In this issue of the American Journal of Obstetrics and Gynecology , Dr Chen and colleagues report interesting findings from Alberta, Canada, which add important insight into our understanding of the causes of birth defects, the leading cause of infant mortality. The study found that both short (0-5 months) and long (24-35 months) interpregnancy intervals (IPIs), measured as the time between the birth of a child and conception of the next child, were associated with an increased occurrence of congenital anomalies. Previous studies from Israel and Washington State identified a similar association, thus these findings strengthen the evidence supporting an association between IPI and congenital anomalies. Because the cause of many birth defects is elusive, this study fills an important gap in knowledge that will provide immediate opportunities to decrease birth defects and thereby infant mortality.

IPI has been studied with regard to a variety of other adverse perinatal outcomes, as well. In a metaanalysis of data from 67 articles published from 1966 through 2006, Conde-Agudelo and colleagues showed that IPIs <6 months or >59 months were associated with an increased risk for preterm birth, low birthweight, and small for gestational age. Wendt et al further showed an increased risk for stillbirth and early neonatal death with IPIs <7 months.

What these analyses have shown is that IPI is a “Goldilocks phenomenon”; the ideal IPI is not too short or too long–it must be just right. An IPI <6 months is too short because it confers an increased risk for congenital anomalies as well as preterm birth, low birthweight, small for gestational age, stillbirth, and early neonatal death. Too long has been variously studied as an IPI >24 months, 36 months, and even 59 months, but fairly consistently, perinatal risks rise starting at approximately 24 months. Just right seems to be an IPI between 18-24 months, the time frame with the lowest perinatal risk.

The most commonly cited explanation for the association between a short IPI and adverse perinatal outcomes is maternal depletion of nutrient stores, especially when a woman is breast-feeding. While much has been written to support the role of folate depletion specifically, the findings of Chen et al run counter to this argument. They found that the incidence of the folate-dependent congenital anomalies, namely neural tube defects, cleft lip and palate, cardiovascular defects, urinary tract anomalies, and limb defects, was not increased in the group of women with very short IPIs whereas the occurrence of folate-independent anomalies almost doubled. Because birth defects have a complex etiology, with both genetic and environmental contributions, folate may play a role in certain women or for certain birth defects. But a simple explanation that folate depletion causes birth defects does not tell the whole story. Research looking at the interplay between genetic variation and folate level may help to elucidate the role of folate in the etiology of certain birth defects.

What else could explain the relationship between extremes of IPI and birth defects? Perhaps the observed association is due to residual confounding, given that many risk factors for adverse perinatal outcomes are also risk factors for short or long IPIs, such as socioeconomic status, relationship status, and pregnancy intention. Another possible explanation is that high or low maternal weight can alter nutritional status and metabolism in short and long IPIs and contribute to the occurrence of birth defects. Maternal medical conditions such as asthma, diabetes, and hypertension, which can be poorly controlled due to the stress of a newborn in the case of a short IPI or poorly controlled due to limited access to care in the case of a long IPI, may play a role in the etiology of birth defects. For long IPIs, advancing maternal age as well as declining reproductive capacity and fertility must certainly contribute to the occurrence of birth defects, including aneuploidies as well as structural anomalies.