Pregnancy, Immunity, and the Developing Brain: impact of alcohol exposure in early development

Alcohol consumption during pregnancy is well recognized for its damaging effects on fetal development, yet many of the underlying biological mechanisms remain vaguely understood, especially regarding its impact on neurodevelopment. Increasingly, researchers are focusing on one system that plays a critical role during pregnancy, and that is the maternal immune system

This blog summarizes the research article titled

"Altered maternal immune networks are associated with adverse child neurodevelopment: Impact of alcohol consumption during pregnancy"

published by Dr Joanne Weinberg’s team at the University of British Columbia, Canada with international collaboration with Khmelnytsky Perinatal Center and Rivne Oblast Medical Diagnostic Center in Ukraine, and the University of California, San Diego.

Healthy maternal immune environment is essential for fetal development. During pregnancy, immune secretions, cytokines and chemokines, help coordinate communication between the mother and the baby. These signalling molecules regulate processes ranging from placental function to neural development. Because of this, disruptions to immune balance during sensitive developmental windows alter the trajectory of brain development and place the child on a “pathway to pathology.”

Over the past two decades, many studies have attempted to identify maternal immune markers associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. However, findings have been inconsistent. Some studies report elevated inflammatory markers during pregnancy, while others observe reduced levels of the same molecules. This inconsistency reveals an important limitation: focusing on single cytokines in isolation may oversimplify how the immune system functions.

Rather than acting independently, cytokines operate as interconnected networks. Like members of an orchestra, their biological effects depend on individual signals and how those signals interact and change over time. As a result, researchers are increasingly adopting network-based approaches that examine coordinated immune patterns instead of isolated biomarkers.

Alcohol exposure during pregnancy provides a particularly important model for studying these interactions. Chronic alcohol consumption is known to influence inflammatory signalling, and evidence suggests that alcohol use during pregnancy can alter maternal cytokine levels. What remains less clear is how alcohol reshapes broader immune networks, and whether those immune changes may help explain why some children experience neurodevelopmental delay while others do not.

To investigate this, the authors analyzed maternal blood samples during the second and third trimesters of pregnancy from women enrolled through the OMNI-Net Ukraine Birth Defects Prevention Program, part of the CIFASD consortium.

Participants were grouped based on alcohol exposure and child neurodevelopmental outcome. This allowed the researchers to compare alcohol-exposed pregnancies resulting in either typical development (A/TD) or neurodevelopmental delay (A/ND).

Maternal blood samples were used to measure a broad panel of 40 cytokines and chemokines, generating the maternal immune profiles. Rather than limiting their analysis to individual molecules, authors examined how cytokines interacted as coordinated networks throughout pregnancy.

Child development was assessed after birth, evaluating cognitive, language, and motor development at 6 and 12 months of age. Together, this longitudinal design enabled the researchers to connect the maternal immune profile with early neurodevelopmental outcomes in the child.

Before the authors examined participants' inflammatory milieu, they asked whether the groups were similar enough to be comparable between the minimal/ zero alcohol consumption and high/chronic alcohol use during pregnancy.

• In the mothers, most baseline characteristics such as BMI, pregnancy history, education, prenatal supplements were similar between groups; however, some differences stood out, and they were the following:

  • Mothers in the alcohol exposed/ neurodevelopmental delay (A/ND) group had a lower socioeconomic status and were more likely to smoke during pregnancy. Importantly, however, the amount of alcohol consumed did not vary by much within participants of this group.

    
    

• In children, conditions associated with fetal alcohol spectrum disorders (FASD) were more common in the alcohol-exposed groups. Notably, children of an A/ND group showed a thin vermilion border (upper lip being thinner than normal), which is a classic facial feature associated with FASD.

  
  

Not surprisingly, cognitive and motor development scores were lower in children classified with neurodevelopmental delay, but this is where the study gets more interesting:

Not every alcohol-exposed child showed the same outcome, which suggests the maternal immune network may be the answer to this variability.

When the researchers looked at individual cytokines, important differences began to emerge:

During the second trimester, mothers in the alcohol-exposed group whose children showed neurodevelopmental delay (A/ND) had higher levels of cytokines IL-15 and IL-10 relative to controls. Other inflammatory signals showed upward trends, suggesting that the maternal immune environment was already shifting during pregnancy. The figure below, taken directly from the paper, shows maternal immune profiles during pregnancy between the four groups:

1. control/ typical development

2. control/ neurodevelopmental delay

3. alcohol/ typical development

4. alcohol/neurodevelopmental delay

Figure 1. Maternal immune profiles during pregnancy differ across child neurodevelopmental outcomes and alcohol exposure (Wienberg, J. et al., 2018). Heatmaps show cytokine and chemokine patterns during the second and third trimesters. Red indicates higher levels and green indicates lower levels relative to the group average. Distinct immune signatures emerge between groups, particularly in the second trimester, with the strongest inflammatory profile observed in alcohol-exposed pregnancies associated with neurodevelopmental delay. C/TD: control/ typical development; C/ND: control nerodevelopmental delay; A/TD: alcohol/ typical development; A/ND: alcohol/ neurodevelopmental delay.

The real insight came when the authors stopped looking at cytokines one by one.

Cytokines do not work in isolation, and neither does any system in the body; they behave more like a coordinated network. Instead of asking whether a single cytokine increased or decreased, the researchers examined how groups of cytokines moved together across pregnancy.

This revealed something very interesting: each group showed its own distinct “immune signature.”

During the second trimester, the strongest inflammatory patterns appeared in the alcohol-exposed group with neurodevelopmental delay (A/ND), as shown in Fig. 1 (A/ND). Importantly, not all alcohol-exposed pregnancies looked the same. Mothers in the alcohol-exposed group whose children developed typically (A/TD) showed overlapping, but clearly different, immune patterns (Fig. 1).

The authors then identified several cytokine networks:

• alcohol-exposure network, linked to prenatal alcohol exposure

• exposure/delay network, associated with alcohol exposure and developmental delay

• vulnerability network, a pattern specifically associated with children who later showed neurodevelopmental delay.

  
  

This “vulnerability network” was important because it distinguished between alcohol-exposed pregnancies with typical versus delayed child development. These findings suggest that alcohol exposure alone may not fully determine outcome. The maternal immune response influences the vulnerability.

By the third trimester, immune signatures associated with neurodevelopmental delay became even more pronounced, regardless of alcohol exposure. At the same time, the study identified networks unique to alcohol-independent developmental delay, suggesting that different biological pathways may lead to similar developmental outcomes.

Together, these findings move the field beyond single biomarkers toward a dynamic system: understanding pregnancy as an interconnected immune system whose patterns shape early brain development.

Full reference:

Bodnar, T.S., C. Raineki, W. Wertelecki, L. Yevtushok, L. Plotka, N. Zymak-Zakutnya, G. Honerkamp-Smith, A. Wells, M. Rolland, T.S. Woodward, C.D. Coles, J.A. Kable, C.D. Chambers, J. Weinberg, and D. Collaborative Initiative on Fetal Alcohol Spectrum. 2018. Altered maternal immune networks are associated with adverse child neurodevelopment: Impact of alcohol consumption during pregnancy. Brain Behav Immun. 73:205-215.