The incidence of preterm birth is increasing and remains the major cause of perinatal morbidity and mortality. While approximately 40% of preterm birth is inflammatory in origin (1), the cause of idiopathic preterm birth is unknown, and the lack of suitable experimental paradigms has limited research. Elevated corticotropin releasing hormone levels in mid-pregnancy in mothers who subsequently enter preterm labor (PTL) suggest that idiopathic PTL has its origin well before the peripartum period and involves alterations in the feto-placental endocrine system (2). Preliminary evidence suggests that severe maternal undernutrition (3) or stress (4) early in human pregnancy may result in preterm birth. However, there is little experimental evidence to support this. In all species studied, there is a surge in circulating fetal cortisol concentrations before birth. This cortisol surge is critical for the maturation of many organ systems in preparation for extrauterine life and, in sheep, is essential for the initiation of normal parturition (5). Here, we demonstrate in sheep that moderate maternal undernutrition around the time of conception results in a precocious fetal cortisol surge and preterm birth.

Singleton-bearing ewes were either well fed (ad lib, n 8) or undernourished (UN) to reduce maternal weight by 15%(n 10) from 60 days before until 30 days after conception (term 145 days), with ad libitum intake thereafter (fig. S1). Fetal cortisol and adrenocorticotropin (ACTH) concentrations were measured frequently in late gestation, and ewes were allowed to lamb