Low third-trimester PlGF linked to later ADHD in offspring

Maternal placental growth factor (PlGF) levels that fail to rise late in pregnancy may signal elevated risk of attention-deficit/hyperactivity disorder (ADHD) in offspring, according to a retrospective cohort study published September 23, 2026, in JAMA Psychiatry.¹ Among 176 pregnancies, third-trimester PlGF was significantly lower in mothers whose children were later diagnosed with ADHD, and the association held after adjustment for preeclampsia, fetal growth restriction, and child sex.¹

First author Serena B. Gumusoglu, PhD, assistant professor of obstetrics and gynecology and psychiatry at University of Iowa Health Care, Iowa City, said the results add to evidence that "neurodevelopmental risk begins in utero" and suggest the placenta may play a central role in shaping neurodevelopmental outcomes.²

PlGF trajectories and ADHD risk in the University of Iowa cohort

Investigators used banked maternal plasma from the University of Iowa Perinatal Family Tissue Bank, a longitudinal pregnancy biorepository, and linked samples to offspring electronic health records.¹ Pregnancies were classified as ADHD cases if the child received an ICD-10 F90.x diagnosis; all others served as controls.¹ PlGF was measured on 2 immunoassay platforms and z-scored within platform, and endothelin-1 (ET-1) was measured as a comparator marker of vascular function.¹

The PlGF analysis included 176 pregnancies (54 ADHD, 122 control; mean [SD] maternal age, 30.2 [4.9] years).¹ Generalized estimating equation models showed a significant ADHD × third-trimester interaction (β = −1.26 SD; P < .001) that was unchanged after adjustment for offspring sex, preeclampsia, and fetal growth restriction or small for gestational age (FGR/SGA); no interaction was found in the second trimester.¹ Each 1-SD increase in third-trimester PlGF was associated with lower odds of ADHD (OR, 0.38; 95% CI, 0.20–0.70; P = .002), which the university characterized as roughly 2.6-fold higher odds for each 1-SD decrease.¹˒²

A sensitivity analysis excluding pregnancies complicated by preeclampsia, FGR/SGA, or preterm birth before 34 weeks (n = 142) still showed the third-trimester interaction (β = −0.96 SD; P = .003).¹ ET-1 did not differ by ADHD status in any trimester.¹ Children with ADHD also had higher rates of speech/language disorder (33% vs 13%), learning disability (18% vs 3%), and conduct/oppositional disorder (36% vs 2%) (all P < .001).¹

Placental growth factor and prenatal origins of ADHD

ADHD affects more than 10% of US children aged 3 to 17 years, yet validated biomarkers and mechanistically informed treatments are lacking.¹ PlGF, a placenta-derived member of the vascular endothelial growth factor family, supports placental vascular development and fetoplacental perfusion, and low circulating levels are an established marker of preeclampsia and fetal growth restriction.³ Those placental insufficiency conditions have themselves been linked to offspring ADHD: in a Swedish nationwide cohort of more than 1.2 million children, preterm birth, SGA, and preeclampsia were each associated with higher ADHD incidence, with similar results in sibling-controlled analyses.⁴

Interpreting third-trimester PlGF as an ADHD risk marker

The authors wrote that persistence of the signal after excluding clinically complicated pregnancies suggests subtler placental angiogenic deficits not captured by standard diagnoses, while the absence of a parallel ET-1 change points to disruption of a specific angiogenic pathway rather than generalized vascular dysfunction.¹ Gumusoglu noted the findings indicate the team was not simply flagging already high-risk pregnancies.² If replicated, third-trimester PlGF could inform prenatal risk stratification and help identify children who may benefit from earlier developmental monitoring, the investigators suggested.¹˒²

Study limitations and next steps in placenta-brain axis research

The cohort was modest, drawn from a single center, and predominantly White (approximately 80% in both groups), and the retrospective design cannot establish causality.¹˒² Few ADHD-group pregnancies were complicated by preeclampsia or FGR/SGA; FGR/SGA was in fact more common among controls (14% vs 2%), leaving it unclear whether such complications confound the association or lie on the causal pathway.¹ ADHD status relied on diagnosis codes, and placental weight and histopathology were unavailable.¹ Gumusoglu is now pursuing mouse studies, supported by a Klingenstein Third Generation Foundation fellowship, to test whether reducing PlGF during pregnancy alters offspring neurodevelopment.²

References

1. Gumusoglu SB, Betz A, Storm A, Santillan DA, Santillan MK. Placental growth factor trajectories during pregnancy and child ADHD. JAMA Psychiatry. Published online September 23, 2026. doi:10.1001/jamapsychiatry.2026.2336

2. Brown J. Placenta problems associated with ADHD. University of Iowa Department of Obstetrics and Gynecology. September 30, 2026. Accessed October 22, 2026. https://obgyn.medicine.uiowa.edu/news/2026/09/placenta-problems-associated-adhd

3. Hayes Ryan D, McCarthy FP, O'Donoghue K, Kenny LC. Placental growth factor: a review of literature and future applications. Pregnancy Hypertens. 2018;14:260-264. doi:10.1016/j.preghy.2018.03.003

4. Beer RJ, Cnattingius S, Susser ES, Villamor E. Associations of preterm birth, small-for-gestational age, preeclampsia and placental abruption with attention-deficit/hyperactivity disorder in the offspring: nationwide cohort and sibling-controlled studies. Acta Paediatr. 2022;111(8):1546-1555. doi:10.1111/apa.16375