Restriction lift date: 2021-09-07
The association between hypertensive disorders of pregnancy and neurodevelopmental disorders in the offspring
Maher, Gillian M.
University College Cork
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.
Epidemiology , Preeclampsia , Neurodevelopment , Hypertensive disorders of pregnancy
Maher, G. M. 2020. The association between hypertensive disorders of pregnancy and neurodevelopmental disorders in the offspring. PhD Thesis, University College Cork.