). For the subgroup analysis examining the preeclampsia-ADHD relationship, the OR was 1.23 (95% CI: 1.13, 1.35), and for other HDP-ADHD relationship, the OR was 1.80 (95% CI: 1.25, 2.59). Swedish National Registers: The adjusted Cox model suggested that preeclampsia was associated with 25% increased odds of ASD (Hazard ratio (HR): 1.25, (95% CI: 1.19, 1.30). The sibling-matched analysis reduced the HR to 1.17 (95% CI: 1.06, 1.28). The HR for preeclampsia and SGA combined (used as a crude proxy for preeclampsia with placental dysfunction) was 1.66 (95% CI: 1.49, 1.85) in the adjusted Cox model and 1.95 (95% CI: 1.53, 2.48) in the sibling-matched analysis. In the adjusted Cox model, preeclampsia was associated with a 15% increase in likelihood of ADHD (HR: 1.15, 95% CI: 1.12, 1.19), while the HR for preeclampsia and SGA combined was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, compared to those unexposed to preeclampsia/SGA. The sibling-matched analysis did not materially change these associations. Similar to the findings outlined above, the intergenerational analysis suggested that exposure to preeclampsia was associated with an increased likelihood of ASD and ADHD in offspring. In addition to this, results suggested that preeclampsia in both the child’s mother and grandmother was associated with a 58% increased likelihood of ASD (HR: 1.58, 95% CI: 1.02, 2.46) and 34% increased likelihood of ADHD (HR: 1.34, 95% CI: 1.01, 1.80) in the child. GUI study: Multivariate logistic regression suggested that preeclampsia was not associated with failing any ASQ domain. Preeclampsia was associated with abnormal SDQ cut-off of Emotional (score of ≥5) and Hyperactivity (score of ≥7) domains at age 5 years only. In the linear spline model, mean SDQ score was higher at age 3, 5 and 7-8 years in exposed groups, however did not always reach statistical significance. Conclusions: This thesis rigorously investigates the association between HDP (in particular, preeclampsia) and neurodevelopmental disorders in offspring using a range of analytic approaches, and adjusting for a wide variety of potential confounders. Pooled estimates from previous literature suggested an association between HDP and ASD and ADHD. Furthermore, the data from Swedish National Registers indicate that exposure to preeclampsia or preeclampsia and SGA combined (i.e. SGA baby exposed to preeclampsia) was associated with ASD and ADHD. The stronger association with preeclampsia and SGA combined than preeclampsia alone suggests that placental pathology may be a mechanism for the increased likelihood of ASD and ADHD. Results of the current thesis also suggest that preeclampsia may be associated with adverse neurodevelopmental outcomes across generations. While we did not find strong evidence of associations between preeclampsia and child developmental and behavioural outcomes overall in the GUI study, exposure to preeclampsia was associated with an increased likelihood of subtle behavioural issues in the emotional and hyperactivity domain of the SDQ. The overall conclusion of this thesis suggests an association between HDP and neurodevelopmental outcomes in offspring. It is important to note however, that we cannot rule out the presence of residual confounding in observational studies

Hypertensive disorders of pregnancy and risk of neurodevelopmental disorders in the offspring: a systematic review and meta-analysis protocol

Introduction Hypertensive disorders of pregnancy (HDPs), that is chronic hypertension, gestational hypertension, pre-eclampsia (de novo or superimposed on chronic hypertension) and white coat hypertension, affect approximately 5%–15% of pregnancies. HDP exposure has been linked to an increased risk of autism spectrum disorder, attention deficit/hyperactivity disorder and other neurodevelopmental disorders in children. However, findings are inconsistent, and a clear consensus on the impact of HDPs on the risk of neurodevelopmental disorders is needed. Therefore, we aim to synthesise the published literature on the relationship between HDPs and the risk of neurodevelopmental disorders in the form of a systematic review and meta-analysis. Methods and analysis We will include cohort, case– control and cross-sectional studies in which diagnosis of an HDP was reported, and neurodevelopmental disorders were the outcome of interest based on a preprepared protocol. A systematic search of PubMed, CINAHL, Embase, PsycINFO and Web of Science will be conducted in accordance with a detailed search strategy. Two authors will independently review the titles and abstracts of all studies, perform data extraction using a standardised data collection form and assess study quality using a bias classification tool. Meta-analyses will be performed to calculate overall pooled estimates using the generic inverse variance method. This systematic review will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses. Ethics and dissemination This proposed systematic review and meta-analysis is based on published data, therefore, does not require ethics approval. Findings will be presented at scientific conferences and disseminated through publication in a peer-reviewed journal. Registration CRD42017068258

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/m^{2.7} (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 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.</p

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

A perspective on pre-eclampsia and neurodevelopmental outcomes in the offspring: Does maternal inflammation play a role?

Pre-eclampsia is a leading cause of maternal death and maternal and perinatal morbidity. Whilst the clinical manifestations of pre-eclampsia often occur in late pregnancy, the molecular events leading into the onset of this disease are thought to originate in early pregnancy and result in insufficient placentation. Although the causative molecular basis of pre-eclampsia remains poorly understood, maternal inflammation is recognised as a core clinical feature. While the adverse effects of pre-eclampsia on maternal and fetal health in pregnancy is well-recognised, the long-term impact of pre-eclampsia exposure on the risk of autism spectrum disorder (ASD) in exposed offspring is a topic of on-going debate. In particular, a recent systematic review has reported an association between exposure to pre-eclampsia and increased risk of ASD, however the molecular basis of this association is unknown. Here we review recent evidence for; 1) maternal inflammation in pre-eclampsia; 2) epidemiological evidence for alterations in neurodevelopmental outcomes in offspring exposed to pre-eclampsia; 3) long-term changes in the brains of offspring exposed to pre-eclampsia; and 4) how maternal inflammation may lead to altered neurodevelopmental outcomes in pre-eclampsia exposed offspring. Finally, we discuss the implications of this for the development of future studies in this field

Association between preeclampsia and attention deficit hyperactivity disorder: a population-based and sibling-matched cohort study

Objective: Examine the association between preeclampsia and attention deficit hyperactivity disorder (ADHD), using a large Swedish‐based registry cohort. Methods: This study comprised 2,047,619 children, with 114,934 (5.6%) cases of ADHD. Preeclampsia was based on two alternate definitions: 1. Preeclampsia (using ICD‐9/ICD‐10) 2.Preeclampsia and small for gestational age (SGA) combined. ADHD was determined in one of two ways: 1. If a diagnosis of ADHD was present in the National Patient Register or 2.If an individual was in receipt of ADHD medication in the Prescribed Drug Register. Multivariate Cox proportional hazards regression analysis allowed adjustment for several perinatal/sociodemographic factors. Sibling‐matched analysis further controlled for shared genetic and familial confounding. Results: In the adjusted Cox model, preeclampsia was associated with an increase in likelihood of ADHD (HR: 1.15, 95% CI: 1.12, 1.19). The HR for preeclampsia and those born SGA was 1.43 (95% CI: 1.31, 1.55) in the adjusted model, compared to those unexposed to preeclampsia/SGA. The sibling‐matched analysis did not materially change these associations (HR: 1.13, 95% CI: 1.05, 1.22) and 1.55 (95% CI: 1.28, 1.88). Conclusions: Exposure to preeclampsia or preeclampsia/SGA was associated with ADHD, independent of genetic/familial factors shared by siblings. However, it is important to note that sibling‐matched analysis can only adjust for factors that are constant between pregnancies, therefore residual confounding cannot be ruled out. Further research is needed to explore modifiable risk factors and identify those most‐at‐risk babies following delivery

Association between preeclampsia and autism spectrum disorder: a population-based study

Background: The environmental contribution of autism spectrum disorder (ASD) is approximately 17%–50%, highlighting the importance of investigating factors potentially contributing to the likelihood of its development, and of gaining a greater understanding of the pathogenesis surrounding ASD. The objective of this study was to examine the association between preeclampsia and ASD using a population‐based cohort study. Methods: All singleton live births in Sweden from 1982 to 2010 were included, using data from Swedish National Registers. Exposures of interest included: (a) preeclampsia (classified according to ICD‐8, ICD‐9 and ICD‐10) and (b) preeclampsia and small for gestational age (SGA) combined, used as a proxy for preeclampsia with placental dysfunction. ASD status was based on ICD‐9 and ICD‐10. The cohort consisted of 2,842,230 children, with 54,071 cases of ASD. Follow‐up began from the child's first birthday, and data were censored at first diagnosis of ASD, death, migration or end of study period (31st December 2016). We conducted multivariate Cox proportional hazards regression analysis, adjusting for several perinatal and sociodemographic factors, selected a priori. We further controlled for shared genetic and familial confounding using sibling‐matched analysis. Results: In the adjusted Cox proportional hazards regression analysis, preeclampsia was associated with a 25% increase in the likelihood of ASD (Hazard Ratio (HR): 1.25, 95% CI:1.19, 1.30) compared with those unexposed to preeclampsia, while in the sibling‐matched analysis the HR was 1.17 (95% CI: 1.06, 1.28). The HR for preeclampsia and SGA combined was 1.66 (95% CI: 1.49, 1.85) in the adjusted Cox model and 1.95 (95% CI: 1.53, 2.48) in the sibling‐matched analysis. Conclusions: Exposure to preeclampsia or preeclampsia/SGA (i.e. SGA baby exposed to preeclampsia) was associated with ASD. The stronger association with preeclampsia/SGA than preeclampsia alone suggests that placental pathology may be a mechanism for the increased likelihood of ASD

Predicting risk of postpartum haemorrhage during the intrapartum period in a general obstetric population

Objective: To develop and validate (both internally and externally) a prediction model examining a combination of risk factors in order to predict postpartum haemorrhage (PPH) in a general obstetric Irish population of singleton pregnancies. Study design: We used data from the National Maternal and Newborn Clinical Management System (MN-CMS), including all singleton deliveries at Cork University Maternity Hospital (CUMH), Ireland during 2019. We defined PPH as an estimated blood loss of = 1000 ml following the birth of the baby. Multivariable logistic regression with backward stepwise selection was used to develop the prediction model. Candidate predictors included maternal age, maternal body mass index, parity, previous caesarean section, assisted fertility, gestational age, fetal macrosomia, mode of delivery and history of PPH. Discrimination was assessed using the area under the receiver operating characteristic curve (ROC) C-statistic. We used bootstrapping for internal validation to assess overfitting, and conducted a temporal external validation using data from all singleton deliveries at CUMH during 2020. Results: Out of 6,077 women, 5,807 with complete data were included in the analyses, and there were 270 (4.65%) cases of PPH. Four variables were considered the best combined predictors of PPH, including parity (specifically nulliparous), macrosomia, mode of delivery (specifically operative vaginal delivery, emergency caesarean section and prelabour caesarean section), and history of PPH. These predictors were used to develop a nomogram to provide individualised risk assessment for PPH. The original apparent C-statistic was 0.751 (95% CI: 0.721, 0.779) suggesting good discriminative performance. There was minimal optimism adjustment to the C-statistic after bootstrapping, indicating good internal performance (optimism adjusted C-statistic: 0.748). Results of external validation were comparable with the development model suggesting good reproducibility. Conclusions: Four routinely collected variables (parity, fetal macrosomia, mode of delivery and history of PPH) were identified when predicting PPH in a general obstetric Irish population of singleton pregnancies. Use of our nomogram could potentially assist with individualised risk assessment of PPH and inform clinical decision-making allowing those at highest risk of PPH be actively managed

Predicting perineal trauma during childbirth using data from a general obstetric population [version 2; peer review: 2 approved]

Background: Perineal trauma is a common complication of childbirth and can have serious impacts on long-term health. Few studies have examined the combined effect of multiple risk factors. We developed and internally validated a risk prediction model to predict third and fourth degree perineal tears using data from a general obstetric population. Methods: Risk prediction model using data from all singleton vaginal deliveries at Cork University Maternity Hospital (CUMH), Ireland during 2019 and 2020. Third/fourth degree tears were diagnosed by an obstetrician or midwife at time of birth and defined as tears that extended into the anal sphincter complex or involved both the anal sphincter complex and anorectal mucosa. We used univariable and multivariable logistic regression with backward stepwise selection to develop the models. Candidate predictors included infant sex, maternal age, maternal body mass index, parity, mode of delivery, birthweight, post-term delivery, induction of labour and public/private antenatal care. We used the receiver operating characteristic (ROC) curve C-statistic to assess discrimination, and bootstrapping techniques were used to assess internal validation. Results: Of 8,403 singleton vaginal deliveries, 8,367 (99.54%) had complete data on predictors for model development. A total of 128 women (1.53%) had a third/fourth degree tear. Three variables remained in the final model: nulliparity, mode of delivery (specifically forceps delivery or ventouse delivery) and increasing birthweight (per 100 gram increase) (C-statistic: 0.75, 95% CI: 0.71, 0.79). We developed a nomogram to calculate individualised risk of third/fourth degree tears using these predictors. Bootstrapping indicated good internal performance. Conclusions: Use of our nomogram can provide an individualised risk assessment of third/fourth degree tears and potentially aid counselling of women on their potential risk