Pregnancy is not only a monumental event in a woman’s life; it is also a time of changes in physiology and the hormone system that have no parallel in any other phase of life. Every bodily system is affected, including the brain.

Only in recent years have researchers begun to measure and assess pregnancy-related brain changes, which affect literally billions of people with implications that modify both mental and physical health during pregnancy but also likely continue to be important for the remainder of the lifespan.

Elseline Hoekzema, Ph.D., of Amsterdam University Medical Center in the Netherlands, devoted her 2017 BBRF Young Investigator grant to a project about pregnancy and the brain that continues to bear fruit. Now, she and colleagues including Dr. Milou Straathof report on research that follows up on their important prior work, which demonstrated that reproduction is associated with widespread changes in women’s brain structure—a result that has been subsequently replicated in studies conducted across the world.

The initial research showed that pregnancy induced major changes in brain structure and connectivity that likely relate to the anticipation of the mother to new tasks involving bonding with and caring for her infant. As Dr. Hoekzema and colleagues note, “all studies investigating pregnancy-related brain changes so far have focused solely on first-time mothers, leaving it unclear whether similar brain changes occur as a result of subsequent pregnancies.”

In their newly published study, appearing in Nature Communications, Dr. Hoekzema and team address this gap in understanding. Carrying a child to term “may involve long-lasting changes in human mothers measured beyond the postpartum period,” they note. “In middle-aged women, pregnancies have been linked to brain age,” with women experiencing multiple pregnancies “having [biologically] younger-looking brains” compared with those who had a single pregnancy or who never carried a child to term. “Additionally, pregnancy has been associated with cortical thickness, functional connectivity, and grey matter volume in women during later life.” Pregnancy may also affect cognition, they noted, and modify risk for and effects of various brain disorders of later life, such as Alzheimer’s disease and stroke.

Although there is good reason to suspect that all these relationships are possible or likely, it remains unclear whether a first and second pregnancy have different impacts on the brain’s structure and function. To learn whether this is the case, the team recruited a cohort of 110 women. All received sets of multiple brain scans: a high-resolution anatomical MRI; a resting-state functional MRI (which measures brain activity when the mind is not focused on a particular task); a diffusion-weighted MRI (to analyze the structure of the brain’s white matter); and a magnetic resonance spectroscopy (MRS) scan (to measure levels of neural metabolites—the products of normal brain functioning, which help gauge neuronal integrity, energy metabolism, and neurotransmission).

Of the 110 women recruited, 40 had a first pregnancy after the initial set of scans; 30 had a second pregnancy, and 40 did not become pregnant and never had been (these women served as controls). The women who became pregnant during the study were given additional scans in the early and late postpartum periods; the control women received additional scans at similar intervals. The women having second pregnancies were about 32, on average; those in the first-pregnancy and never-pregnant groups were about 29.

The main result of the team’s analysis was the finding that the brain is affected in distinctive ways across a second pregnancy compared with a first, to the extent that retrospectively, it was possible on the basis of changes in the scan information alone (i.e., scans taken at different time points from the start of the study) whether a woman had experienced one, two, or no pregnancies.

Analyses focusing on differences in brain plasticity across a first and second pregnancy revealed to the team “both distinct and overlapping neural networks involved.” The overlapping areas were mostly located in the default mode network (DMN), a set of interacting brain regions that are most active when a person is at rest, awake, and not focused on the outside world. Other significantly overlapping areas included the frontoparietal and ventral attention networks. The team knew from prior work that these introspective and higher-order cognitive networks are strongly affected during a first pregnancy both structurally and functionally. The new data further suggest “that these networks represent the main networks associated with pregnancy-induced brain plasticity, whether in a first or subsequent pregnancy.”

Overall, the researchers believe these and related overlapping changes are “a primary adaptation in women who become a mother for the first time, which is then fine-tuned in a similar but more subtle way during a second pregnancy.” It is well-established that the DMN is important in introspection, self-perception, and social cognition. The cuneus, the “main area” where the team found a differential effect of a first and second pregnancy on functional network coherence, is “a core structure serving the neural representation of the self.” Changes in the DMN in a first pregnancy “have been interpreted as shifts in a mother’s self-perception and ability to understand her child’s needs and feeling.” Similarly, associations with mother-infant bonding in the new data suggest that changes in the volume of certain brain regions (they are reduced in volume) in a first pregnancy “more strongly contribute to the induction of maternal behavior, whereas in a second pregnancy these changes play a smaller role, as such behavior had already been established.”

In both first- and second-time mothers, links between changes in brain area volumes and maternal mental health were observed. “Interestingly volume changes in the brain “were more prominently associated with mental health status during a second pregnancy, but with mental health in the postpartum period after a first pregnancy. “We speculate that this may be due to higher stress levels during a second pregnancy since the mother needs to care for another child during her pregnancy,” the team wrote. More research is called for, they said.

Another contrast: areas affected in a second pregnancy were not localized to the same degree in the introspection-related DMN and cognitive frontoparietal network, but instead were more prominently located in networks involved with the responsiveness to external stimuli, goal-oriented attention, and task demands. “Such changes can be speculated to prepare a woman for the increased demands associated with caring for multiple children at the same time,” the researchers said.

The new study demonstrates that the brain is altered across a second pregnancy, involving changes in grey and white matter, as well as resting-state brain activity, and show that both first and second pregnancies, while both involving major changes in brain volume and plasticity, each make a “unique mark on a women’s brain,” with notable implications for postpartum depression in a first pregnancy and stress experienced during gestation in mothers experiencing their second pregnancy.