A sibling study of the prenatal and perinatal risks for cerebral palsy.

Background

To evaluate the associations between prenatal and perinatal factors and CP risk using a statewide sibling-comparison design.

Methods

We established a cohort of over 4 million singleton births in California during 2007-2015, and we identified families with outcome-discordant siblings of 1213 CP and 1544 non-CP. We estimated odds ratio (OR) and 95% confidence interval (CI) for CP according to perinatal factors including preterm birth (PTB), small for gestational age, low Apgar score, and prenatal factors including maternal pregnancy complications (perinatal infection, gestational diabetes, preeclampsia) and lifestyle-related factors (cigarette smoking, pre-pregnancy overweight).

Results

The perinatal factors remained strongly associated with CP using sibling design, although the point estimates were smaller for PTB (cohort OR = 4.72, 95%CI 4.42-5.04, sibling OR = 3.49, 95%CI 2.74-4.46) and low Apgar score (cohort OR = 19.62, 95%CI 17.99-21.41, sibling OR = 8.79, 95%CI 5.49-14.08). In sibling design, the associations between maternal pregnancy complications or pre-pregnancy overweight and CP risk were attenuated to null. We observed stronger effects between maternal cigarette smoking and CP in the sibling design, however sensitivity tests indicated possible bias from carryover effects.

Conclusion

Adverse perinatal factors remained strongly associated with childhood CP, while uncontrolled confounding bias required considerations for pregnancy complications and CP development.

Impact

We conducted a population-based sibling comparison study to evaluate the associations between several prenatal and perinatal factors and cerebral palsy (CP). Preterm birth, small for gestational age, and low Apgar score at birth remained strongly associated with CP using the sibling comparison design. The associations between several maternal pregnancy complications and CP were close to null in the sibling comparison design, raising the possibility of uncontrolled confounding bias in the cohort analyses. We demonstrated that a sibling comparison design can provide valuable information to triangulate research evidence for CP etiology, but a careful implementation and interpretation of findings is warranted.

COI Statement

Competing interests: The authors declare no competing interests. Informed consent: This study protocol was approved by the official institutional review board in Yale University (IRB#2000028297) and the California Committee for the Protection of Human Subjects (Project#12-10-0861) and was exempted from informed consent requirement because there was no contact with human subject.

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