Hipótesis

In our first aim, we examined the association between maternal diabetes and hypertension and ASD. Diagnoses of any diabetes or hypertensive disorder during pregnancy were identified from prenatal medical records, caregiver phone interview, and mailed-in questionnaires (for diabetes). In addition, serial blood pressure measurements from clinic and hospital records were available for hypertension as well as results from diagnostic tests for gestational diabetes.

Our analysis did not show an association between diabetes in pregnancy and ASD, but did show an association with maternal hypertensive disorders and ASD. Additionally, maternal diabetes and hypertensive disorders were both associated with DD. While we did observe an association with diabetes and hypertension and neurodevelopmental disorders, only hypertension was associated with ASD. We did not observe notable differences in the associations for ASD with ID versus ASD without ID, contrary to previous studies (167).

There are several possible biological mechanisms to explain how diabetes and

hypertensive disorders in pregnancy may affect fetal neurodevelopment. A plausible explanation is through inflammation and oxidative stress that occurs with chronic hypertension (22, 120). Inflammation can lead to changes in DNA methylation and gene expression (Rose et al., 2012) and some inflammatory markers are also known to cross the blood brain barrier possibly altering neural cell connections (22, 49). Oxidative stress is also associated with cell death and

92

Diabetes and hypertension can also affect neurodevelopment through over-nutrition and neonatal hyperglycemia or under-nutrition and intrauterine growth restriction, respectively. Diabetes is associated with over-nutrition of the fetus often resulting in an infant that is macrosomic or large for gestational age (257). Larger infants are more likely to suffer birth complications and trauma, such as head injury and hypoxia, which can affect future brain development (258, 259). Infants from diabetic mothers are also at higher risk of having neonatal hyperglycemia, which has been associated with brain injury (260) and changes in brain

development (179). Hypertension is associated with under-nutrition and intrauterine growth restriction (148), and often results in infants that are born preterm or small for gestation age (261). Several studies have established a connection between infants small for gestational age and changes in neurodevelopment (262, 263). However, it is still undetermined if there is a biological interaction with hypertension and growth restriction that increases the risk for ASD. This can be investigated in the future using SEED data that will become available with the larger sample size provided by additional SEED phase 2 and 3 data.

We observed stronger associations with pre-existing hypertension, particularly with DD. This may be related to the timing of the condition during pregnancy and fetal brain development. However, associations were also observed with preeclampsia, eclampsia, and HELLP, which occur later in pregnancy. These groups were not mutually exclusive and 18% of mothers with preexisting hypertension went on to have preeclampsia. The stronger association with pre- existing hypertension may also be attributed to prolonged and severe conditions having a more harmful effect. In our study, it was difficult to assess the severity of a hypertensive disorder. One indicator was preterm delivery, with which we observed stronger effect estimates with

93

with sustained hypertension is to deliver early, this variable may instead remove mothers with a misclassified exposure. Future investigations should assess if there is a joint effect of having a severe condition during a critical time window in which a hypertensive mother is at higher risk of having a child with ASD or DD.

We observed stronger associations in mothers with a ‘Confirmed’ condition reported in both the medical record and through maternal report, or in a diagnostic test. Weaker associations for confirmed conditions may reflect exposure misclassification or the possibility that confirmed cases represented more severe conditions in pregnancy. While limiting the analyses to confirmed condition status strengthened effect estimates, this did not change the interpretation of results for hypertensive disorders. However, it did strengthen the association between diabetes and DD.

Adjusting for BMI and diabetes did not materially alter the effect estimates for

hypertensive disorders. Previous studies have reported an interaction with high BMI and both maternal diabetes and hypertension (12, 166, 167). Comparing BMI stratum-specific estimates, we did not observe differences in the association among mothers with pre-pregnancy BMI in the low/normal, overweight, or obese categories. Our results suggest that weight status may not play a role in the association between maternal hypertension and ASD.

Overall, our results mostly agree with other case-control studies (12, 43, 52, 163), but there are subtle differences that may be due to the study population and sample size, with SEED having the largest number of affected dyads over multiple sites in the United States. While our results were similar to some cohort studies evaluating this association (8, 67, 71, 165), they differed from others (68, 144, 166, 167). Conducting a cohort study with a rare exposure and rare outcome is difficult however, and most of these studies relied on registries or large

94

In conclusion, we observed observations with hypertensive disorders and both ASD and DD. We also observed weaker associations with diabetes and DD. We hypothesize that this may be due alterations in fetal nutrition and development during pregnancy, which deserves further investigation.

Public health implications

Our study provides additional support that hypertension may be associated with

developmental disorders, including ASD. This association may be present due to the effects of hypertension on the fetus, such as growth restriction and increased likelihood of preterm birth. Further studies are necessary to understand the biological mechanism through which this association operates. Measures can be implemented to better manage hypertensive disorders in pregnancy in order to mitigate environments that may place the infant at higher risk for

developing ASD. While some hypertensive disorders are not well-managed or preventable, identifying hypertensive disorders as a risk factor for ASD can possibly result in earlier screening and better monitoring for developmental disorders. Several studies have shown the benefits of early diagnosis on child developmental outcomes (264, 265), and these results may help identify children at risk for developmental disorders earlier.