“Preterm birth” is defined as “birth at less than 37 completed weeks of gestation”. Prematurity used to be viewed as an “unpredictable and inevitable fact of life”. Medical efforts have thus focused on improving the consequences of prematurity rather than preventing its occurrence. This approach has resulted in improved neonatal outcomes, but it remains costly in terms of both the suffering of infants and their families and the economic burden on society. Prevention is preferred, and current research is being directed toward reaching this goal. Another problem is that the world’s preterm birth rate has been consistently rising. In 2006, preterm births constituted ~13% of live births in the United States, an increase of 20% since 1990 (when it was ~10.4%). Trends in most other high-income countries are similar to those in the United States.
According to estimates by the World Health Organization, among the 130 million infants born each year worldwide, 8 million die before reaching their first birthday. In the U.S. 17–34% of these infant deaths are attributable to prematurity, and only about half the cases of prematurity result from identifiable causes. Among the reasons, other than iatrogenic [i.e. caused inadvertently by a physician, surgeon, medical treatment, or diagnostic procedure] preterm delivery, are maternal conditions –– such as preeclampsia and fetal distress. However, in the past decade, the number of preterm Caesarean sections performed, regardless of gestational age, has increased by 33 to 50%, without a similar change in maternal risk profiles. This pattern suggests a lowering of the “requirements” for preterm Caesarean delivery. Other antecedents of preterm birth include multiple gestations arising from assisted reproductive technologies involving implantation of multiple embryos and advanced maternal age. In addition, surgical intervention for management of cervical intra-epithelial cancer, or more invasive lesions, is associated with an increased risk of preterm birth by a factor of approximately two.
Despite evidence that genetic factors contribute to duration of gestation and risk of preterm birth, robust associations with genetic variants have not been identified until now. Authors [see the attached elegant article and editorial] used large data sets that included gestational duration to determine possible genetic associations. They performed a genome-wide association study (GWAS) in 43,568 women of European ancestry using gestational duration as a continuous trait, and term vs preterm (<37 weeks) birth as a dichotomous outcome. They examined samples from three Nordic data sets (involving a total of 8,643 women) to test for replication of genomic loci that had significant genome-wide association (P <5.0 x 10–8) or an association with suggestive significance (P <1.0 x 10–6) in the discovery set. Four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. [EBF1 = early B-cell factor-1; EEFSEC = eukaryotic elongation factor, selenocysteine-tRNA specific; AGTR2 = angiotensin II receptor type-2; WNT4 = WNT family member-4, one of a group of highly conserved signal transduction pathways that pass signals into a cell through cell surface receptors]. Functional analysis showed that an implicated variant in WNT4 alters binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets [ADCY5 = adenylate cyclase-5; RAP2C = member of the RAS oncogene family]; these variants also showed genome-wide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genome-wide significance. An analysis of mother–infant dyads suggested that these variants act at the level of the maternal genome. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control –– support their mechanistic involvement. For some of us interested in selenite (HSeO3–) uptake [Oncotarget 2016; 7: 35327], this study provides a whole new horizon of research proposals with regard to the ZIP8 transporter that has been shown to move selenium into the cell. N Engl J Med 6 Sept 2o17; DOI: 10.1056/NEJMoa1612665 & editorial (preprint)