Abstract
Introduction
Hypertensive disorders of pregnancy (HDP) or prepregnancy overweight/obesity are independently associated with the risk for certain neurodevelopmental and psychiatric disorders in offspring. These two conditions often co‐exist but the risk from combined exposure is unknown. We investigated whether specific subtypes of maternal HDP, along with prepregnancy overweight/obesity, were associated with the distinct risk of neurodevelopmental and psychiatric disorders in offspring during childhood.
Material and Methods
This prospective, population‐based cohort study used data from 652 732 singleton children born alive in Finland between 2004 and 2014 and followed until 2018. The Cox proportional hazards model was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI).
Results
Children exposed to both chronic hypertension and obesity exhibited a 2.4–3.5‐fold higher risk for mood disorders, specific developmental disorder, autism spectrum disorders, and attention‐deficit/hyperactivity disorders. Similarly, exposure to both gestational hypertension and overweight increased the risk for anxiety disorders and attention‐deficit hyperactivity disorders by 2.4‐fold. Meanwhile, combined exposure to preeclampsia and overweight increased the risk of mood and anxiety disorders, specific developmental disorders, and other behavioral disorders, by 1.8–2.2‐fold. The effect size of combined exposure to HDP and overweight/obesity was greater than that of the individual exposure to HDP subtypes or overweight/obesity. Furthermore, overweight/obesity synergistically modified these associations between the HDP subtype exposure and offspring mental disorders, except for specific developmental disorders.
Conclusions
Our findings suggest that combined exposure to different subtypes of HDP and higher prepregnancy BMI have distinct impacts on the mental health of offspring. Notably, a more pronounced effect was observed in cases where chronic hypertension and obesity coexisted. Future research should focus on exploring dose‐related relationships rather than amalgamating maternal HDP for investigating the offspring outcomes.
Keywords: ADHD, anxiety disorder, autism spectrum disorders, hypertension, mental health, neurodevelopmental disorders, obesity
Combined exposure to maternal prepregnancy with high BMI and hypertension was associated with a higher risk of certain mental disorders than that of individual exposure alone. High BMI status modified the association between maternal hypertension and these offspring mental disorders synergistically.
Abbreviations
- ADHD
attention‐deficit/ hyperactivity disorders
- aHR
adjusted hazard ratios
- ASD
autism spectrum disorders
- ATC
anatomical therapeutic chemical
- BMI
body mass index
- CI
confidence intervals
- HDP
hypertensive disorders of pregnancy
- HILMO
Finnish Care Registers for Health Care
- ICD‐10
International Statistical Classification of Diseases and Related Health Problems, Tenth Revision
- ID
intellectual disability
- SDD
specific developmental disorders
Key points.
Prenatal exposures to hypertension and higher BMI were synergistically associated with higher risks of certain mental disorders in offspring during childhood, with notable sex‐specific effect sizes, and may be an important risk factor for developing childhood mental disorders.
1. INTRODUCTION
Hypertensive disorders of pregnancy (HDP) constitute a group of conditions, including gestational hypertension, chronic hypertension, preeclampsia/eclampsia, and chronic hypertension with superimposed preeclampsia. 1 , 2 HDP, with rising prevalence globally, stands as one of the leading causes of maternal and fetal morbidity and mortality. 3 , 4 Pregnant women with HDP have a disturbed gestational environment including systemic inflammation and oxidative stress, 5 which might interfere with brain development during the critical window of in utero phase, consequently increasing the risk of neurodevelopmental disorders in offspring. 6 HDP has been reported to be associated with a 1.2–1.6‐fold higher risk of attention‐deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID) in offspring, which were not solely explained by familial confounding. 7 Additionally, studies have demonstrated a 2.3‐fold higher risk of childhood depression associated with HDP. 8 Other studies have reported that HDP is a risk factor for mood or anxiety disorders in offspring. 9 , 10 , 11 Overall, this suggests that HDP might be a potential risk factor for also other neuropsychiatric conditions in children or adolescents.
Due to sedentary lifestyles in the past two decades, the prevalence of obesity has become a pandemic in both low‐middle‐income as well as high‐income countries. 8 Particularly, there is an alarming prevalence of obesity among women of childbearing age worldwide. 9 , 12 , 13 , 14 Maternal obesity was found to be associated with the risk of neurodevelopmental disorders in offspring, where particularly ADHD and ASD have been studied. 15 , 16 , 17
Multiple studies have indicated that HDP is associated with obesity. 12 , 13 , 14 For example, obesity in pregnant women is associated with three to four times higher risk for preeclampsia compared to women with normal weight. 18 , 19 , 20 Considering the interrelation between maternal obesity and HDP conditions, both of which are associated with certain neurodevelopmental disorders in offspring, it is crucial to explore the potential additive or interactive effects of maternal obesity and HDP on the neurodevelopmental and psychiatric disorders in the offspring.
Thus, using data from Finnish national health registers, we have investigated whether specific subtypes of maternal HDP, in conjunction with maternal prepregnancy obesity/overweight, are associated with increased risks of neurodevelopmental or psychiatric disorders in offspring. We hypothesized that maternal prepregnancy obesity and HDP have synergistic effects on the risk of neurodevelopmental or psychiatric disorders in offspring.
2. MATERIAL AND METHODS
2.1. Study population
For this population‐based cohort study, we used data from all singleton live births recorded in the Finnish Medical Birth Register, between January 1, 2004 and December 31, 2014. We linked their data to the Finnish Register on Reimbursement Drugs, and the Finnish Care Registers for Health Care (HILMO) using unique personal identification numbers assigned to all citizens and permanent residents of Finland. Exclusion criteria were missing data on maternal BMI, and maternal underweight (BMI < 18.5 kg/m2).
2.2. Exposures
Maternal prepregnancy body mass index (BMI) was captured during the early prenatal visit, that is, 7–10 weeks of pregnancy, and was retrieved from the Medical Birth Register. Maternal BMIs were categorized into three subtypes as follows: normal (≥18.5 and <25 kg/m2), overweight (≥25–<30 kg/m2), and obese (≥30 kg/m2).
The information on maternal HDP was obtained from the HILMO and Medical Birth Register and was categorized into four subtypes as follows: normotension (with no diagnosis of chronic hypertension and/or HDP in earlier or current pregnancy), gestational hypertension (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD‐10) code O13), preeclampsia (ICD‐10 code O11 and O14), and chronic hypertension (ICD‐10 code I10‐I13 and O10). In the Finnish healthcare setting, gestational hypertension is defined as systolic ≥140 mmHg or diastolic ≥90 mmHg blood pressure with onset after 20 weeks of pregnancy without proteinuria and biochemical or hematological abnormalities; while preeclampsia is defined as systolic ≥140 mmHg or diastolic ≥90 mmHg blood pressure with onset after 20 weeks of pregnancy, accompanied by the presence of proteinuria; and chronic hypertension is defined as blood pressure which exceeds 140/90 mmHg before pregnancy or before 20 weeks of pregnancy. If a mother had more than one hypertension diagnosis, the exposure was set in the following order: first preeclampsia, then chronic hypertension, and gestational hypertension.
2.3. Outcomes
We used ICD‐10 codes to ascertain neurodevelopmental and psychiatric disorders from HILMO in individuals between 1996 and 2018, and dispensation of psychotropic drugs (Anatomical Therapeutic Chemical (ATC) codes) from Register on Reimbursement Drugs between 1996 and 2014 (Table 1). Psychotropic medications were defined according to the ATC classification system: antipsychotics, anxiolytics, hypnotics, and sedatives (ATC groups N05); antidepressants (ATC group N06A); stimulants (ATC group N06B).
TABLE 1.
List of included neurodevelopmental and psychiatric disorders along with ICD‐10 codes, number of diagnosed children, and the proportions that were identified (until December 2018) of the estimated number of cases that would have received a diagnosis before 16 years of age (requiring the youngest cases to be followed up until 2030).
| Neurodevelopmental and psychiatric disorders of interest | ICD‐10 codes | Number of diagnosed children | Estimated proportion identified (%) |
|---|---|---|---|
| Any neurodevelopmental and psychiatric disorders | F00–F99 | 31 861 | 41.6 |
| Mood disorders | F30–F39 and F92 | 8392 | 26.4 |
| Anxiety disorders | F40–F43 and F93 | 14 732 | 34.1 |
| Eating disorders | F50 | 863 | 21.0 |
| Sleeping disorders | F51 | 2946 | 44.4 |
| Personality disorders | F60–F69 | 295 | 44.4 |
| Intellectual disabilities | F70–F79 | 3942 | 65.3 |
| SDD | F80–F83 | 30 382 | 79.8 |
| ASD | F84 | 6218 | 54.4 |
| ADHD and conduct disorders | F90 and F91 | 16 275 | 45.7 |
| Other behavioral and emotional disorders | F98 | 14 270 | 61.3 |
Note: The Finnish Care Registers for Health Care (HILMO) contains data on all hospital in‐patient treatments (since 1969) as well as out‐patient treatments by physicians in specialized care (since 1998) and includes all psychiatric diagnoses. The diagnosis of pediatric neurodevelopmental and psychiatric disorders in HILMO has been validated. 21 Estimated proportion identified was calculated as number of diagnosed cases divided by the denominator being: proportion of diagnosed cases among those born in 2004 (this birth cohort was followed up for 15 years).
Abbreviations: ADHD, attention‐deficit/hyperactivity disorders; ASD, autism spectrum disorders; SDD, specific developmental disorders.
Total cohort size 595436.
2.4. Covariates
Characteristics that from previous reports are known to be associated with maternal BMI, HDP, and offspring outcomes are presented in a directed acyclic graph (Figure S1) and those available were retrieved from the registries and used as covariates in this study.
The covariates included were the maternal characteristics age at childbirth, country of origin (Finland, other countries), cohabitation status at birth (yes, no), parity (0, ≥1), occupation (upper white‐collar worker, lower white‐collar worker, blue‐collar worker, other, missing), smoking status during pregnancy (yes, no) identified from the Medical Birth Register, and diabetes mellitus status (none, pregestational [type 1 and type 2] or gestational), history of any inpatient (from 1987: ICD‐8290–317, ICD‐9290–319 and ICD‐10 F00‐F99) or outpatient (from 1998: ICD‐10 codes F00‐F99) psychiatric disorder (yes, no), history of systemic inflammatory disease (ICD‐10 codes M30‐M36; yes, no) identified through the HILMO, and use of any psychotropic drug during pregnancy (N05 and N06; yes, no) identified through the Register on Reimbursement Drugs. The child characteristics were birth year of a child and sex of the child (boy, girl), identified from the Medical Birth Register.
2.5. Statistical analyses
The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between prenatal exposure to maternal HDP and the risk for neurodevelopmental or psychiatric disorders in offspring. Interactions between maternal hypertension (classified as chronic hypertension, preeclampsia, gestational hypertension, or no hypertension) and BMI status (normal weight, overweight, or obese) were examined for any neurodevelopmental or psychiatric disorder in offspring by fitting a multiplicative interaction term, adjusting for the aforementioned covariates. Upon detecting a statistically significant interaction, subsequent analyses of associations between prenatal exposure to maternal HDP and the risk for individual neurodevelopmental or psychiatric disorders in offspring were stratified according to maternal BMI status and adjusted for the above‐mentioned covariates, resulting in adjusted HR (aHR). Subsequently, if combined HDP and BMI status were associated with a higher risk than individual exposures alone, statistical interaction between the two exposures was tested at a multiplicative scale in a full‐factor model adjusted for the listed covariates. Proportional hazards model assumptions were assessed graphically using scaled Schoenfeld residual plots, showing no evidence of nonproportional hazards. To control for Type 1 errors, given the number of analyses conducted, a statistical significance threshold of p = 0.005 (i.e., 0.05/10, Bonferroni correction for 10 specific offspring diagnoses) was set for the main adjusted analysis.
Subgroup analyses were performed to examine whether the effect estimates differed between boys and girls.
For the sensitivity analysis, we estimated the effect of exposure to HDP and maternal BMI on the dispensation of psychotropic medication among the children. The psychotropic medication included ATC group N05 drugs (antipsychotics, anxiolytics, hypnotics, and sedatives), group N06A drugs (antidepressants), and group N06B drugs (stimulants and nootropics). Antipsychotics were not excluded from N05 as they are sometimes prescribed off‐label for childhood behavioral disorders. In addition, to account for the potential influence on effect estimates of neonatal factors that are known to be associated with psychiatric disorders in offspring, we performed a sensitivity analysis by adjusting separately for preterm birth (<37 weeks; yes, no), low birth weight (<2500 g; yes, no), small for gestational age (defined as birth weight less than 5th percentile for gestational age; yes, no), and low Apgar score at 5 min (Apgar score 0–6; yes, no). Here, two‐sided p < 0.05 was considered statistically significant.
Furthermore, given the increased risk of neurodevelopmental disorders among children born to mothers with pregestational diabetes (type 1 or type 2), we excluded children whose mothers had pregestation diabetes from the analysis.
All statistical analyses were performed using SAS software, version 9.4 (SAS Institute Inc). Data were analyzed between August 1, 2022 and December 10, 2023.
3. RESULTS
A total of 652 732 singleton live births from Finland were recorded between 2004 and 2014, of which 34 020 (5.2%) children were excluded due to missing maternal prepregnancy BMI data and 23 276 were excluded due to maternal underweight (BMI <18.5 kg/m2), resulting in 595 436 children for the final analysis.
Of the 595 436 children, 19 348 (3.1%) were prenatally exposed to gestational hypertension, 8640 (1.3%) to maternal chronic hypertension, 13 851 (2.2%) to preeclampsia, and 135 055 (22.7%) were born to mothers with overweight and 74 094 (12.4%) to mothers with obesity, during pregnancy. The mean (SD) maternal age at childbirth was 30.2 (5.4) years (Table 2).
TABLE 2.
Maternal and child characteristics of the study cohort stratified by maternal HDP and BMI (N = 595 436).
| Variables | Normotension | Gestational hypertension | Preeclampsia | Chronic hypertension | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Normal | Overweight | Obese | Normal | Overweight | Obese | Normal | Overweight | Obese | Normal | Overweight | Obese | |
| Child‐birth year | ||||||||||||
| 2004–2007 | 126 201 (34.36) | 40 697 (32.85) | 19 491 (30.87) | 3548 (40.4) | 2069 (38.79) | 1678 (34.01) | 1237 (45.16) | 1022 (43.66) | 1380 (39.61) | 2542 (34.03) | 1096 (31.51) | 803 (31.71) |
| 2008–2011 | 140 092 (38.14) | 47 426 (38.28) | 23 971 (37.96) | 3326 (37.87) | 2015 (37.78) | 1878 (38.06) | 957 (34.94) | 853 (36.44) | 1294 (37.14) | 2957 (39.59) | 1390 (39.97) | 969 (38.27) |
| 2012–2014 | 101 002 (27.50) | 35 779 (28.88) | 19 682 (31.17) | 1909 (21.74) | 1250 (23.43) | 1378 (27.93) | 545 (19.9) | 466 (19.91) | 810 (23.25) | 1971 (26.39) | 992 (28.52) | 760 (30.02) |
| Sex assigned at birth | ||||||||||||
| Boy | 188 415 (51.3) | 63 134 (50.95) | 32 089 (50.82) | 4557 (51.88) | 2903 (54.42) | 2615 (53) | 1375 (50.2) | 1214 (51.86) | 1793 (51.46) | 3725 (49.87) | 1787 (51.38) | 1279 (50.51) |
| Girl | 178 880 (48.70) | 60 768 (49.05) | 31 055 (49.18) | 4226 (48.12) | 2431 (45.58) | 2319 (47.00) | 1364 (49.8) | 1127 (48.14) | 1691 (48.54) | 3745 (50.13) | 1691 (48.62) | 1253 (49.49) |
| Maternal age at childbirth, year | ||||||||||||
| <20 | 8900 (2.42) | 2172 (1.75) | 895 (1.42) | 298 (3.39) | 104 (1.95) | 75 (1.52) | 29 (1.06) | 11 (0.47) | 8 (0.23) | 285 (3.82) | 67 (1.93) | 59 (2.33) |
| 20–24 | 56 949 (15.5) | 17 744 (14.32) | 9503 (15.05) | 1416 (16.12) | 931 (17.45) | 791 (16.03) | 188 (6.86) | 143 (6.11) | 205 (5.88) | 1330 (17.8) | 616 (17.71) | 512 (20.22) |
| 25–29 | 119 529 (32.54) | 37 796 (30.5) | 19 630 (31.09) | 2836 (32.29) | 1478 (27.71) | 1399 (28.35) | 632 (23.07) | 444 (18.97) | 793 (22.76) | 2408 (32.24) | 1095 (31.48) | 735 (29.03) |
| 30–34 | 118 062 (32.14) | 39 862 (32.17) | 19 713 (31.22) | 2559 (29.14) | 1497 (28.07) | 1461 (29.61) | 920 (33.59) | 728 (31.1) | 1070 (30.71) | 2135 (28.58) | 1006 (28.92) | 688 (27.17) |
| 35 or more | 63 855 (17.39) | 26 328 (21.25) | 13 403 (21.23) | 1674 (19.06) | 1324 (24.82) | 1208 (24.48) | 970 (35.41) | 1015 (43.36) | 1408 (40.41) | 1312 (17.56) | 694 (19.95) | 538 (21.25) |
| Parity a | ||||||||||||
| 0 | 158 151 (43.06) | 45 001 (36.32) | 20 597 (32.62) | 5670 (64.56) | 2874 (53.88) | 2507 (50.81) | 1239 (45.24) | 907 (38.74) | 1271 (36.48) | 5007 (67.03) | 2047 (58.86) | 1323 (52.25) |
| 1 or more | 209 144 (56.94) | 78 901 (63.68) | 42 547 (67.38) | 3113 (35.44) | 2460 (46.12) | 2427 (49.19) | 1500 (54.76) | 1434 (61.26) | 2213 (63.52) | 2463 (32.97) | 1431 (41.14) | 1209 (47.75) |
| Maternal country of origin | ||||||||||||
| Finnish | 333 483 (90.79) | 112 916 (91.13) | 58 317 (92.36) | 8341 (94.97) | 5096 (95.54) | 4730 (95.87) | 2636 (96.24) | 2256 (96.37) | 3360 (96.44) | 6917 (92.6) | 3236 (93.04) | 2387 (94.27) |
| Other countries | 33 812 (9.21) | 10 986 (8.87) | 4827 (7.64) | 442 (5.03) | 238 (4.46) | 204 (4.13) | 103 (3.76) | 85 (3.63) | 124 (3.56) | 553 (7.4) | 242 (6.96) | 145 (5.73) |
| Maternal cohabitation status at birth | ||||||||||||
| Married | ||||||||||||
| Yes | 32 934 (8.97) | 10 599 (8.55) | 5619 (8.90) | 670 (7.63) | 369 (6.92) | 410 (8.31) | 233 (8.51) | 184 (7.86) | 275 (7.89) | 797 (10.67) | 410 (11.79) | 306 (12.09) |
| Other | 334 361 (91.03) | 113 303 (91.45) | 57 525 (91.1) | 8113 (92.37) | 4965 (93.08) | 4524 (91.69) | 2506 (91.49) | 2157 (92.14) | 3209 (92.11) | 6673 (89.33) | 3068 (88.21) | 2226 (87.91) |
| Maternal occupation | ||||||||||||
| Upper white collar worker | 68 860 (18.75) | 18 169 (14.66) | 6755 (10.70) | 1629 (18.55) | 739 (13.85) | 575 (11.65) | 560 (20.45) | 355 (15.16) | 435 (12.49) | 1345 (18.01) | 481 (13.83) | 272 (10.74) |
| Lower white collar worker | 113 979 (31.03) | 42 940 (34.66) | 22 167 (35.11) | 3093 (35.22) | 2168 (40.64) | 1963 (39.79) | 1015 (37.06) | 968 (41.35) | 1418 (40.70) | 2317 (31.02) | 1186 (34.10) | 893 (35.27) |
| Blue collar Worker | 41 736 (11.36) | 17 781 (14.35) | 10 851 (17.18) | 1108 (12.62) | 759 (14.23) | 859 (17.41) | 307 (11.21) | 312 (13.33) | 682 (19.58) | 818 (10.95) | 514 (14.78) | 382 (15.09) |
| Other | 61 567 (16.76) | 19 681 (15.88) | 10 645 (16.86) | 1412 (16.08) | 766 (14.36) | 744 (15.08) | 382 (13.95) | 339 (14.48) | 436 (12.51) | 1235 (16.53) | 525 (15.09) | 417 (16.47) |
| Missing | 81 153 (22.09) | 25 331 (20.44) | 12 726 (20.15) | 1541 (17.55) | 902 (16.91) | 793 (16.07) | 475 (17.34) | 367 (15.68) | 513 (14.72) | 1755 (23.49) | 772 (22.20) | 568 (22.43) |
| Smoking during pregnancy | ||||||||||||
| Yes | 50 565 (13.77) | 20 340 (16.42) | 12 864 (20.37) | 1287 (14.65) | 825 (15.47) | 925 (18.75) | 304 (11.10) | 300 (12.82) | 624 (17.91) | 941 (12.60) | 571 (16.42) | 446 (17.61) |
| No | 316 730 (86.23) | 103 562 (83.58) | 50 280 (79.63) | 7496 (85.35) | 4509 (84.53) | 4009 (81.25) | 2435 (88.9) | 2041 (87.18) | 2860 (82.09) | 6529 (87.4) | 2907 (83.58) | 2086 (82.39) |
| Maternal diabetes | ||||||||||||
| None | 334 271 (91.01) | 94 671 (76.41) | 36 690 (58.11) | 7717 (87.86) | 3896 (73.04) | 2708 (54.88) | 2305 (84.15) | 1434 (61.26) | 1449 (41.59) | 6499 (87) | 2513 (72.25) | 1331 (52.57) |
| Type 1 or 2 | 2226 (0.61) | 1483 (1.20) | 1804 (2.86) | 131 (1.49) | 117 (2.19) | 206 (4.18) | 93 (3.40) | 141 (6.02) | 430 (12.34) | 237 (3.17) | 150 (4.31) | 168 (6.64) |
| Gestational | 30 798 (8.39) | 27 748 (22.4) | 24 650 (39.04) | 935 (10.65) | 1321 (24.77) | 2020 (40.94) | 341 (12.45) | 766 (32.72) | 1605 (46.07) | 734 (9.83) | 815 (23.43) | 1033 (40.8) |
| Maternal history of psychiatric disorders | ||||||||||||
| Yes | 6108 (1.66) | 2405 (1.94) | 1652 (2.62) | 140 (1.59) | 80 (1.50) | 120 (2.43) | 42 (1.53) | 53 (2.26) | 76 (2.18) | 132 (1.77) | 76 (2.19) | 76 (3.00) |
| No | 361 187 (98.34) | 121 497 (98.06) | 61 492 (97.38) | 8643 (98.41) | 5254 (98.50) | 4814 (97.57) | 2697 (98.47) | 2288 (97.74) | 3408 (97.82) | 7338 (98.23) | 3402 (97.81) | 2456 (97) |
| Maternal history of systemic inflammatory disease b | ||||||||||||
| Yes | 3024 (0.82) | 1139 (0.92) | 694 (1.10) | 101 (1.15) | 54 (1.01) | 59 (1.20) | 42 (1.53) | 34 (1.45) | 46 (1.32) | 81 (1.08) | 42 (1.21) | 20 (0.79) |
| No | 364271 (99.18) | 122763 (99.08) | 62450 (98.9) | 8682 (98.85) | 5280 (98.99) | 4875 (98.8) | 2697 (98.47) | 2307 (98.55) | 3438 (98.68) | 7389 (98) | 3436 (98.79) | 2512 (99.21) |
| Maternal use of any psychotropic drugs during pregnancy c | ||||||||||||
| Yes | 19 620 (5.34) | 7723 (6.23) | 4942 (7.83) | 570 (6.49) | 326 (6.11) | 435 (8.82) | 187 (6.83) | 187 (7.99) | 331 (9.50) | 438 (5.86) | 247 (7.10) | 233 (9.20) |
| No | 347 675 (94,66) | 116 179 (93,77) | 58 202 (92,17) | 8213 (93,51) | 5008 (93,89) | 4499 (91,18) | 2552 (93,17) | 2154 (92,01) | 3153 (90,5) | 7032 (94,14) | 3231 (92,9) | 2299 (90,8) |
Note: Data are presented as number (%) of children. Preeclampsia was defined based on the International Classification of Diseases, Tenth Revision (ICD‐10) codes O11 and O14. Chronic hypertension was defined based on ICD‐10 codes I10‐I13 and O10. Gestational hypertension was defined based on ICD‐10 code O13. Maternal BMIs were categorized as normal (≥18.5 and <25 kg/m2), overweight (≥25–<30 kg/m2), and obese (≥30 kg/m2). Type 2 diabetes was defined as pregestational type 2 diabetes (ICD‐10 code E11, E14, or O24.1 and/or the use of Anatomic Therapeutic Chemical class A10B drugs) without insulin purchase before or during pregnancy. Gestational diabetes was defined as an ICD‐10 code O24.4 diagnosis without the purchase of insulin before or during pregnancy. Type 1 diabetes was defined as an ICD‐10 code E10.
Parity was defined as the number of previous births to a fetus with ≥22 weeks of gestation, regardless of whether the child was born alive or stillborn.
Maternal systemic inflammatory disease was identified based on ICD‐10 codes M30 to M36.
Maternal use of psychotropic medications during pregnancy was determined based on Anatomical Therapeutic Chemical classification system codes N05 and N06.
All included children, comprising 304 886 boys (51.2%), were followed for a median age of 5.5 years (interquartile range: 2.8–8.3). Within this period, 31 861 (5.3%) children were diagnosed with neurodevelopmental or psychiatric disorders: n = 8392 (1.4%) for mood disorders, n = 14 732 (2.5%) for anxiety disorders, n = 863 (0.1%) for eating disorders, n = 2946 (0.5%) for sleeping disorders, n = 295 (0.05%) for personality disorder, n = 3942 (0.7%) for ID, n = 30 382 (5.1%) for SDD, n = 6218 (1.0%) for ASD, n = 16 275 (2.7%) for ADHD or CD, and n = 14 270 (2.4%) for other behavioral and emotional disorders (Table S1).
Further, 35 239 children (5.9%) had psychotropic medication dispensed to them, which included antipsychotics and hypnotics or anxiolytics (n = 9445, ATC group N05 drugs), antidepressants (n = 334, ATC group N06A drugs), and stimulants (n = 4613, ATC group N06B drugs) (Table S1).
There was a statistically significant interaction between hypertension (with the categories chronic hypertension, preeclampsia, gestational hypertension, or none) and BMI status (normal weight, overweight, or obesity) concerning the risk of any neurodevelopmental or psychiatric disorder (pinteraction <0.0001). This led us to conduct further analyses stratifying by BMI status, with children born to mothers with normotension and normal prepregnancy BMI serving as our reference group.
3.1. Mothers with normotension stratified by maternal prepregnancy BMI
Children born to mothers with normotension and obesity exhibited a higher risk of any F‐diagnosis (aHR = 1.27; 95% CI, 1.23–1.32) compared to the reference group. Larger effect sizes for risk estimates were observed for specific individual F‐diagnoses groups, including eating disorders (aHR = 1.67), ID (aHR = 1.65), specific developmental disorders (SDD) (aHR = 1.55), ADHD or CD (aHR = 1.46), mood disorders (aHR = 1.44), anxiety disorders (aHR = 1.33), and other behavioral and emotional disorders (aHR = 1.23) (Figure 1 and Table S2).
FIGURE 1.
Adjusted hazard ratios (HRs) for neurodevelopmental and psychiatric disorders in relation to maternal HDP and BMI (All live spontaneous singleton pregnancies born between 1996 and 2014 in Finland followed until 2018). ADHD, attention‐deficit/hyperactivity disorders; ASD, autism spectrum disorders; CD, conduct disorders; SDD, specific developmental disorders. p values that survive multiple comparison correction (p < 0.005) are marked with*. Statistically significant posthoc interactions (p < 0.05) between HDP and BMI categories are indicated with #.
In contrast, children born to mothers with normotension and overweight had a similar risk for any F‐diagnosis (aHR = 1.03; 95% CI, 1.00–1.07) compared to the reference group. However, larger effect sizes for risk estimates were observed for individual F‐diagnoses groups, including ID (aHR = 1.26), SDD (aHR = 1.19), mood disorders (aHR = 1.15), ADHD or CD (aHR = 1.12), and other behavioral and emotional disorders (aHR = 1.09) (Figure 1 and Table S2).
Interestingly, children born to mothers with normotension and overweight or obesity had a lower risk for sleeping disorders (aHR in the range of 0.66–0.80) compared to the reference group.
3.2. Mothers with chronic hypertension stratified by maternal prepregnancy BMI
Children born to mothers with chronic hypertension and normal BMI exhibited a similar risk of any F‐diagnosis as the reference group (Figure 1 and Table S2). However, upon investigating individual F‐diagnosis groups, notably a larger effect size for risk was observed solely for SDD (aHR = 1.32).
While, children born to mothers with chronic hypertension and obesity had higher risks for mood disorders, ID, SDD, ASD, ADHD or CD, and other behavioral and emotional disorders compared to the reference group. The effect sizes of combined exposure to chronic hypertension and obesity were higher compared to the individual exposure to chronic hypertension or obesity for mood disorders (aHR = 3.19; 95% CI, 2.71–3.77), SDD (aHR = 2.40; 95% CI, 2.17–2.66), ASD (aHR = 3.46; 95% CI, 2.92–4.09), and ADHD or CD (aHR = 2.74; 95% CI, 2.40–3.12) (Figure 1 and Table S2). Furthermore, obesity modified the risks of chronic hypertension synergistically for mood disorders (χ 2 = 18.9; p interaction <0.0001), ASD (χ 2 = 36.4; p interaction <0.0001), ADHD or CD (χ 2 = 20.7; p interaction <0.0001), but not for SDD (χ 2 = 3.6; p interaction = 0.06).
Children born to mothers with chronic hypertension and overweight had higher risks for SDD (aHR = 1.58) and ADHD or CD (aHR = 1.43) compared to the reference group (Figure 1 and Table S2). Nevertheless, the effect sizes of combined exposure were not larger than those of individual exposure to chronic hypertension or overweight.
3.3. Mothers with gestational hypertension stratified by maternal prepregnancy BMI
Children born to mothers with gestational hypertension and normal BMI exhibited similar risks for any F‐diagnosis compared to the reference group (Figure 1 and Table S2). Similar results were found when assessing these F‐diagnosis groups separately.
While, those born to mothers with combined exposure to gestational hypertension and overweight had higher risks for anxiety disorders, SDD, and ADHD or CD (Figure 1 and Table S2). The effect sizes of combined exposure to gestational hypertension and overweight were higher for anxiety disorders (aHR = 2.43; 95% CI, 2.32–2.72) and ADHD or CD (aHR = 2.45; 95% CI, 2.20–2.73) compared to individual exposure to either gestational hypertension or overweight alone. Furthermore, overweight synergistically modified the risk of gestational hypertension for both anxiety disorders (χ 2 = 80.8; p interaction <0.0001) and ADHD or CD (χ 2 = 113.1; p interaction <0.0001).
Children born to mothers with gestational hypertension and obesity had higher risks for mood disorders (aHR = 1.84), anxiety disorders (aHR = 1.60), ID (aHR = 1.98), SDD (aHR = 1.76), and ADHD or CD (aHR = 1.40) compared to the reference group (Figure 1 and Table S2). However, the effect sizes of combined exposure were not larger than those of individual exposure to gestational hypertension or obesity.
3.4. Mothers with preeclampsia stratified by maternal prepregnancy BMI
Children born to mothers with preeclampsia and normal BMI exhibited a higher risk of any F‐diagnosis (aHR = 1.41; 95% CI, 1.28–1.55) compared to the reference group (Figure 1 and Table S2). Upon investigating individual F‐diagnosis groups, larger effect sizes for risk estimates were observed for ID (aHR = 1.48), SDD (aHR = 1.43), ASD (aHR = 1.43), ADHD or CD (aHR = 1.23), and other behavioral and emotional disorders (aHR = 1.34).
Children exposed to both preeclampsia and overweight had higher risks for mood disorders (aHR = 2.23; 95% CI, 1.83–2.72), anxiety disorders (aHR = 1.85; 95% CI,1.57–2.18), SDD (aHR = 1.82; 95% CI, 1.62–2.04), and other behavioral and emotional disorders (aHR = 2.15; 95% CI, 1.85–2.50) compared to both the reference group and those exposed to either preeclampsia or overweight alone (Figure 1 and Table S2). Additionally, overweight synergistically modified the risks of preeclampsia for mood disorders (χ 2 = 20.3; p interaction <0.0001), and other behavioral and emotional disorders (χ 2 = 12.8; p interaction = 0.0003), but not for SDD (χ 2 = 0.95; p interaction = 0.33) or anxiety disorders.
Similarly, children exposed to both preeclampsia and obesity had higher risks for ID, SDD, and ADHD or CD compared to the reference group (Figure 1 and Table S2). The effect sizes of combined exposure to both preeclampsia and obesity for SDD (aHR = 1.98; 95% CI, 1.74–2.25) and ADHD or CD (aHR = 1.94; 95% CI, 1.63–2.30) were higher than that of the individual exposure to either preeclampsia or obesity. However, obesity did not modify the preeclampsia risks for SDD or ADHD or CD.
3.5. Subgroup analysis
The associations for prenatal exposure to both maternal HDP and higher BMI with risk for psychiatric disorders in offspring differed by sex. There was a more pronounced risk for mood and anxiety disorders among boys than girls, and for ASD among girls than boys (Tables S3–S5). Furthermore, the interaction terms for sex were significant in the association between combined exposure to chronic hypertension and obesity (χ 2 = 331.29; p interaction <0.001), gestational hypertension and obesity (χ 2 = 69.72; p interaction <0.001), and preeclampsia and overweight (χ 2 = 142.15; p interaction <0.001) with mood disorders. The interaction terms for sex were also significant in the association between combined exposure to gestational hypertension and overweight (χ 2 = 426.63; p interaction <0.001), and preeclampsia and overweight (χ 2 = 91.22; p interaction <0.001) with anxiety disorders.
In addition, the interaction terms for sex were significant in the association between combined exposure to chronic hypertension and overweight (χ 2 = 36.03; p interaction <0.001) and chronic hypertension and normal BMI (χ 2 = 24.13; p interaction <0.001) with ASD.
3.6. Sensitivity analysis
Consistent with the main findings (Table S2), we observed a higher risk of psychotropic medication dispensation among children born to mothers with chronic hypertension and obesity compared to those born to mothers with normotension and normal BMI. Specifically, the effect sizes were higher for antidepressants (N06A) and psychostimulants (N06B), than for anxiolytics, hypnotics, and sedatives (N05) (Table 3 and Table S1).
TABLE 3.
Adjusted hazard ratios (aHR) for offspring psychotropic medications in relation to maternal HDP and BMI.
| HDP categorized by maternal BMI [kg/m2] | Any medication (n = 13 525) | Anxiolytics, hypnotics and sedatives (n = 9956) | Antidepressants (n = 434) | Stimulants (n = 4786) |
|---|---|---|---|---|
| aHR 95% CI | aHR 95% CI | aHR 95 %CI | aHR 95% CI | |
| Normotension (n = 576 873) | ||||
| Normal (reference) | 1 | 1 | 1 | 1 |
| Overweight | 1.00 (0.96–1.04) | 0.93 (0.88–0.98) | 0.61 (0.44–0.84) | 0.95 (0.88–1.03) |
| Obese | 1.13 (1.06–1.19) | 0.95 (0.89–1.02) | 0.65 (0.43–0.98) | 1.32 (1.20–1.44) |
| Gestational hypertension (n = 19 348) | ||||
| Normal | 0.88 (0.76–1.01) | 0.87 (0.74–1.03) | 0.77 (0.34–1.72) | 0.67 (0.52–0.87) |
| Overweight | 2.55 (2.28–2.85) | 2.93 (2.60–3.30) | 3.67 (2.16–6.22) | 0.87 (0.64–1.19) |
| Obese | 1.06 (0.90–1.26) | 1.01 (0.83–1.23) | 0.42 (0.10–1.71) | 1.32 (1.04–1.68) |
| Chronic hypertension (n = 8640) | ||||
| Normal | 0.83 (0.64–1.08) | 0.82 (0.60–1.11) | NA | 0.73 (0.45–1.17) |
| Overweight | 1.17 (0.92–1.47) | 0.92 (0.68–1.24) | 0.43 (0.06–3.08) | 1.20 (0.82–1.76) |
| Obese | 2.19 (1.90–2.53) | 2.44 (2.09–2.85) | 11.57 (8.08–16.56) | 3.49 (2.90–4.21) |
| Preeclampsia (n = 13 851) | ||||
| Normal | 1.23 (1.07–1.42) | 1.09 (0.92–1.3) | 0.63 (0.23–1.71) | 1.30 (1.04–1.64) |
| Overweight | 1.08 (0.88–1.34) | 0.89 (0.68–1.16) | 0.64 (0.16–2.60) | 1.22 (0.89–1.66) |
| Obese | 1.10 (0.86–1.41) | 0.80 (0.57–1.11) | 0.39 (0.05–2.78) | 1.44 (1.00–2.06) |
Note: Anti‐psychotropic medications were defined according to the ATC classification system: antipsychotics, anxiolytics, hypnotics, and sedatives (ATC group N05); antidepressants (AT group N06A); and stimulants (ATC group N06B). The maternal BMIs were categorized into three subtypes as follows: normal (≥18.5 and <25 kg/m2), overweight (25–30 kg/m2), and obese (≥30 kg/m2). The hypertensive disorders of pregnancy (HDP) were categorized into four subtypes as follows: normotension (with no diagnosis of chronic hypertension and/or HDP in earlier or current pregnancy), gestational hypertension (ICD‐10 code O13), preeclampsia (ICD‐10 code O11 and O14), and chronic hypertension (ICD‐10 code I10‐I13 and O10). All the analyses were adjusted for maternal age, maternal country of origin, cohabitation status at birth, parity, maternal occupation, smoking during pregnancy, diabetes mellitus; maternal history of psychiatric disorders, maternal history of systemic inflammatory disease, maternal use of any psychotropic drugs during pregnancy, sex of a child, and birth year of a child.
Further, we also found a higher risk of psychotropic medication dispensation among those born to mothers with gestational hypertension and overweight, with higher effect sizes observed for antidepressants and anxiolytics, hypnotics, and sedatives (Table 3 and Table S1).
Moreover, additional adjustments for preterm birth, low birth weight, SGA, or low Apgar scores at 5 min, as well as the exclusion of children born to mothers with pregestational diabetes, yielded findings similar to those of the main analysis (Tables S6 and S7).
4. DISCUSSION
Our findings revealed that combined exposure to maternal chronic hypertension and prepregnancy obesity increased the risk of mood disorders, SDD, ASD, and ADHD or CD, by 2.4–3.5‐fold in comparison to those without exposure to HDP or higher BMI status. Similarly, combined exposure to both maternal gestational hypertension and prepregnancy overweight increased the risk of anxiety disorders, and ADHD or CD in offspring, by 1.3–2.4‐fold. In addition, combined exposure to preeclampsia and prepregnancy overweight increased the risk of mood and anxiety disorders, SDD, and other behavioral disorders in offspring, by 1.8–2.2‐fold. Importantly, the effect sizes associated with combined exposure surpassed those of individual exposures to either the HDP or the higher maternal BMI status alone. Moreover, higher maternal BMI status modified the relationships between HDP and the risk of disorders in offspring, except for SDD, suggesting synergistic effects on the risk of offspring neurodevelopmental or psychiatric disorders. These findings remained consistent even after adjusting for birth factors, underscoring their robustness. The robustness of our results for chronic and gestational hypertension was further supported by the high dispensation rate of psychotropic medication among individuals born to mothers with chronic hypertension and obesity, or with gestational hypertension and overweight. To the best of our knowledge, this study reports for the first time the combined effects of HDP along with maternal prepregnancy BMI on the risk for psychiatric disorders in offspring. Furthermore, sex‐specific associations were observed for maternal HDP and higher prepregnancy BMI with offspring psychiatric disorders, particularly, mood, anxiety disorders, and ASD. Overall, our study suggests that in‐utero exposure to certain types of HDP and higher prepregnancy BMI had a synergistic effect on the risk for mental disorders of offspring, at least for ASD, mood disorders, ADHD or CD, and SDD.
Previous observational studies have reported an independent association for HDP or prepregnancy overweight/obesity with a higher risk of neurodevelopmental disorders, particularly ASD and ADHD, in offspring. 6 , 7 , 15 , 22 , 23 , 24 , 25 However, in our study, we observed no association between prepregnancy overweight/obesity and the risk of ASD in offspring. 23 But, in normal‐weight mothers, preeclampsia was associated with a higher risk of ASD (aHR = 1.43) or ADHD (aHR = 1.23) in offspring, which were at magnitudes seen in other studies. 26 , 27 Possible explanations for differences in observations between studies could be attributed to the study design, control of confounding factors, or correction for multiple testing. 6 , 23 For example, Lahti‐Pulkkinen et al. investigated HDP and psychiatric disorders in offspring, adjusting for confounders such as maternal prepregnancy BMI, 6 whereas our study categorized and distinguished HDP types and maternal prepregnancy BMI status separately and had a strict threshold for statistical significance.
Consistent with prior studies, we observed an independent association between maternal HDP, particularly preeclampsia, or higher prepregnancy BMI status, with an increased risk of SDD (aHRs 1.19–1.55) and ID (aHRs 1.26–1.65). 7 , 24 , 28 , 29 , 30 , 31 , 32 Similarly, consistent with prior studies, we observed an independent association of maternal obesity with the risk for ADHD (aHRs = 1.46). 7 , 15 In addition, we found an independent association of maternal obesity with the risk for mood disorders (aHRs = 1.44) and anxiety disorders (aHRs = 1.33). These results aligned with a meta‐analysis that reported an increased risk of mood and anxiety disorders among individuals exposed to maternal obesity (relative risk RR, 1.92; 95% CI, 1.72–2.11). 11
The mechanism linking the association of maternal chronic hypertension and overweight/obesity with the risk of psychiatric disorders in offspring is complex. However, through experimental studies, several potential mechanisms have been proposed. Women with chronic hypertension are known to be associated with higher insulin resistance, chronic inflammation, and endothelial dysfunction. 33 On the other hand, women with prepregnancy obesity have elevated expression of proinflammatory cytokines, such as interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and C‐reactive protein (CRP). 34 , 35 Many cytokines are known to cross the placenta. 36 And, the placenta of obese mothers itself is capable of mounting an immune response which results in increased secretion of IL‐1, tumor necrosis factor‐alpha (TNFα), IL‐7, and CRP, 37 which is likely to influence the intrauterine environment. 38 Previous studies have also shown that higher maternal BMI during early pregnancy was associated with altered functioning of the hypothalamus–pituitary–adrenal axis in offspring, and disturbance in this axis is characteristic of individuals suffering from mental disorders. 39 , 40 In addition, abnormal metabolic factors, such as hyperinsulinism, insulin resistance, and lipid profile alterations are common to both chronic hypertension and prepregnancy obesity, which could interact with fetal programming. 41 , 42
The major strength of this study is the large sample size and the population‐based design where the diagnoses were obtained using data linkage through national registers, likely reducing the self‐selection bias. Further, we adjusted for several maternal and birth factors that are known to be associated with offspring psychiatric disorders.
However, there are some limitations to be acknowledged. First, due to the unavailability of data, we were unable to investigate the potential role of paternal diagnoses or maternal physical activity and diet during pregnancy. Second, we did not have any information on blood pressure to investigate the dose‐related severity of HDP, and we had no data on maternal weight gain during pregnancy. Third, late‐onset psychiatric disorders could not be studied due to the limited follow‐up time (Table 1). Fourth, we were underpowered to additionally explore residual confounding due to unmeasured sibling‐shared familial factors such as genetics. Finally, our study is restricted to the Finnish population, and the generalizability of the results to other ethnicities should be made cautiously.
5. CONCLUSION
Our results indicate that combined exposure to different subtypes of maternal HDP and higher prepregnancy BMI have distinct impacts on the risk of mental disorders in offspring. Notably, a more pronounced effect is observed in cases where chronic hypertension and obesity coexist. These findings emphasize the importance of early screening and necessary interventions for children born to women with both HDP and higher BMI. Future studies exploring maternal hypertensive conditions should differentiate and examine chronic conditions from gestational ones, as they manifest distinct effects on the offspring and effect of both single and combined exposures to metabolic disturbances should be considered.
AUTHOR CONTRIBUTIONS
Conceptualization: Samson Nivins, Parvin Kumar and Catharina Lavebratt; Methodology: Samson Nivins, Parvin Kumar, Xinxia Chen, Mika Gissler, and Catharina Lavebratt; Formal analysis and investigation: Mika Gissler; Writing—original first draft preparation: Samson Nivins; Writing—review and editing—all authors; Funding acquisition: Catharina Lavebratt; Resources: Mika Gissler; Supervision and critical revision: Catharina Lavebratt. All authors approved the final manuscript as submitted and Mika Gissler had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
FUNDING INFORMATION
This study was funded by the Swedish Research Council, Sweden (CL, 2022–01188), the Swedish Brain Foundation, Sweden (CL, FO2023‐0335), Bo and Ulla Lundevall, the regional agreement on medical training and clinical research (ALF) between Region Stockholm and Karolinska Institutet, Sweden (CL, RS2021‐0855).
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
ETHICS STATEMENT
This cohort study was approved by the Finnish register keeping authorities (THL Finnish Institute for Health and Welfare [THL/3922/16.02.00/2022 on December 29, 2022] and KELA Social Insurance Institute of Finland [THL/5391/14.02.00/2022 on May 5, 2023]) and Ethics Review Board in Sweden (2023–03041 on August 28, 2023). Informed consent was not required since the study material was based on register data only and no registered persons were contacted. The researchers had no access to personally identifiable information. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Supporting information
Data S1:
Figure S1: Directed acyclic graph representing the causal assumptions used for covariate selection based on existing literature, where nodes represent ancestors of exposures and/or outcomes, and arrows represent biasing or causal paths.
Table S1: Numbers of children with psychiatric diagnosis and psychotropic medication stratified by maternal HDP and BMI.
Table S2: Adjusted hazard ratios for neurodevelopmental and psychiatric disorders in offspring by maternal HDP and BMI.
Table S3: Boys: adjusted hazard ratios for neurodevelopmental and psychiatric disorders in boys in relation to maternal HDP and BMI.
Table S4: Girls: adjusted hazard ratios for neurodevelopmental and psychiatric disorders in girls in relation to maternal HDP and BMI.
Table S5: Sex‐stratified: numbers of children with psychiatric diagnosis stratified based on sex, maternal HDP, and BMI.
Table S6: Birth factor adjustments: adjusted hazard ratios for neurodevelopmental and psychiatric disorders in relation to maternal HDP and BMI adjusted for preterm birth, low birth weight, small for gestational age, and Apgar score at 5 min.
Table S7: Adjusted hazard ratios (HRs) for neurodevelopmental and psychiatric disorders in relation to maternal HDP and BMI after excluding children exposed to either type 1 or type 2 diabetes (N = 588 250).
ACKNOWLEDGMENTS
The graphical abstract was created in BioRender. Lavebratt, C. (2024) BioRender.com/g93g647.
Nivins S, Kumar P, Chen X, Gissler M, Lavebratt C. Prenatal exposure to maternal hypertension and higher body mass index and risks of neurodevelopmental and psychiatric disorders during childhood. Acta Obstet Gynecol Scand. 2025;104:319‐330. doi: 10.1111/aogs.15021
Samson Nivins and Parvin Kumar contributed equally as co‐first authors.
REFERENCES
- 1. Luger RK, Kight BP. Hypertension in pregnancy. StatPearls Publishing; 2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430839/ [PubMed] [Google Scholar]
- 2. Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am J Obstet Gynecol. 2000;183:S1‐S22. [PubMed] [Google Scholar]
- 3. ACOG Practice Bulletin No. 202: gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:1. [DOI] [PubMed] [Google Scholar]
- 4. Behrens I, Basit S, Melbye M, et al. Risk of post‐pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study. BMJ. 2017;358:j3078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Barker DJ, Bagby SP, Hanson MA. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol. 2006;2:700‐707. [DOI] [PubMed] [Google Scholar]
- 6. Lahti‐Pulkkinen M, Girchenko P, Tuovinen S, et al. Maternal hypertensive pregnancy disorders and mental disorders in children. Hypertension. 2020;75:1429‐1438. [DOI] [PubMed] [Google Scholar]
- 7. Wang H, László KD, Gissler M, et al. Maternal hypertensive disorders and neurodevelopmental disorders in offspring: a population‐based cohort in two Nordic countries. Eur J Epidemiol. 2021;36:519‐530. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Dachew BA, Scott JG, Betts K, Mamun A, Alati R. Hypertensive disorders of pregnancy and the risk of offspring depression in childhood: findings from the Avon longitudinal study of parents and children. Dev Psychopathol. 2020;32:845‐851. [DOI] [PubMed] [Google Scholar]
- 9. Tuovinen S, Räikkönen K, Pesonen AK, et al. Hypertensive disorders in pregnancy and risk of severe mental disorders in the offspring in adulthood: the Helsinki birth cohort study. J Psychiatr Res. 2012;46:303‐310. [DOI] [PubMed] [Google Scholar]
- 10. Dachew BA, Scott JG, Mamun A, Alati R. Hypertensive disorders of pregnancy and the risk of anxiety disorders in adolescence: findings from the Avon longitudinal study of parents and children. J Psychiatr Res. 2019;110:159‐165. [DOI] [PubMed] [Google Scholar]
- 11. Gong X, Fan Z, Xu H, et al. The risk of offspring mood and anxiety disorders in the context of prenatal maternal somatic diseases: a systematic review and meta‐analysis. Epidemiol Psychiatr Sci. 2022;31:e6. [Google Scholar]
- 12. Fernández Alba JJ, Mesa Páez C, Vilar Sánchez Á, et al. Sobrepeso y obesidad como factores de riesgo de los estados hipertensivos del embarazo: estudio de cohortes retrospectivo [overweight and obesity at risk factors for hypertensive states of pregnancy: a retrospective cohort study]. Nutr Hosp. 2018;35:874‐880. [DOI] [PubMed] [Google Scholar]
- 13. Marchi J, Berg M, Dencker A, Olander EK, Begley C. Risks associated with obesity in pregnancy, for the mother and baby: a systematic review of reviews. Obes Rev. 2015;16:621‐638. [DOI] [PubMed] [Google Scholar]
- 14. Spradley FT. Metabolic abnormalities and obesity's impact on the risk for developing preeclampsia. Am J Physiol Regul Integr Comp Physiol. 2017;312:R5‐R12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Andersen CH, Thomsen PH, Nohr EA, Lemcke S. Maternal body mass index before pregnancy as a risk factor for ADHD and autism in children. Eur Child Adolesc Psychiatry. 2018;27:139‐148. [DOI] [PubMed] [Google Scholar]
- 16. Kong L, Chen X, Gissler M, Lavebratt C. Relationship of prenatal maternal obesity and diabetes to offspring neurodevelopmental and psychiatric disorders: a narrative review. Int J Obes. 2020;44:1981‐2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Edlow AG. Maternal obesity and neurodevelopmental and psychiatric disorders in offspring. Prenat Diagn. 2017;37:95‐110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Bodnar LM, Ness RB, Markovic N, Roberts JM. The risk of preeclampsia rises with increasing prepregnancy body mass index. Ann Epidemiol. 2005;15:475‐482. [DOI] [PubMed] [Google Scholar]
- 19. Artama M, Gissler M, Malm H, Ritvanen A, Drugs and Pregnancy Study Group . Nationwide register‐based surveillance system on drugs and pregnancy in Finland 1996‐2006. Pharmacoepidemiol Drug Saf. 2011;20:729‐738. [DOI] [PubMed] [Google Scholar]
- 20. Mbah AK, Kornosky JL, Kristensen S, et al. Super‐obesity and risk for early and late pre‐eclampsia. BJOG. 2010;117:997‐1004. [DOI] [PubMed] [Google Scholar]
- 21. Lampi KM, Sourander A, Gissler M, et al. Brief report: validity of Finnish registry‐based diagnoses of autism with the ADI‐R. Acta Paediatr. 2010;99:1425‐1428. [DOI] [PubMed] [Google Scholar]
- 22. Li YM, Ou JJ, Liu L, Zhang D, Zhao JP, Tang SY. Association between maternal obesity and autism Spectrum disorder in offspring: a meta‐analysis. J Autism Dev Disord. 2016;46:95‐102. [DOI] [PubMed] [Google Scholar]
- 23. Matias SL, Pearl M, Lyall K, et al. Maternal prepregnancy weight and gestational weight gain in association with autism and developmental disorders in offspring. Obesity (Silver Spring). 2021;29:1554‐1564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Brand JS, Lawlor DA, Larsson H, Montgomery S. Association between hypertensive disorders of pregnancy and neurodevelopmental outcomes among offspring. JAMA Pediatr. 2021;175:577‐585. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Maher GM, O'Keeffe GW, Kearney PM, et al. Association of Hypertensive Disorders of pregnancy with risk of neurodevelopmental disorders in offspring: a systematic review and meta‐analysis. JAMA Psychiatry. 2018;75:809‐819. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Maher GM, Dalman C, O'Keeffe GW, et al. Association between preeclampsia and attention‐deficit hyperactivity disorder: a population‐based and sibling‐matched cohort study. Acta Psychiatr Scand. 2020;142:275‐283. [DOI] [PubMed] [Google Scholar]
- 27. Sun BZ, Moster D, Harmon QE, Wilcox AJ. Association of Preeclampsia in term births with neurodevelopmental disorders in offspring. JAMA Psychiatry. 2020;77:823‐829. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Sanchez CE, Barry C, Sabhlok A, et al. Maternal pre‐pregnancy obesity and child neurodevelopmental outcomes: a meta‐analysis. Obes Rev. 2018;19:464‐484. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Neves PAR, Gatica‐Domínguez G, Santos IS, et al. Poor maternal nutritional status before and during pregnancy is associated with suspected child developmental delay in 2‐year old Brazilian children. Sci Rep. 2020;10:1851. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Hinkle SN, Schieve LA, Stein AD, Swan DW, Ramakrishnan U, Sharma AJ. Associations between maternal prepregnancy body mass index and child neurodevelopment at 2 years of age. Int J Obes. 2012;36:1312‐1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Basatemur E, Gardiner J, Williams C, Melhuish E, Barnes J, Sutcliffe A. Maternal prepregnancy BMI and child cognition: a longitudinal cohort study. Pediatrics. 2013;131:56‐63. [DOI] [PubMed] [Google Scholar]
- 32. Lee PMY, Tse LA, László KD, Wei D, Yu Y, Li J. Association of maternal body mass index with intellectual disability risk. Arch Dis Child Fetal Neonatal Ed. 2021;106:584‐590. [DOI] [PubMed] [Google Scholar]
- 33. Battarbee AN, Sinkey RG, Harper LM, Oparil S, Tita ATN. Chronic hypertension in pregnancy. Am J Obstet Gynecol. 2020;222:532‐541. [DOI] [PubMed] [Google Scholar]
- 34. Das UN. Is obesity an inflammatory condition? Nutrition. 2001;17:953‐966. [DOI] [PubMed] [Google Scholar]
- 35. Brown AS, Sourander A, Hinkka‐Yli‐Salomäki S, McKeague IW, Sundvall J, Surcel HM. Elevated maternal C‐reactive protein and autism in a national birth cohort. Mol Psychiatry. 2014;19:259‐264. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Zaretsky MV, Alexander JM, Byrd W, Bawdon RE. Transfer of inflammatory cytokines across the placenta. Obstet Gynecol. 2004;103:546‐550. [DOI] [PubMed] [Google Scholar]
- 37. Challier JC, Basu S, Bintein T, et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta. 2008;29:274‐281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Edlow AG, Glass RM, Smith CJ, Tran PK, James K, Bilbo S. Placental macrophages: a window into fetal microglial function in maternal obesity. Int J Dev Neurosci. 2019;77:60‐68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Kumpulainen SM, Heinonen K, Kaseva N, et al. Maternal early pregnancy body mass index and diurnal salivary cortisol in young adult offspring. Psychoneuroendocrinology. 2019;104:89‐99. [DOI] [PubMed] [Google Scholar]
- 40. Zorn JV, Schür RR, Boks MP, Kahn RS, Joëls M, Vinkers CH. Cortisol stress reactivity across psychiatric disorders: a systematic review and meta‐analysis. Psychoneuroendocrinology. 2017;77:25‐36. [DOI] [PubMed] [Google Scholar]
- 41. Kitajima M, Oka S, Yasuhi I, Fukuda M, Rii Y, Ishimaru T. Maternal serum triglyceride at 24‐‐32 weeks' gestation and newborn weight in nondiabetic women with positive diabetic screens. Obstet Gynecol. 2001;97:776‐780. [DOI] [PubMed] [Google Scholar]
- 42. Lopez‐Jaramillo P, Barajas J, Rueda‐Quijano SM, Lopez‐Lopez C, Felix C. Obesity and preeclampsia: common pathophysiological mechanisms. Front Physiol. 2018;9:1838. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1:
Figure S1: Directed acyclic graph representing the causal assumptions used for covariate selection based on existing literature, where nodes represent ancestors of exposures and/or outcomes, and arrows represent biasing or causal paths.
Table S1: Numbers of children with psychiatric diagnosis and psychotropic medication stratified by maternal HDP and BMI.
Table S2: Adjusted hazard ratios for neurodevelopmental and psychiatric disorders in offspring by maternal HDP and BMI.
Table S3: Boys: adjusted hazard ratios for neurodevelopmental and psychiatric disorders in boys in relation to maternal HDP and BMI.
Table S4: Girls: adjusted hazard ratios for neurodevelopmental and psychiatric disorders in girls in relation to maternal HDP and BMI.
Table S5: Sex‐stratified: numbers of children with psychiatric diagnosis stratified based on sex, maternal HDP, and BMI.
Table S6: Birth factor adjustments: adjusted hazard ratios for neurodevelopmental and psychiatric disorders in relation to maternal HDP and BMI adjusted for preterm birth, low birth weight, small for gestational age, and Apgar score at 5 min.
Table S7: Adjusted hazard ratios (HRs) for neurodevelopmental and psychiatric disorders in relation to maternal HDP and BMI after excluding children exposed to either type 1 or type 2 diabetes (N = 588 250).