Mini CAT Assignment Name – Summer Anderson
Scenario: 34yo F G1P1 with hx of preeclampsia wonders if she should have another child, as she has read online that preeclampsia increases the risk of her child developing autism.
Clinical Question: For pregnant women diagnosed with preeclampsia, is there an increased risk for autism in their offspring?
PICO Question:
P🡪 Offspring
I🡪 Women with preeclampsia
C🡪 Women without preeclampsia
O🡪 Autism in offspring
What type of scenario is this?
□ Therapy/ Prevention □ Diagnosis □ Etiology □ Prognosis □ Screening □ Prevalence
□ Harms
Type of study best to answer this question: (think about the level of evidence)
□ Meta-analysis □ Systematic Review □ Randomized Controlled Trial □ Cohort Study
□ Case Control Study □ Case Series/Report
Search Strategy:
PICO Search Terms
| P | I | C | O |
| Offspring | Preeclampsia | NO preeclampsia | Autism |
| Neonates | hypertension | NO hypertension | Autism spectrum disorder |
| Child* (children) | Toxemia | NO toxemia | Childhood autism |
| Pediatric | Pregnancy-induced hypertension | No pregnancy-induced hypertension | Early infantile autism |
| Preeclamptic toxemia | NO preeclamptic toxemia | Autistic disorder |
Filters Applied:
- Recent publications within the past 5 years
- Recent publications within the past 10 years
- Review
- Full Article
- Journal
Databases Used:
- PubMed
- Wiley Online Library
- Cochrane Library
- Google Scholar
- BMJ
Results:
| Database | Filter | Articles Returned |
| PubMed | English/Last 5 years/Full Text/Full Article/ | 818 |
| Wiley Online Library | English/ 2015-2020/ Journals | 204 |
| Cochrane Library | English/Last 5 years/Children’s health/Public Health/Intervention | 20 |
| Google Scholar | 2010-2020/Include patients/Include Citations | 2450 |
Articles Chosen for Inclusion:
| Citation | Jenabi E, Karami M, Khazaei S, Bashirian S. The association between preeclampsia and autism spectrum disorders among children: a metaanalysis. Korean J Pediatr. 2019;62:126–30. |
| Abstract | Purpose: In this meta-analysis, relevant case-control and cohort studies were pooled to evaluate the association between preeclampsia and the risk of autism spectrum disorders (ASDs) in children.Methods: A search for relevant studies in major databases, including Web of Science, PubMed, and Scopus, was performed up to May 2018. The odds ratios (ORs) or rate ratios (RRs) with 95% confidence intervals (CIs) were extracted from eligible studies to determine the association among studies.Results: The pooled estimates of ORs and RRs indicated a significant association between preeclampsia and ASD [(OR, 1.36; 95% CI, 1.12–1.60) and (RR, 1.30; 95% CI, 1.20–1.41)]. Conclusions: Despite existing controversy, our findings indicated that preeclampsia was associated with an increased risk of ASD among children. |
| Link | https://www-ncbi-nlm-nih-gov.york.ezproxy.cuny.edu/pmc/articles/PMC6477549/ |
| Reason for Inclusion | This study is a meta-analysis done using the PRISMA system to ensure quality, providing information from various studies with various outcomes that encompass over 7 million study participants. It was done in 2019 and it included relevant case-control and cohort studies studies and extracted odds ratios / rate ratios with 95% confidence intervals to determine association between preeclampsia in mothers and autism spectrum disorder in children. |
| Citation | Maher, G. M., O’Keeffe, G. W., Dalman, C., Kearney, P. M., McCarthy, F. P., Kenny, L. C., et al. (2020). Association between preeclampsia and autism spectrum disorder: A population-based study. Journal of Child Psychology and Psychiatry,61(2), 131–139. |
| Abstract | 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. |
| Link | https://onlinelibrary-wiley-com.york.ezproxy.cuny.edu/doi/10.1111/jcpp.13127 |
| Reason for Inclusion | This study was chosen because it used a population-based cohort study with a cohort of 2,842,320 children with 54,071 cases of autism spectrum disorder. It followed up with children beginning with their first birthday, and included children of mothers with preeclampsia during pregnancy. The study also used a multivariate regression analysis and adjusted for perinatal and sociodemographic factors. |
| Citation | Xu RT, Chang QX, Wang QQ, et al. Association between hypertensive disorders of pregnancy and risk of autism in offspring: a systematic review and meta-analysis of observational studies. Oncotarget. 2017;9(1):1291‐1301. Published 2017 Dec 7. |
| Abstract | Background: Autism spectrum disorder (ASD) is a common severe pervasive neurodevelopmental disorder of undetermined etiology. Environmental exposures, especially pregnancy complications, have been increasingly recognized as a potential risk factor for ASD. Our aim was to (1) systematically evaluate the association between hypertensive disorders of pregnancy (HDP) and the risk of ASD in offspring, (2) specifically draw a subgroup analysis of disease severity in patients with HDP to achieve more sufficient evidence on this issue. Results: A total of 21 studies were identified with more than 6.5 million participants, including 31,027 ASD probands. A comparative meta-analysis established that offspring born premature to HDP were significantly associated with ASD than matched controls (OR = 1.42, 95% CI: 1.34–1.50). Subgroup analysis of clinical classification include: (1) gestational hypertension, (2) pre-eclampsia, (3) chronic hypertension complicating pregnancy (CHP). The offspring of mothers with pre-eclampsia and CHP have slightly higher risk (OR = 1.43; OR = 1.48, respectively) of ASD than those of mothers with gestational hypertension (OR = 1.37). In consistence with most previous researches, higher ASD prevalence was observed in male than female (OR = 1.38), indicating a potential role for gender in the pathophysiology of ASD.Materials and Methods: We conducted a systematic literature search on PubMed, EMBASE, Web of Science, PsycINFO database and China National Knowledge Infrastructure up to Jun. 2017. Statistical analysis was performed using Stata 10.0. Conclusions: This meta-analysis implies a possible link between HDP and the risk of ASD in offspring. However, further investigation should be conducted to confirm this conclusion, and intensive prenatal surveillance and early prediction for ASD is needed. |
| Link | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787439/ |
| Reason for Inclusion | This study was chosen because it is a systematic review and meta-analysis of 21 observational studies done that included more than 6.5 million participants, including 31,027 autism spectrum disorder probands. It used a comparative meta-analysis to compare the association of hypertensive disorders of pregnancy with autism spectrum disorder outcomes. |
| Citation | Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, Hertz-Picciotto I. Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay. JAMA Pediatr. 2015;169(2):154‐162 |
| Abstract | Increasing evidence suggests that autism spectrum disorder (ASD) and many forms of developmental delay (DD) originate during fetal development. Preeclampsia may trigger aberrant neurodevelopment through placental, maternal and fetal physiologic mechanisms. Objective: To determine whether preeclampsia is associated with ASD and/or DD. Design, Setting and Participants:The CHildhhood Autism Risks from Genetics and the Environment (CHARGE) Study is a population-based case-control investigation of ASD and/or DD origins. Children from 20 California counties aged 24-60 months at the time of recruitment, and living in catchment areas with a biologic parent fluent in English or Spanish were enrolled from January 29, 2003 through April 7, 2011. Children with ASD (n=517) and DD (n=194) were recruited through the California Department of Developmental Services, the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute and referrals. Controls with typical development (TD) controls (n=350) were randomly selected from birth records and frequency-matched on age, sex, and broad geographic region. Physicians diagnosing preeclampsia were masked to neurodevelopmental outcome, and those assessing neurodevelopmental function were masked to preeclampsia status.Exposure: Preeclampsia and placental insufficiency were self-reported and abstracted from medical records. Main Outcome Measure: The Autism Diagnostic Observation Schedule and Autism Diagnostic Interview–Revised were used to confirm ASD, whereas children with DD and TD were confirmed by Mullen Scales of Early Learning and Vineland Adaptive Behavior Scales and were free of autistic symptoms. Hypotheses were formulated before data collection. Results: Children with ASD were twice as likely to have been exposed in utero to preeclampsia as controls with TD after adjustment for maternal educational level, parity, and prepregnancy obesity (adjusted odds ratio, 2.36; 95% CI, 1.18-4.68); risk increased with greater preeclampsia severity (test for trend p=0.02). Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia (adjusted odds ratio, 5.49; 95% CI, 2.06-14.64). Conclusions and Relevance: Preeclampsia, particularly severe disease, is associated with ASD and DD. Faulty placentation manifests in the mother as preeclampsia with vascular damage, enhanced systemic inflammation and insulin resistance; in the placenta as oxygen and nutrient transfer restriction and oxidative stress; and in the fetus as growth restriction and progressive hypoxemia. All are potential mechanisms for neurodevelopmental compromise. |
| Link | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416484/ |
| Reason for Inclusion | This study was chosen because it used a population-based case control investigation to determine autism spectrum disorder and any relation it has to maternal preeclampsia. It had a control group with typical development randomly selected to compare to the autism spectrum disorder group. The physicians diagnosing preeclampsia were masked to the neurodevelopmental outcome, and the physicians assessing neurodevelopmental outcome were masked to preeclampsia status to eliminate any bias. |
| Citation | Cordero, C., Windham, G.C., Schieve, L.A., Fallin, M.D., Croen, L.A., Siega‐Riz, A.M., Engel, S.M., Herring, A.H., Stuebe, A.M., Vladutiu, C.J. and Daniels, J.L. (2019), Maternal diabetes and hypertensive disorders in association with autism spectrum disorder. Autism Research, 12: 967-975 |
| Abstract | Previous studies have shown complications of pregnancy, often examined in aggregate, to be associated with autism spectrum disorder (ASD). Results for specific complications, such as maternal diabetes and hypertension, have not been uniformly consistent and should be investigated independently in relation to ASD in a large community‐based sample. The Study to Explore Early Development (SEED), a US multisite case–control study, enrolled children born in 2003–2006 at 2–5 years of age. Children were classified into three groups based on confirmation of ASD (n = 698), non‐ASD developmental delay (DD; n = 887), or controls drawn from the general population (POP; n = 979). Diagnoses of any diabetes or hypertensive disorder during pregnancy were identified from prenatal medical records and maternal self‐report. Logistic regression models estimated adjusted odds ratios (aOR) and confidence intervals (CI) adjusting for maternal age, race/ethnicity, education, smoking during pregnancy, and study site. Models for hypertension were additionally adjusted for parity and plurality. Among 2,564 mothers, we identified 246 (9.6%) with any diabetes and 386 (15.1%) with any hypertension in pregnancy. After adjustment for covariates, any diabetes during pregnancy was not associated with ASD (aOR = 1.10 [95% CI 0.77, 1.56]), but any hypertension was associated with ASD (aOR = 1.69 [95% CI 1.26, 2.26]). Results were similar for DD, and any diabetes (aOR = 1.29 [95% CI 0.94, 1.78]) or any hypertension (aOR = 1.71 [95% CI 1.30, 2.25]). Some pregnancy complications, such as hypertension, may play a role in autism etiology and can possibly serve as a prompt for more vigilant ASD screening efforts. Autism Res 2019, 12: 967–975. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. |
| Link | https://onlinelibrary-wiley-com.york.ezproxy.cuny.edu/doi/10.1002/aur.2105 |
| Reason for Inclusion | This study was included because it was a multisite case-control study that included three groups–autism spectrum disorder, non-ASD delay, and control. They used odds ratios and confidence intervals to adjust for age, race.ethnicity, and other variables that could affect the data. This study included 2,564 mothers and assessed the association between diabetes and hypertensive disorders and autism spectrum disorder in children. |
Summary of the Evidence:
| Author (Date) | Level of Evidence | Sample/Setting(# of subjects/ studies, cohort definition etc. ) | Outcome(s) studied | Key Findings | Limitations and Biases |
| Jenabi et al., 2019The association between preeclampsia and autism spectrum disorders among children: a metaanalysis. | Meta-analysis | Pooled studies selected from relevant, case-control and cohort studies Epidemiological studies with sample size of 7,561,696 participants | Association between preeclampsia and the risk of autism spectrum disorders in children in all case-control and cohort studies | Significant association between mothers with a history of preeclampsia and diagnosis of children with autism spectrum disorder Longer exposure to preeclampsia during early fetal life may associate with neurodevelopment at critical stage of fetal development that can lead to behavioral disorders Inadequate oxygenation in placenta and poor placental development common in preeclampsia, causing intrauterine growth restriction and abnormal trophoblast differentiation. Bilarer folding of abnormal trophoblasts is associated with ASD. Therefore, preeclampsia increases risk for developing autism. | Studies conducted in various countries, making generalizability more questionable Prenatal or perinatal risk factors could be confounders Data from some studies was not sufficient to perform subgroup analysis from confounding variables |
| Maher et al., 2019Association between preeclampsia and autism spectrum disorder: a population-based study | Population-based cohort study, epidemiological study | All live births in Sweden from 1982 to 2010, with 2,842,230 children and 54,071 cases of autism spectrum disorder | Examine the association between preeclampsia and autism spectrum disorder in a population-based cohort study | Preeclampsia was associated with a 25% increase in the likelihood of autism spectrum disorder compared to those unexposed to preeclampsia after controlling for other confounding variables There was a much stronger association with preeclampsia and small gestational age(representing preeclampsia with placental dysfunction) and autism than preeclampsia alone, suggesting that placental pathology may be a mechanism for increasing likelihood of autism spectrum disorder | Follow up of children was only 6 years after birth, so some may have not yet been diagnosed, especially considering many are diagnosed in school years Severe cases may have been overrespresented prior to 2001 due to reliance on inpatient diagnoses Lack of robust data on gestational hypertension Possible confounding variables not controlled for |
| Xu et al., 2017Association between hypertensive disorders of pregnancy and risk of autism in offspring: a systematic review and meta-analysis of observational studies | Systematic review and meta-analysis of observational studies | Exposures of interest included preeclampsia, ASD status including over 6.5 million participants and 31,027 autism spectrum disorder probrands | Systematically evaluate the association between hypertensive disorders of pregnancy and risk of autism spectrum disorder in offspringDraw a subgroup analysis of disease severity in patients with hypertensive disorders of pregnancy to achieve more sufficient evidence | Offspring born premature to hypertensive disorders of pregnancy were significantly associated with autism spectrum disorder Intrauterine exposure to hypertensive pregnancy disorders is associated with a 24% increase in the odds of autism spectrum disorderHypertensive disorders of pregnancy influence fetal CNS development, and preeclampsia had a higher risk for autism spectrum disorder than gestational hypertension | Many studies do not include blood pressure grade of hypertensive disorders of pregnancy and drug treatment are seldom mentioned in the studies includedStudies that were larger, multi-center, and high quality would have led to more persuasive conclusions for this meta-analysisHard to generalize due to geographic restriction of the studies–America and Europe |
| Walker et al., 2016 Preeclampsia, placental insufficiency, and autism spectrum disorder or developmental delay | Population-based case-control epidemiologic study | Children diagnosed with autism spectrum disorder from California counties aged 24-60 months as well as controls randomly selected and frequency-matched on age, sex, and region | Child development status, specifically autism spectrum disorder, developmental delays, and typical development | Preeclampsia was seen two times more often in the gestations of children with autism spectrum disordersMothers of children with autism spectrum disorder or developmental delays were significantly more likely to have had placental insufficiency, preeclampsia, or bothWomen with preeclampsia had more than double the risk of having a child with autism spectrum disorderMore severe disease of the mother during pregnancy had a higher association with autism spectrum disorder | Large sample size but hard to generalize results worldwide considering participants were only from California countiesThere could be other confounding variables that were not controlled for |
| Cordero et al., 2019 | Multisite case-control study | 2,564 children born in 2003-2006 classified into groups of autism spectrum disorder, development delay, or controls | Association between common complications in pregnancy and autism spectrum disorder in mothers and children | Hypertension may play a role in autism etiologyHypertensive disorders of pregnancy were associated with both autism spectrum disorder and developmental delaysTHis suggested a more general neurodevelopmental effect, and that maternal conditions during pregnancy alter gestational environment and are involved in autism etiology | Limited data to characterize potential for sample selectivityPossible bias or confounding from unknown variables |
Conclusion(s): Overall, all studies found some association between preeclampsia or hypertensive disorders of pregnancy and autism spectrum disorder. Multiple results showed that the increased severity of the disease in mothers led to an increased likelihood of autism spectrum disorder in the offspring. There is more research needed to be done, considering there is such a specific timeframe for the neural development of autism spectrum disorder in fetal development. However, with the current research that exists, there is a clear association between preeclampsia and autism.
Clinical Bottom Line:
While more research needs to be done to further support current findings, it has been shown that there is association between mothers with preeclampsia and children developing autism spectrum disorder. The studies investigated above were all very recent, with large sample sizes and in various regions. All five studies showed an increased likelihood for autism spectrum disorder in children born to mothers with preeclampsia or hypertensive pregnancy disorders. Additionally, it seems that severity of the maternal disease also impacts the likelihood of autism spectrum disorder development. Many studies mentioned the effect of preeclampsia on the placenta, leading to an insufficiency that impacts the development of the fetus. In terms of clinical practice, it is important to be aware of this association and inform patients of preventative actions that can be taken for preeclampsia and other hypertensive disorders of pregnancy.
