Maternal depressive symptoms during pregnancy, placental expression of genes regulating glucocorticoid and serotonin function and infant regulatory behaviors.

BACKGROUND: Glucocorticoids and serotonin may mediate the link between maternal environment, fetal brain development and 'programming' of offspring behaviors. The placenta regulates fetal exposure to maternal hormonal signals in animal studies, but few data address this in humans. We measured prospectively maternal depressive symptoms during pregnancy and mRNAs encoding key gene products determining glucocorticoid and serotonin function in term human placenta and explored associations with infant regulatory behaviors. METHOD: Bi-weekly self-ratings of the Center for Epidemiologic Studies Depression Scale from 12th to 13th gestational week onwards and term placental mRNAs of 11beta-hydroxysteroid dehydrogenase type 2 (HSD2B11), type 1 (HSD1B11), glucocorticoid (NR3C1), mineralocorticoid receptors (NR3C2) and serotonin transporter (SLC6A4) were obtained from 54 healthy mothers aged 32.2 ± 5.3 years with singleton pregnancies and without pregnancy complications. Infant regulatory behaviors (crying, feeding, spitting, elimination, sleeping and predictability) were mother-rated at 15.6 ± 4.2 days. RESULTS: Higher placental mRNA levels of HSD2B11 [0.41 standard deviation (s.d.) unit increase per s.d. unit increase; 95% confidence interval (CI) 0.13-0.69, p = 0.005], HSD1B11 (0.30, 0.03-0.57, p = 0.03), NR3C1 (0.44, 0.19-0.68, p = 0.001) and SLC6A4 (0.26, 0.00-0.53, p = 0.05) were associated with more regulatory behavioral challenges of the infant. Higher placental NR3C1 mRNA partly mediated the association between maternal depressive symptoms during pregnancy and infant regulatory behaviors (p < 0.05). CONCLUSIONS: Higher placental expression of genes regulating feto-placental glucocorticoid and serotonin exposure is characteristic of infants with more regulatory behavioral challenges. Maternal depression acts, at least partly, via altering glucocorticoid action in the placenta to impact on offspring regulatory behaviors.

Maternal depressive symptoms throughout pregnancy are associated with increased placental glucocorticoid sensitivity.

BACKGROUND: Maternal prenatal depression predicts post-partum depression and increases risk of prematurity and low birth weight. These effects may be mediated by altered placental function. We hypothesized that placental function would be influenced by the gestational week of experiencing depressive symptoms and aimed to examine associations between maternal depressive symptoms during pregnancy and placental expression of genes involved in glucocorticoid and serotonin transfer between mother and fetus. METHOD: We studied women participating in a prospective pregnancy cohort: the Prediction and Prevention of Preeclampsia (PREDO) Study, Helsinki, Finland. Maternal depressive symptoms were assessed at 2-week intervals throughout pregnancy in 56 healthy women with singleton, term pregnancies. Messenger ribonucleic acid (mRNA) levels of glucocorticoid (GR) and mineralocorticoid (MR) receptors and serotonin transporter (SLC6A4), 11ß-hydroxysteroid dehydrogenase type 1 (HSD1) and 2 (HSD2) were quantified in placental biopsies. RESULTS: In adjusted analyses women who reported higher depressive symptoms across the whole pregnancy had higher mRNA levels of GR [effect size 0.31 s.d. units, 95% confidence interval (CI) 0.01-0.60, p = 0.042] and MR (effect size 0.34 s.d. units, 95% CI 0.01-0.68, p = 0.047). These effects were significant for symptoms experienced in the third trimester of pregnancy for GR; findings for MR were also significant for symptoms experienced in the second trimester. GR and MR mRNA levels increased linearly by having the trimester-specific depressive symptoms scores 0, 1 or 2-3 times above the clinical cut-off for depression (p = 0.003, p = 0.049, respectively, and p = 0.004, p = 0.15 in adjusted analyses). CONCLUSIONS: Our findings offer potential gestational-age-specific mechanisms linking maternal depressive symptoms during pregnancy via placental biology. Future studies will test whether these also link with adverse offspring outcomes.

Late preterm birth, post-term birth, and abnormal fetal growth as risk factors for severe mental disorders from early to late adulthood.

BACKGROUND: Late preterm births constitute the majority of preterm births. However, most evidence suggesting that preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for gestational age, which have been previously associated with psychopathology risk in younger ages. METHOD: Of 12 597 Helsinki Birth Cohort Study participants, born 1934-1944, 664 were born late preterm, 1221 post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identified from national hospital discharge and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders. RESULTS: Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental disorder. However, men born late preterm had a significantly increased risk of suicide. Post-term birth predicted significantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders. Individuals born SGA had significantly increased risks of any mental and substance use disorders. Women born LGA had an increased risk of psychotic disorders. CONCLUSIONS: Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased among individuals born SGA and individuals born post-term.

Maternal hypertensive disorders during pregnancy: adaptive functioning and psychiatric and psychological problems of the older offspring.

OBJECTIVE: To study whether pre-eclampsia and hypertension without proteinuria during pregnancy are associated with adaptive functioning, and psychiatric and psychological problems, of older offspring. DESIGN: Retrospective longitudinal cohort study. SETTING: Participants in the Helsinki Birth Cohort 1934-44 Study. POPULATION: A cohort of 778 participants born after normotensive, pre-eclamptic, or hypertensive pregnancies, defined based on the mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals. METHODS: Pearson's chi-squared tests and multivariable logistic regression. MAIN OUTCOME MEASURES: Achenbach System of Empirically Based Assessment Older Adult Self-Report scores, completed at age 69.3 years (SD 3.1 years). RESULTS: Compared with offspring born after normotensive pregnancies, offspring born after pre-eclamptic pregnancies had increased odds of reporting total problems (aOR 4.00, 95%CI 1.64-9.77) and problems of particular concern to clinicians (critical items; aOR 5.28, 95%CI 1.87-14.96), as well as: anxious/depressed, functional impairment, memory, thought, and irritable/disinhibited problems on syndrome scales; depressive, somatic, and psychotic problems on Diagnostic and Statistical Manual of Mental Disorders scales; and adjustment problems in relationship satisfaction with spouse/partner. Maternal hypertension without proteinuria was not consistently associated with adjustment and problems (total problems, aOR 1.08, 95%CI 0.75-1.57; critical items, aOR 1.58, 95%CI 0.91-2.72). CONCLUSIONS: Maternal hypertensive disorders in pregnancy, during a period of expectant treatment, carry an increased risk of problems in adaptive functioning and mental wellbeing in the offspring seven decades later. Being the longest follow-up on transgenerational consequences of maternal hypertensive disorders reported thus far, our study points to the life-time increased risk of an adverse intrauterine environment.

OS103. Hypertensive disorders during pregnancy and cognitive decline of the offspring up to old age: the helsinki birth cohort study.

INTRODUCTION: Hypertensive disorders affect the fetal developmental milieu and may point to mechanisms by which prenatal adversity is associated with lower cognitive ability in subsequent life. OBJECTIVES: We tested whether hypertensive disorders during pregnancy predict age-related change in cognitive ability in the offspring up to old age. METHODS: Using mothers' blood pressure and urinary protein measurements from the maternity clinics and birth hospitals, we defined normotensive or hypertensive pregnancies in mothers of 398 men, who participated in the Helsinki Birth Cohort 1934-44 Study. The men underwent the Finnish Defense Forces basic ability test twice, first, during compulsory military service at age 20.1 (SD=1.4) years and, then, in a re-test at age 68.5 (SD=2.9) years. The test yields a total score and subscores for tests measuring verbal, arithmetic and visuospatial reasoning. Scores were standardized with a mean of 100 and standard deviation of 15. RESULTS: Men born after pregnancies complicated by a hypertensive disorder, compared with men born after normotensive pregnancies, scored 3.84 (95% Confidence Interval, 0.77 to 6.91) points lower on total cognitive ability at 68.5 years, and displayed a greater decline in total cognitive ability (2.31, 0.23 to 4.39) after 20.1 years. Of the subscores, associations were strongest for arithmetic reasoning. CONCLUSION: Maternal hypertensive disorders in pregnancy predict lower cognitive ability and greater cognitive decline up to old age. Multidisciplinary research is essential in order to uncover the mechanisms linking hypertensive pregnancy disorders with lower cognitive abilities in the offspring.

Depressive symptoms in adulthood and intrauterine exposure to pre-eclampsia: the Helsinki Birth Cohort Study.

OBJECTIVE: We studied whether pre-eclampsia predicts depressive symptoms in offspring. DESIGN: Retrospective longitudinal cohort study. SETTING: Participants in the Helsinki Birth Cohort 1934-44 Study. POPULATION: We classed 788 women and men born at term after a normotensive, hypertensive or pre-eclamptic pregnancy, by using the mother's blood pressure and urinary protein measurements, at maternity clinics and birth hospitals. METHODS: Linear and logistic regression analyses. We made adjustments for the mother's age and body mass index (BMI) at delivery, the participant's body size at birth/length of gestation, sex and childhood socio-economic status, age and educational attainment at testing. MAIN OUTCOME MEASURES: Beck depression inventory (BDI) scores completed twice, at the ages of 60 and 63 years. RESULT: Participants born after a primiparous pregnancy complicated by pre-eclampsia had over 30% (P < 0.04) higher depressive symptom scores in adulthood compared with those born after a primiparous normotensive pregnancy. We found no evidence of the association between pre-eclampsia and depression among participants born after multiparous pregnancies. Gestational hypertension and depressive symptoms were not significantly associated. The models adjusting for mother's age and BMI at delivery, the participant's body size at birth/length of gestation, sex, childhood socio-economic status, age and educational attainment at testing did not change the results. CONCLUSION: Pre-eclampsia is associated with later depressive symptoms in individuals born at term and after a primiparous pregnancy. These findings are compatible with the adverse fetal 'programming' by a suboptimal prenatal environment.