. 2019 Sep 10;9(3):e275–e291. doi: 10.1055/s-0039-1695004

Table 3. Summary of studies on neurological effects on offspring.

Authors, years of publication	Study design	Study groups ( n )	Offspring birth year/ age when measured	Summary of results	Confounders adjusted for	Definition of preeclampsia
Walker et al, ⁶⁵ 2015	Case control study	Autism spectrum disorder (ASD) (408) TD (277)	24–60 mo	Children with ASD were twice more likely to have been exposed in utero to preeclampsia than controls with TD. OR = 2.36 (95% CI: 1.18–4.68). Risk increased with greater preeclampsia severity ( p = 0.02).	Maternal educational level, parity, and prepregnancy obesity.
Mann et al, ⁶⁶ 2010		Children with ASD (472) Children without ASD (87,205)	1996–2002	Preeclampsia was significantly associated with greater odds of ASD. OR = 1.69 (95% CI: 1.26–2.28), p = 0.0005.	Birth weight.
Burstyn et al, ⁶⁷ 2010	Case control study	Preeclampsia (2,747) Nonpreeclampsia (212,473)	1998–2004	RR (95% CI) of ASD: preeclampsia = 1.49 (95% CI: 1.00–2.23).
Buchmayer et al, ⁶⁸ 2009	Case control study	Patients with ASD (1,216) Patients without ASD (6,080)	1987–2002	Preeclampsia was associated with increased risk of ASD. OR = 1.64 (95% CI:1.08–2.49).	Maternal age, smoking, maternal country of birth, whether the mother lived with the father, and maternal schizophrenia.
Silva et al, ⁶⁹ 2014	Case control study	Male: with ADHD (10,065), without ADHD (23,156) Female: with ADHD (2,926), without ADHD (6,915)	1981–2003 aged < 25 y	Male: preeclampsia was associated with increased risk of ADHD. OR = 1.15 (95% CI: 1.03–1.27). Female: preeclampsia was associated with increased risk of ADHD. OR = 1.28 (95% CI: 1.05–1.56).	Maternal age, Apgar's score at 5 min of birth, and SEIFA (data in model available for full dataset from 1981–2003).
Getahun et al, ⁷⁰ 2013	Nested case- control study	With ADHD (13,613) Without ADHD (68,065)	5–11 y	ADHD children were more likely to be exposed to preeclampsia. OR = 1.34 (95% CI: 1.25–1.44).	Maternal age, education, smoking during pregnancy, parity, prenatal care, household income, psychosocial disorder during pregnancy, child race/ethnicity, and gender.
Halmøy et al, ⁷¹ 2012	Case control study	Offspring with ADHD (2,323) Offspring without ADHD (1,170,073)	1967–1987	ADHD adults were more likely to be exposed to preeclampsia. OR = 1.2 (95% CI: 1.0–1.6).	Year of birth, parity, age of mother at birth, educational level of mother, and marital status of mother.
Amiri et al, ⁷² 2012	Case control study	Offspring with ADHD (164) Offspring without ADHD (166)	9.2 ± 2.23 y in group with ADHD; 9.02 ± 1.53 y in group without ADHD	The frequency of preeclampsia: with ADHD: 3.7%, without ADHD: 4.9%, p = 0.78.
Mann and McDermott, ⁷³ 2011	Case control study	Offspring with ADHD (7,911) Offspring without ADHD (76,810)	1996–2002	Preeclampsia was significantly more common in mothers of children with ADHD (6.2 vs. 5.5%), p = 0.008. OR: preeclampsia = 1.19 (95% CI: 1.03–1.37), p = 0.015.	Infant sex, infant race, maternal education, maternal age, birth weight, alcohol use, and tobacco use.	Identified using ICD-9 codes 642.4–642.7.
Rätsep et al, ⁸⁴ 2016	Cohort study	Preeclampsia (10) Uncomplicated pregnancy (10)	7–10 y	Offspring of preeclampsia had reduced cognitive function including an impairment in working memory and visuospatial processing.	Children's age and sex	New-onset hypertension (> 140/90 mm Hg) and at least one of proteinuria (> 300 mg/d), thrombocytopenia(platelets < 105/L), renal insufficiency (serum creatinine > 1.1 mg/dL), impaired liver function (blood liver transaminases 2 × normal), pulmonary edema, or cerebral or visual disturbances occurring after the 20th week of gestation.
Warshafsky et al, ⁸⁵ 2016	Prospective cohort study	Severe preeclampsia (95) Normotensive pregnancy (140)	1–5 y	Offspring of severe preeclampsia exhibited lower social-cognitive and executive functioning development.		Severe preeclampsia:SBP ≥ 1 60 mm Hg, DBP ≥ 110 mm Hg, proteinuria ≥ 5 g in 24 h or ≥ 3 + on dipstick, oliguria (≤ 500 mL in 24 h), cerebral or visual disturbances, epigastric pain, thrombocytopenia (< 150,000 × 109/L), increase in AST (> 46 U/L) and ALT (> 40 U/L), elevated serum creatinine (> 106 pmol/L), pulmonary edema or cyanosis, IUGR, or eclampsia.
Tuovinen et al, ⁸⁶ 2014	Helsinki birth cohort study	Preeclampsia (24) Normotensive pregnancy (494)	69.3 + 3.1 y	Problems in adaptive functioning to spouse. Preeclampsia: OR = 4.12 (95% CI: 1.35–12.96), p = 0.01. Normotensive pregnancy as referent. Functional impairment. Preeclampsia: OR = 2.99 (95% CI: 1.08–8.24), p = 0.03. Memory/cognition: Preeclampsia: OR = 3.92 (95% CI: 1.39–11.04), p = 0.01. Depressive symptoms. Preeclampsia: OR = 6.79 (95% CI: 2.41–19.08).	Sex, year of birth (1934–1938 vs. 1939–1944), gestational age, weight for gestational age, head circumference at birth, placental weight, father's occupational status in patients childhood, parity, mother's age, BMI at delivery, breastfeeding, own maximum level of education in adulthood, and age at completion of the questionnaire.	SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg occurring after 20 weeks of gestation with a 1 + proteinuria reading on dipstick in random urine sample.
Morsing et al, ⁸⁷ 2014	Case control study	Very preterm birth with exposure to preeclampsia (the exposed PT-IUGR; 11) Very preterm birth without exposure to preeclampsia (the nonexposed PT-IUGR; 23) Appropriate for gestational age without exposure to preeclampsia (PT-AGA; 34)	5–8 y	Verbal IQ: mean + SD the exposed PT-IUGR: 74 ± 16, the nonexposed PT-IUGR: 89 ± 15; p = 0.013. PT-AGA: 96 ± 15, p < 0.001; full scale IQ: mean ± SD the exposed PT-IUGR: 70 ± 19. The nonexposed PT-IUGR: 83 ± 14, p = 0.029; PT-AGA: 90 ± 14, p = 0.001.		DBP > 90 mm Hg on two or more occasions and proteinuria > 300 mg/L.
Griffith et al, ⁸⁸ 2011	Case control study	Children with intellectual disability (1,636) Comparison children (79,230)	3–5 y	Preeclampsia was associated with the increased risk of intellectual disability. OR = 1.579 (95% CI: 1.334–1.870)	Maternal age, white race, education, birth year, and female sex but not low birth weight or preterm status.	ICD-9 codes
Ehrenstein et al, ⁸⁹ 2009	Follow-up	Preeclampsia (604) Normotensive pregnancy (16,555)	18–19 y	Preeclampsia was associated with the increased risk of low cognitive function. (IQ < 85) Prevalence ratio: 1.32 (95% CI: 1.08–1.62).	Maternal age, parity, marital status, and history of diabetes; and for conscripts' year of birth, country of birth, birth weight in grams, and being large for gestational age.	New onset of hypertension (> 140/90 mm Hg blood pressure) in the second half of pregnancy with de novo proteinuria (> 0.3 g over 24 h) or edema.
Eide et al, ¹⁰⁸ 2013	Cohort study	Preeclampsia (15,622)	1967–1982	Schizophrenia Preeclampsia: OR = 1.3 (95% CI: 1.0–1.8).	Maternal age, education, parity; marital status: unmarried, married; sex: male, female, and year of birth.	Increase in blood pressure to at least 140/90 mm Hg after the 20th week of gestation, an increase in DBP ≥ 15 mm Hg or SBP ≥ 30 mm Hg from the level measured before 20th week, with proteinuria (≥ 300 mg/24 h).
Tuovinen et al, ¹⁰⁷ 2010	Cohort study	Preeclampsia	60, 63 y	Depressive symptoms: participants born after preeclampsia had over 30% higher depressive symptom scores than normotensive pregnancy, p < 0.04	Mother's age and BMI at delivery, the participant's body size at birth/length of gestation, sex and childhood socioeconomic status, age and educational attainment at testing	BP ≥ 140/90 mm Hg with proteinuria

Abbreviations: ADHD, attention deficit hyperactivity disorder; ALT, alanine aminotransferase; ASD, autism spectrum disorder; AST, aspartate aminotransferase; CI, confidence interval; ICD-9, international classification of disease, 9th edition; IQ, intelligence quotient; OR, odds ratio; RR, risk ratio; SD, standard deviation; TD, typical development.