Genetic factors in preterm birth
Correspondence: Professor K. Ward, Obstetrics and Gynecology SOM, University of Utah, School of Medicine, 30 N Medical Drive, Room 2B200, Salt Lake City, Utah 84132, USA.
Genetic factors involved in human birthweight have been studied extensively. It is estimated that 40% of birthweight variance is due to genetic factors and the remaining 60% is due to ‘environmental’ factors. The heritability of low birthweight and macrosomia is greater than the heritability of average weights. A strong familial aggregation of low birthweight has been demonstrated among both whites and blacks in the USA1.
Evidence of Genetic Role
Preterm labour has a tendency to recur in pregnancies and there is anecdotal evidence of familial factors, however the genetics of preterm birth have received little systematic study. A history of a prior preterm birth is a major risk factor for preterm birth in subsequent pregnancies. The impact of prior spontaneous preterm birth on subsequent preterm births has been shown to be greatest when the gestational age of the previous preterm birth was between 23 and 27 weeks. Furthermore, Carr-Hill and colleagues looked at the obstetric outcome of 6072 Scottish women and showed that women with one prior preterm birth had a 15% recurrence risk for preterm birth2. With a history of two prior preterm births, the risk of a subsequent preterm birth was 32%.
It is very likely that a major gene(s) are contributory risk factors for preterm birth as there are well-described racial differences in the rate of preterm birth, even when controlled for other contributing aetiological factors. Our analysis of preterm birth in Utah, where extensive genealogy records are available, suggests a familial tendency. Birth certificates from two successive generations were linked and compared revealing that the tendency to deliver a preterm infant is highly heritable. The likelihood of preterm birth occurring is dependent upon many factors many of which have a genetic basis (Table 1).
Table 1. Factors involved in preterm birth influenced by a genetic component.
|• Fetal growth|
|• Gestational clock—hormonal readiness|
|• Uterine activity|
|• Labour cascade|
|• Membrane strength|
|• Susceptibility to infection|
|• Cervical length|
In Utah, we have a relatively low rate of preterm birth due to infections or drug abuse; most cases of preterm labour are ‘idiopathic’. For the past 3 years, every patient on the Obstetric Service at the University of Utah Hospital who delivered prior to 35 weeks gestation has completed a questionnaire about her family history regarding preterm birth. Forty-two percent of women reported that their mother had one or more preterm birth. Because of the large average family size in Utah, women who delivered preterm had an average of 1.2 sisters who were also parous, and many have also delivered preterm. Through this effort we have already identified over 145 sister pairs and several large families with an apparent genetic predisposition to preterm birth.
We and others are using the proven technique of positional cloning (the isolation of a gene solely on the basis of its chromosomal location, without regard to its biochemical function) to investigate genetic factors in preterm birth. ‘Candidate genes’ are being screened first: including the genes for oxytocin, oxytocin receptor, cyclo-oxygenase, nitric oxide synthetase and interleukin-1 receptor. The discovery of a gene predisposing to preterm birth would be a major breakthrough for future research into biology, prediction and therapy of preterm labour.