Periconceptual undernutrition in the sheep causes premature activation of the hypothalamic-pituitary-adrenal (HPA) axis resulting in preterm birth
FH Bloomfield1, MH Oliver2, P Hawkins2, JRG Challis1 & JE Harding2
Objective: to investigate whether periconceptual undernutrition in sheep alters the timing and activation of the fetal HPA axis and thus pregnancy duration. Preterm birth is a major health problem, but its causes are poorly understood.
Methods: Twentyeight nulliparous ewes were randomly assigned to an ad libitum (N, n=8) or restricted diet (maternal body weight reduced by 15-20%; UN, N=10) from 61 d before to 30 d after mating. Thereafter all ewes were fed ad libitum for the remainder of pregnancy. At 118 d vascular catheters were inserted in fetus and ewe and blood samples withdrawn at regular intervals until delivery. Ewes delivered normally and lambs were weighed and measured. Plasma samples were stored at -80 degC until analysis for cortisol (F), ACTH and progesterone (P4) by radioimmunoassay.
Results: At surgery, there were no differences in fetal measurements between groups. UN fetuses delivered earlier than N fetuses (139.6 plus/minus 2.1 vs 145.1plus/minus 0.7 d, p lessthan 0.05 (Kaplan Meier survival analysis)) and 5 UN vs 0 N fetuses were preterm (<139 d gestation, p<0.05). Excluding preterm fetuses, there were no differences in birth weight or crown-rump length, but UN fetuses were thinner (girth 38.9 plus/minus 0.8 vs 41.9 plusminus 1.1 cm, p<0.05). In preterm fetuses (all UN) F (p<0.0001) and ACTH (p<0.0001) rose, and P4 (p<0.01) fell, significantly earlier than in term fetuses. There were no differences between UN and N groups in fetuses born at term. The ACTH to F ratio in preterm fetuses was twice that in term fetuses, consistent with the feed-forward loop seen in late-gestation, but was not significantly different between nutritional groups in term fetuses.
Conclusion: We have shown for the first time that maternal periconceptual undernutrition results in precocious activation of the fetal HPA axis and preterm birth.