In diabetic pregnancy, the fetus is at risk for congenital malformation, stillbirth, and perinatal death. Although the incidence of stillbirth and perinatal death has decreased as control of diabetes in pregnancy has improved, the incidence of malformation has not decreased and may even have increased. The present authors review some of the experimental work that has been undertaken to determine the cause of this impasse.At or near term, the mammalian placenta is impermeable to insulin, which cannot, therefore, be the cause of congenital malformations. The authors favor an alternative explanation, based on the hypothesis that an “insulin-like” substance is present in the fetoplacental unit at an appropriate stage in embryogenesis. By “like” substance, they mean, not an analogue, but an insulin homologue, specifically designated relaxin.Relaxin is related to insulin through a common ancestral polypeptide resembling proinsulin. Its usual source is the corpus luteum, but it is found also in the decidua and the term placenta. Among other functions, relaxin enhances secretion of collagenase and plasminogen. This property may lead to collagen degradation in fetal membranes and to eventual rupture at parturition.Relaxin influences the distensibility of the nonpregnant uterus in animals without ovaries maintained on estrogen, but has little effect alone. For maximum effect and greatest increase in the collagen framework, relaxin must be combined with estrogen and progesterone in accurate dosage.In pregnant women, one stimulus to relaxin production is hCG. The serum profiles of relaxin and hCG are similar. Moreover, in nonpregnant women, injection of hCG during the late follicular phase causes relaxin secretion. In women having cesarean sections, a linear relation was found between progesterone and relaxin concentrations in the serum of blood from the ovarian vein on the side of the corpus luteum.The authors studied the known functions of relaxin in relation to the development of the embryonic palate. During fetal development, the palatal shelves undergo reorientation from their initial vertical position lateral to the tongue to a horizontal alignment cephalad to it and fuse to form the secondary palate. Swelling of the shelves is generally attributed to production of sulphated proteoglycans in the matrix, and shelf remoulding and direction of movement are physically controlled by concomitantly developed collagen, arranged in a specific way. Cleft palate may be produced experimentally by drugs that inhibit proteoglycan synthesis (such as cortisone, chlorcyclizine, and diazonorleucine) and by those that cause abnormalities of fetal collagen. This effect is not limited to the palate but involves the whole embryo.When acting with specific amounts of estrogen and progesterone, relaxin has effects on collagen that resemble those of substances causing cleft palate in laboratory animals. If, in normal circumstances, a high relaxin secretion is avoided during the stage of organogenesis, disharmony among the three hormones could give rise to numerous malformations other than cleft palate.Among diabetic women studied before the 10th week of pregnancy, investigators found that those in whom diabetes was not well controlled had estradiol, prolactin, and hCG levels below the range associated with normal pregnancy, and that these rose to normal after careful control of the diabetes with insulin. It is possible, therefore, that administered insulin, while correcting maternal plasma glucose, may, by raising circulating hCG and estrogen concentrations (and thus increasing relaxin levels), trigger a teratogenic response in certain predisposed embryos.