Placental health in late pregnancy linked to childhood ADHD

Attention deficit/hyperactivity disorder (ADHD) in children may be associated with problems with the health of the placenta during late pregnancy, according to a new study by University of Iowa Health Care researchers. The findings, published in JAMA Psychiatry, help to identify a risk factor in pregnancy that is linked to ADHD in children, and potentially points to new treatment targets for ADHD. 

ADHD is a common neurodevelopmental condition that affects up to 10% of American children between the ages of 3 and 17. The symptoms of ADHD, including problems with paying attention, hyperactivity, and impulsivity, can negatively impact many aspects of a person's life, including academic and professional achievement. However, there is a lack of understanding about the potential causes of this neurodevelopmental condition. 

Previous studies suggest that ADHD and other neurodevelopmental conditions may start before birth and may even be related to problems with the placenta. Following these clues, a team of University of Iowa Health Care researchers investigated how changes in the levels of placental growth factor (PlGF), an important biomarker of placental health during pregnancy, were related to subsequent ADHD diagnoses in children born from those pregnancies. 

They found that low levels of PlGF in the third trimester were associated with a higher risk of ADHD diagnosis in children. 

This study adds to the evidence that neurodevelopmental risk begins in utero and suggests that the placenta may play a major role in shaping neurodevelopmental outcomes. It raises the exciting possibility that factors known to be related to pregnancy and maternal health, like PlGF, may also tell us something about how the baby's brain is developing." 

Serena (Banu) Gumuslogu, PhD, UI assistant professor of obstetrics and gynecology, and psychiatry, and first author on the new study

Placenta-brain axis may influence neurodevelopment 

The placenta is responsible for supplying blood and nutrients to the baby, as well as removing waste and protecting against toxin or viral and bacterial exposure. Placental growth factor, or PlGF, is a key protein made by the placenta that is also a marker of placenta health. Low levels of PlGF are a known warning sign for pregnancy complications, like preeclampsia. 

The UI team used maternal blood samples banked from 176 pregnancies in the UI Department of Obstetrics and Gynecology's Perinatal Family Tissue Bank to investigate whether levels of PlGF were also related to risk for ADHD years later. 

The team measured PlGF levels from banked maternal blood samples collected during all three trimesters of these pregnancies. The maternal blood samples were then linked to health records of the offspring, allowing the team to track which pregnancies resulted in ADHD diagnoses and which did not. 

"In pregnancies that resulted in a child later diagnosed with ADHD, we saw that PlGF levels did not have the typical increase in the third trimester," says Gumusoglu, who also is a member of the Iowa Hawkeye Intellectual and Developmental Disabilities Research Center (Hawk-IDDRC). "Each standard-deviation drop in PlGF was associated with 2.6 times higher odds of a later ADHD diagnosis in the child." 

The study showed no significant difference in PlGF levels in the first or second trimesters. In addition, the levels of another protein involved in vascular health and function in pregnancy, endothelin-1, were also not different between the ADHD group and the non-ADHD group. 

Importantly, the link between low third trimester levels of PlGF and ADHD was still observed even after the researchers accounted for pregnancies with preeclampsia, growth restriction, or early preterm birth, conditions that are already linked to ADHD, and to reduced levels of PlGF. 

"This is important because it indicates that we aren't just flagging 'sick' pregnancies," Gumusoglu says. "Our results point to subtle placental changes in pregnancies that did not have a clinical diagnosis yet still resulted in neurodevelopmental differences in children." 

Next steps 

Gumusloglu cautions that these are early findings in a fairly small group of pregnancies from one medical center, and do not determine if low levels of PlGF might be a cause of ADHD. However, identifying this association gives the researchers new ideas about potential mechanisms linking placental health and brain development in babies, which can be tested in the lab. Gumusoglu recently received The Klingenstein Third Generation Foundation Fellowship to support studies where she will investigate whether reducing PlGF levels in pregnant mice is sufficient to alter neurodevelopment in the offspring. 

"This work links what is classically considered an obstetric concern - abnormal PlGF - to neurodevelopmental outcomes years later in children," she says. "If our result is replicated in a larger sample and if a causal relationship is supported by studies in mice, it would suggest that measuring pregnancy levels of PlGF might help identify children who would benefit from earlier developmental monitoring." 

In addition to Gumusoglu, the research team also included Alexandria Betz, DO, Andy Storm, MD, Donna Santillan, PhD, and Mark Santillan, MD, PhD. Mark Santillan and Donna Santillan direct the Obstetrics and Gynecology Perinatal Family Tissue Bank, which was a critical resource for this work.