The question of whether systemic use of corticosteroids during the first trimester of pregnancy increases the risk of congenital malformations in people has still not been resolved. Here, we present the results of a case-control study on the relationship of corticosteroids during pregnancy and oral clefts in the newborn infant. Data are derived from the Spanish Collaborative Study of Congenital Malformations (ECEMC). Case subjects were 1,184 liveborn infants with nonsyndromic oral clefts. The results of the logistic regression analysis, show a relationship between exposure to corticosteroids during the first trimester of pregnancy and an increased risk of cleft lip (with or without cleft palate) in the newborn infants (OR = 6.55; CI = 1.44-29.76; P = 0.015), controlled for potential confounder factors, such as maternal smoking, maternal hyperthermia, first-degree malformed relatives with cleft lip with or without cleft palate, and maternal treatment with antiepileptics, benzodiazepines, metronidazole, or sex hormones during the first trimester of pregnancy. Thus, we believe that the use of corticosteroids during the first trimester of pregnancy, should be restricted to the following situations: for life-threatening situations, for those diseases without any other safe therapeutic alternative, or for those cases with replacement therapy.