Journal Article Annotations
2024, 1st Quarter

Aging

Annotations by Zachary Harvanek, MD, PhD.
April, 2024

Placental accelerated aging in antenatal depression.

PUBLICATION #1 — Aging

Placental accelerated aging in antenatal depression.

Haleema Saeed, Jing Wu, Markos Tesfaye, Katherine L Grantz, Fasil Tekola-Ayele

Abstract: J Acad Consult Liaison Psychiatry. 2024 Feb 22:S2667-2960(24)00023-5. doi: 10.1016/j.jaclp.2024.02.003. Online ahead of print.

Background:
Antenatal maternal depression is associated with poor pregnancy outcomes and long-term effects on the offspring. Previous studies have identified links between antenatal depression and placental DNA methylation and between placental epigenetic aging and poor pregnancy outcomes, such as preterm labor and preeclampsia. The relationship between antenatal depression and poor pregnancy outcomes may be partly mediated via placental aging.

Objective:
This study aimed to investigate whether antenatal depressive symptoms are associated with placental epigenetic age acceleration, an epigenetic aging clock measure derived from the difference between methylation age and gestational age at delivery.

Study design:
The study included 301 women who provided placenta samples at delivery as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies – Singletons that recruited participants from diverse race and ethnic groups at 12 US clinical sites (2009-2013). Women underwent depression screening using the Edinburgh Postnatal Depression Scale up to 6 times across the 3 trimesters of pregnancy. Depressive symptoms status was determined for each pregnancy trimester using an Edinburgh Postnatal Depression Scale score, in which a score of ≥10 was defined as having depressive symptoms and a score of <10 was defined as not having depressive symptoms. Placental DNA methylation was profiled from placenta samples. Placental epigenetic age was estimated using a methylation-based age estimator (placental “epigenetic clock”) that has previously been found to have high placental gestational age prediction accuracy for uncomplicated term pregnancies. Placental age acceleration was defined to be the residual upon regressing the estimated epigenetic age on gestational age at delivery. Associations between an Edinburgh Postnatal Depression Scale score of ≥10 and an Edinburgh Postnatal Depression Scale score of <10 in the first, second, and third trimesters of pregnancy (ie, depressive symptoms vs none in each trimester) and placental age acceleration were tested using multivariable linear regression adjusting for maternal age, parity, race and ethnicity, and employment.

Results:
There were 31 (10.3%), 48 (16%), and 49 (16.4%) women with depressive symptoms (ie, Edinburgh Postnatal Depression Scale score of ≥10) in the first, second, and third trimesters of pregnancy, respectively. Of these women, 21 (7.2%) had sustained first- and second-trimester depressive symptoms, 19 (7%) had sustained second- and third-trimester depressive symptoms, and 12 (4.8%) had sustained depressive symptoms throughout pregnancy. Women with depressive symptoms in the second trimester of pregnancy had 0.41 weeks higher placental age acceleration than women without depressive symptoms during the second trimester of pregnancy (β=0.21 weeks [95% confidence interval, -0.17 to 0.58; P=.28] during the first trimester of pregnancy; β=0.41 weeks [95% confidence interval, 0.10-0.71; P=.009] during the second trimester of pregnancy; β=0.17 weeks [95% confidence interval, -0.14 to 0.47; P=.29] during the third trimester of pregnancy). Sustained first- and second-trimester depressive symptoms were associated with 0.72 weeks higher placental age acceleration (95% confidence interval, 0.29-1.15; P=.001) than no depressive symptom in the 2 trimesters. The association between second-trimester depressive symptoms and higher placental epigenetic age acceleration strengthened in the analysis of pregnancies with male fetuses (β=0.53 weeks; 95% confidence interval, 0.06-1.08; P=.03) but was not significant in pregnancies with female fetuses.

Conclusion:
Antenatal depressive symptoms during the second trimester of pregnancy were associated with an average of 0.41 weeks of increased placental age acceleration. Accelerated placental aging may play an important role in the underlying mechanism linking antenatal depression to pregnancy complications related to placental dysfunction.

Keywords:
DNA methylation; epigenetic clock; fetal sex; maternal mental health; pregnancy; premature senescence; prenatal screening; second trimester.

Annotation

The finding:
In an prospective observational study of pregnant women (n = 301), women with depressive symptoms (defined as Edinburgh Postpartum Depression Scale > 10) in the second trimester had biologically older placentas as measured by a placental epigenetic clock. This finding was specific to the second trimester, and was not driven by preeclampsia, eclampsia, or gestational diabetes. In sub-group analyses, this association was specific to male fetuses, although the trend was in a similar direction for female fetuses.

Strength and weaknesses:
Strengths of this study include a prospective design, the use of multiple methods to date pregnancies (LMP and ultrasound), and multiple sensitivity analyses including accounting for cell composition as well as obstetric-related illnesses which could be related to placental health. Weakness of this study include a relatively low sample size and no correction for multiple comparisons. There were also relatively strict exclusion criteria (women with pre-existing anxiety or depression requiring medications were excluded), which may limit the generalizability of the study.

Relevance:
These findings suggest that depression during pregnancy is associated with placental changes that may increase the risk for complications. Notably, 1 week of placental age acceleration has been associated with a 2-fold increase in odds for low birthweight, and in this study depressive symptoms were associated with 0.4 weeks of age acceleration. It remains unclear what effect, if any, treatment of depressive symptoms would have on these placental changes.