Clinical Context
Antenatal corticosteroids (ACS), typically betamethasone or dexamethasone, are standard of care for pregnant women at risk of preterm delivery between 24-34 weeks gestation. ACS accelerate fetal lung maturation, dramatically reducing respiratory distress syndrome, intraventricular hemorrhage, and neonatal mortality. The Auckland Steroid Trial (1969-1974) was one of the seminal studies establishing this practice, now considered one of the most impactful interventions in perinatal medicine.
However, corticosteroids profoundly affect developing organ systems beyond the lungs. The fetal hypothalamic-pituitary-adrenal (HPA) axis, metabolic programming, and growth pathways are all glucocorticoid-sensitive. Follow-up studies of ACS-exposed individuals have shown subtle alterations in stress responses, insulin sensitivity, and cardiovascular parameters into adulthood. The developmental origins of health and disease (DOHaD) paradigm suggests that early-life exposures can program lifelong disease risk.
This remarkable 50-year follow-up extends the question further: Do the effects of in utero corticosteroid exposure transmit to the next generation? Transgenerational effects—where exposures in one generation affect the health of grandchildren—could occur through epigenetic mechanisms, germline modifications, or altered parenting and environment. The Auckland Steroid Trial’s long duration and careful documentation make it uniquely positioned to address this question.
Study Summary (PICO Framework)
Summary:
In second-generation individuals (F2) whose parents received antenatal corticosteroids in utero, parental ACS exposure was associated with detectable endocrine and metabolic changes compared to F2 individuals without parental ACS exposure, with potential alterations in growth and metabolic health suggesting transgenerational effects.
| PICO | Description |
|---|---|
| Population | Second-generation (F2) individuals—grandchildren of the original trial participants. |
| Intervention | Parental (F1) in utero exposure to antenatal corticosteroids. |
| Comparison | F2 individuals without parental ACS exposure (control arm descendants). |
| Outcome | Endocrine and metabolic changes detected in F2, including alterations in growth and metabolic health. Evidence of transgenerational effects. |
Clinical Pearls
1. Transgenerational effects represent a profound shift in thinking about treatment consequences. Traditional pharmacology considers direct effects on the treated individual. Transgenerational effects mean that treating a pregnant woman might affect her grandchildren—individuals who don’t exist yet and never received the drug themselves. This extends the ethical and clinical calculus of treatment decisions significantly.
2. Epigenetic mechanisms likely explain transgenerational transmission. DNA methylation, histone modifications, and non-coding RNAs can be altered by glucocorticoid exposure and transmitted through germline cells to subsequent generations. Unlike genetic mutations, epigenetic marks can be environmentally induced during fetal development and carried forward, affecting gene expression in unexposed descendants.
3. The benefits of ACS still likely outweigh risks, but long-term surveillance is warranted. ACS reduce neonatal mortality and severe morbidity from prematurity—immediate, life-saving benefits. Transgenerational metabolic effects, while concerning, appear subtle based on this description. The risk-benefit calculus still favors ACS use for indicated preterm pregnancies, but long-term outcome monitoring of exposed populations is scientifically and ethically important.
4. The 50-year follow-up duration is extraordinary and scientifically valuable. Most drug studies have follow-up measured in months to years. This 50-year follow-up spanning three generations provides uniquely long-term data impossible to replicate in contemporary trials. The Auckland cohort represents an irreplaceable scientific resource for understanding very long-term treatment consequences.
Practical Application
Continue ACS for indicated preterm pregnancies: Despite transgenerational effects, the mortality reduction from ACS in preterm delivery remains compelling. Don’t withhold indicated ACS based on theoretical long-term concerns. The grandchildren affected by metabolic changes would likely not exist without the life-saving effects of ACS on their preterm-born parents.
Avoid repeated or unnecessary ACS courses: Given evidence of dose-related effects, minimize ACS exposure to what’s clinically indicated. The practice of repeated weekly ACS courses has already been curtailed based on earlier follow-up studies. Reserve ACS for pregnancies genuinely at risk of imminent preterm delivery; avoid “just in case” dosing.
Consider transgenerational effects in counseling: For families with history of ACS exposure, awareness that subsequent generations might have subtle metabolic differences could inform health monitoring. This doesn’t mean creating anxiety, but acknowledging that developmental exposures may have lasting effects worth watching.
Support long-term cohort studies: Research infrastructure enabling 50-year follow-ups requires sustained funding, participant engagement, and institutional commitment. Clinicians and healthcare systems should support such research as it provides irreplaceable insights into treatment consequences impossible to obtain otherwise.
How This Study Fits Into the Broader Evidence
The developmental origins of health and disease (DOHaD) hypothesis, pioneered by David Barker, established that in utero exposures affect adult disease risk. Studies of Dutch Hunger Winter survivors and their offspring demonstrated transgenerational effects of famine. ACS studies extend this paradigm to pharmaceutical exposures.
Earlier Auckland Steroid Trial follow-ups at 30 years showed that ACS-exposed individuals (F1) had increased insulin resistance compared to controls. The current 50-year follow-up extends this to their children (F2), demonstrating transgenerational transmission of metabolic programming effects.
Animal studies have demonstrated mechanisms for transgenerational glucocorticoid effects: altered DNA methylation in HPA axis genes, modified stress response programming, and metabolic pathway changes that persist across generations. This human study provides crucial clinical correlation to the extensive preclinical literature.
Limitations to Consider
The specific endocrine and metabolic changes in F2 aren’t detailed in the summary—magnitude and clinical significance are unclear. Confounding factors across 50 years (socioeconomic changes, different prenatal care, lifestyle factors) are challenging to control. Selective attrition over 50 years may bias the surviving cohort. The F2 generation inherits genes from both exposed and unexposed parents, potentially diluting effects. Effect sizes and clinical relevance of observed differences need context.
Bottom Line
This 50-year follow-up of the Auckland Steroid Trial demonstrated that antenatal corticosteroid exposure produced detectable endocrine and metabolic effects in the grandchildren (F2 generation) of originally exposed pregnancies, suggesting transgenerational transmission of developmental programming effects. While ACS remain indicated for threatened preterm delivery given their life-saving immediate benefits, this study highlights the importance of minimizing unnecessary exposure and continuing long-term surveillance of ACS-exposed populations. The finding underscores that prenatal interventions can have consequences extending far beyond the immediate generation.
Source: Libby G. Lord, et al. “Second Generation Effects of Antenatal Corticosteroid Exposure: 50-Year Follow-Up of the Auckland Steroid Trial.” Read article here.
