A Periconceptional Nutritional Origin for Noninfectious Preterm Birth Frank H. Bloomfield, 1,2 * Mark H. Oliver, 2 Paul Hawkins, 2 Melanie Campbell, 1 David J. Phillips, 3 Peter D. Gluckman, 2 John R. G. Challis, 1 Jane E. Harding 2 The incidence of preterm birth is increasing and remains the major cause of perinatal morbidity and mortality. While approximate- ly 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 sub- sequently enter preterm labor (PTL) suggest that idiopathic PTL has its origin well before the peripartum period and involves alter- ations in the feto-placental endocrine system (2). Preliminary evidence suggests that se- vere maternal undernutrition (3) or stress (4 ) early in human pregnancy may result in pre- term birth. However, there is little experi- mental evidence to support this. In all species studied, there is a surge in circulating fetal cortisol concen- trations before birth. This corti- sol surge is critical for the matu- ration 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 preco- cious fetal cortisol surge and pre- term 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 normally (6 ). Fetuses from UN ewes were delivered earlier than ad lib con- trols (mean gestation length 139 versus 146 days, P  0.05) (Fig. 1A). Fetal plasma cortisol con- centrations also increased earlier in fetuses from UN ewes (P  0.0001) (Fig. 1B). In half of these, there was a precocious rise in cortisol and the fetuses were delivered pre- term (2 SD below the mean for this flock) (Fig. 1A). Fetal ACTH concentrations were higher in all UN fetuses, regardless of timing of birth (P  0.01) (Fig. 1C). We excluded infection as a cause of deliv- ery by measuring maternal and fetal circulating concentrations of interleukin-6 (IL-6) and tu- mor necrosis factor– (TNF-)(6 ). IL-6 con- centrations were not elevated in any fetus [UN, 0.03 (0.01–1.04) ng/ml; ad lib, 0.03 (0.01– 0.14) ng/ml; (median (range)], and maternal IL-6 and fetal and maternal TNF- concentra- tions were undetectable. Our finding that a modest reduction in food intake commencing before conception and con- tinuing for only 30 days thereafter induces pre- mature delivery in sheep may have major im- plications. Fetal nutrient requirements are ex- tremely small at 30 days gestation, and thus maternal undernutrition is unlikely to have lim- ited nutrient availability for fetal growth. Con- sistent with this, fetuses of both groups were of similar size. Rather, the periconceptional nutri- tional insult led to accelerated fetal hypothalam- ic-pituitary-adrenal axis (HPAA) maturation. Although a precocious cortisol surge occurred in only half of the UN fetuses, ACTH concen- trations were increased in all fetuses, and the UN group was delivered early across the whole gestational age spectrum. We hypothesize that maturation of the fetal HPAA must reach a threshold level to initiate the “feed forward” loop, when pituitary ACTH production increas- es concomitantly with increasing cortisol con- centrations, which eventually leads to initiation of labor, and that this threshold was reached only in half the UN group. It is of interest that only 50% of women who enter PTL actually deliver prematurely ( 7 ) and that gestation length is shortened in women with poor nutritional reserves at the beginning of pregnancy ( 3). A modest nutritional restriction around the time of conception, therefore, may have far-reaching consequences for the fetus, with accelerated maturation of the fetal adrenal gland resulting in preterm birth. If these find- ings are applicable to human pregnancy, then a focus on events around the time of concep- tion may hold the key to prevention of one of the major causes of preterm birth. References and Notes 1. R. L. Goldenberg, J. C. Hauth, W. W. Andrews, N. Engl. J. Med. 342, 1500 (2000). 2. M. Fadalti et al., Ann. N.Y. Acad. Sci. 900, 89 (2000). 3. C. M. Fall, personal communication. 4. N. Dole et al., Am. J. Epidemiol. 157, 14 (2003). 5. J. R. G. Challis, S. G. Matthews, W. Gibb, S. J. Lye, Endocrine Rev. 21, 514 (2000). 6. Materials and Methods are available as supporting online material on Science Online. 7. G. C. Liggins, R. N. Howie, Pediatrics 50, 515 (1972). 8. We thank T. Smith-Wong, S. Rossenrode, G. Hobson, and A. E. O’Connor for technical assistance; J.-P. Scheer- link for provision of reagents; and the Canadian Insti- tutes for Health Research, the Health Research Council of New Zealand, the Royal Australasian College of Physicians, and the National Health and Medical Re- search Council of Australia for funding. Supporting Online Material www.sciencemag.org/cgi/content/full/300/5619/606/DC1 Materials and Methods Fig. S1 1 Department of Physiology, University of Toronto, Toronto, Canada. 2 Liggins Institute, University of Auckland, Private Bag 92019, Auckland, New Zealand. 3 Centre for Molecular Reproduction and Endocrinolo- gy, Monash University, Clayton, Victoria 3168, Australia. *To whom correspondence should be addressed. E- mail: f.bloomfield@auckland.ac.nz A B C Cumulative probability of nondelivery 1.0 0.8 0.6 0.4 0.2 0 125 130 135 140 145 150 Gestational age (d) Gestational age (d) Gestational age (d) 125 130 135 140 145 150 125 130 135 140 145 150 Cortisol (ng/ml) ACTH (pg/ml) 500 100 10 45 30 15 0 Fig. 1. (A) Kaplan-Meier survival analysis of gestation length. Solid line, UN; dashed line, ad lib. (B) Cortisol and (C) ACTH concentrations in fetal plasma from 125 days gestation until delivery [ad lib (▫), UN delivering at term (●), individual UN fetuses delivering preterm (, }, , ‚, E)]. Values are mean  SE. Ad lib, n = 8; UN, n = 10. ***P  0.0001, **P  0.01, *P  0.05 (UN versus ad lib). BREVIA 25 APRIL 2003 VOL 300 SCIENCE www.sciencemag.org 606 on August 12, 2007 www.sciencemag.org Downloaded from