A new study involving more than 337,000 children turns a well-known picture of early brain development on its head. Fetuses who later developed epilepsy, autism or an intellectual disability had, on average, slightly larger heads in mid-pregnancy. The finding shifts some of the focus away from birth and back to brain growth during pregnancy.
A pregnancy scan is usually a snapshot. The doctor or midwife measures the fetus’s head and body to assess growth and detect major abnormalities here and now – not to determine anything about the child’s brain several years later.
But what if some of these completely ordinary measurements nevertheless contain traces of the brain’s early course?
Researchers in Denmark investigated this by linking routine scans in mid-pregnancy with nationwide registers of diagnoses in children. The study is not about predicting diagnoses during pregnancy but about understanding whether cerebral palsy, epilepsy, autism and intellectual disability may leave early traces before birth.
As the children were followed through the registers, the measurements showed something different from what had been expected.
“The fetuses who later receive one of these diagnoses actually have slightly larger heads in the middle of pregnancy. This is surprising, because if you fast-forward 20 weeks to birth, the small heads are precisely the warning sign of an underdeveloped brain. It is therefore remarkable that a smaller head in the fetus at week 20 appears to be associated with a lower risk,” explains Mads Langager Larsen, doctor and researcher from the Centre for Foetal Medicine at Rigshospitalet, Copenhagen, Denmark.
The research has been published in Paediatric and Perinatal Epidemiology.
From routine scans to childhood diagnoses
The researchers used standard measurements from the scan: head width, the biparietal diameter, head circumference, abdominal circumference and femur length. They also calculated the fetus’s weight, enabling them to compare the size of the skull with the rest of the body’s growth.
The researchers then linked the measurements to Denmark’s diagnosis registers and followed the children until the end of 2022. This enabled them to compare a snapshot from the middle of pregnancy with clinical diagnoses many years later.
In total, 13,414 children (4%) received at least one of the four diagnoses included in the study: cerebral palsy, epilepsy, intellectual disability or autism. Just under 70% were boys. In their analyses, the researchers considered the child’s sex, the mother’s body-mass index, the mother’s level of education and the mother’s smoking during pregnancy.
“In Denmark, we have a national screening programme that almost all pregnant women accept, and we can link the scans to registers containing all the diagnoses. This is not possible in many other places in the world, and when working with such rare diagnoses, there is a real need for datasets of this size,” says Mads Langager Larsen.
A signal so small that only a large dataset can reveal it
When the diagnoses were analysed individually, epilepsy, intellectual disability and autism stood out in particular. Children with these diagnoses had, on average, a slightly larger biparietal diameter – that is, the width of the head from side to side – at the second-trimester scan. For epilepsy, a larger head circumference was also associated with a higher risk. The size of the difference did not make the result important but the direction.
According to Mads Langager Larsen, the difference in head width was, on average, around 0.14 millimetres.
“These are differences as small as the thickness of a sheet of paper, so you certainly cannot use them to say anything about an individual child. But when we have so many scans, we can see a signal at population level, and we can use that to say something about when these disorders arise,” explains Mads Langager Larsen.
While the size of the skull pointed in an unexpected direction, the body followed a more familiar pattern. A larger abdominal circumference and a higher estimated fetal weight were associated with a lower risk of intellectual disability. This is more consistent with what is already known about restricted fetal growth and later vulnerability. It was therefore the measurements of the head in particular that came as a surprise.
A shorter femur, in contrast, was associated with a higher risk of both cerebral palsy and epilepsy. The head and body did not, therefore, necessarily tell the same story in the second trimester.
This makes the result remarkable: during the scan, the head measurements did not follow the pattern seen at birth, in which a small head can be a sign of an underdeveloped brain and a poorer prognosis.
A new finding in a field of research without simple answers
According to Mads Langager Larsen, the findings suggest that some of the origins of developmental disorders may be traced back to the second trimester, when the brain is undergoing rapid development. This is when nerve cells are formed, migrate to their designated locations and begin to form the early connections that will later underpin brain function. If growth follows a different rhythm, this may be a sign that the brain is on a different trajectory – long before the child shows any symptoms or receives a diagnosis.
The findings shift the focus away from the birth itself as the decisive moment for many developmental disorders. Fetal growth restriction and small head circumference at birth have long been associated with later vulnerability. However, in the middle of pregnancy, the picture may be more complex, and a single measurement at birth does not necessarily tell the whole story about the brain’s development before birth.
This does not mean that antenatal scans can predict diagnoses or that the study shows whether any of these disorders can be prevented.
Previous studies have also failed to point unequivocally in the same direction. Several smaller studies have found no clear link between fetal measurements in mid-pregnancy and later functioning, whereas others have linked higher fetal weight or head measurements to better developmental outcomes later in childhood. Part of the discrepancy may result from the fact that previous studies have often measured early developmental tests, IQ or academic skills, whereas the new study follows the children through to clinical diagnoses.
The study therefore does not settle the question on its own. However, it lends greater weight to the findings because the researchers were able to follow more than 337,000 children from fetal life through to childhood. Nevertheless, it cannot explain whether the larger head measurements reflect faster brain growth, an altered growth pattern or other processes during pregnancy.
“We have now found that there is a difference, but not where in the brain it is located. The next step is to use the many scans we have to examine the brain’s structure in 3D during the second and third trimesters, so that we can go deeper than simply measuring the distance between the ears or head circumference. In the long term, this may help to identify which structures develop differently and what, if anything, can be done about it,” says Mads Langager Larsen.
