The Health Outcome

In 2002, 11.9 percent of US births were delivered preterm (before 37 weeks gestation) (1). Preterm birth (PTB) is associated with increased infant mortality and morbidity, as well as high costs from both short-term hospitalization and long-term disability. The study reviewed here was conducted in Australia where the PTB rate is lower than in the US at 7.6% (6% 32-36 weeks gestation, 0.8% 28-31 weeks gestation, and 0.8% 20-27 weeks gestation) but still has a substantial public health impact.

Evidence suggests that genetic susceptibility of the mother and/or fetus play a role in the risk of preterm birth. Twin studies have shown that the heritability of PTB is approximately 30% (2,3) and women are more likely to have a preterm birth who were preterm themselves (4). Approximately 20% of women who have had a previous PTB deliver preterm in a subsequent pregnancy with the same partner (5); however, women who have had a previous preterm birth and change partners between pregnancies reduce their risk of a recurrent preterm birth by one-third (6). This suggests a role for the paternal or fetal genome. Inflammatory cytokine polymorphisms in the fetal and/or maternal genome have been associated with increased PTB risk in a number of recent association studies (7-9).

The Finding

This case-control study examined the relationship between preterm birth before 35 weeks gestation and 22 single nucleotide polymorphisms in genes that encode inflammatory cytokines and mediators of host defense and apoptosis. Study subjects included 202 white case participants (68% of total eligible) who had spontaneous labor and delivery between 20-34 weeks gestation and were treated at Women's and Children's Hospital, North Adelaide South Australia and 185 White control participants (88% of total eligible) with no history of PTB and at least one term birth (>37 weeks). The control participants were recruited from women who attended the antenatal clinic. All 22 SNPs were analyzed individually for association with three preterm birth categories: under 35 weeks gestation, under 29 weeks gestation and preterm premature rupture of the membranes (PPROM). Additional analyses examined haplotypes on groups of SNP's in individual genes and demographic characteristics.

Each SNP and haplotype was then analyzed by a stepwise backwards multiple logistic regression model that included smoking, alcohol use, substance use, IL1B+3962A, IL10-GCC and TGFB1-GT. This analysis showed that preterm birth at <29 weeks gestation was associated with the interleukin-4 -590 C/C genotype (OR 3.4; 95% CI 1.2-9.6), the TNF haplotype +488A/-238G/-308G (OR 2.3; 95% 1.1-5.5 p=0.04) and MBL2 54Asp (OR2.3; 95% CI 1.1-5.0 p=0.2). The presence of the IL10 haplotype1082A/-819T/-592A was associated with the risk of PTB < 29 weeks (OR 2.1; 95% CI 1.0-4.1 p=0.04) as well as PPROM (OR 1.9; 95% CI 1.1-3.2 p=0.02).

Analysis of demographic factors showed that smoking was associated with preterm birth <29 weeks gestation (OR 2.3; CI 1, 1-4.9 p=0.03). Alcohol use was associated with increased PTB risk at < 35 weeks (OR 2.3; CI 1.5-3.5), <29 weeks (OR 2.4; CI 1.2-5.0) and PPROM (OR 1.7 CI 1.1-2.7). Any substance use was associated with PTB risk at < 35 weeks (OR 3.7; CI 1.4-9.8) as well as PPROM (OR 3.0; CI 1.0-8.4). None of these associations were significant when corrected by the Bonferroni method.

The authors concluded polymorphisms that modulate the immune response might have a role in preterm birth and PPROM.

Public Health Implications

PTB is a critical public health problem because of its high prevalence and associated morbidity and mortality. All of the polymorphisms examined in this paper are represented in the population at greater than 10% prevalence. This high prevalence of both the health outcome and the polymorphism exposures increases the potential impact of any true associations. However, these findings are preliminary and the impact of this research on public health remains to be seen.

The literature suggests that PTB might the result of an abundant inflammatory response (7-10) . In such a model, multiple genetic susceptibilities and environmental exposures would act together to increased risk of preterm birth. These authors have the data to address components of this hypothesis by examining the effects multiple pro-inflammatory polymorphisms and environmental exposures on the risk of preterm birth. However, the analysis presented here does not examine the combined impact of multiple polymorphisms and/or environmental exposures that have the related biological effects. For example, one could examine the effects of one, two and three pro-inflammatory polymorphisms and environmental exposures on the risk of preterm birth. Analyzing the data in this way may show strong combinatory effects of pro-inflammatory cytokines and environmental exposures on the risk of PTB. Future studies are also needed to examine the effects of the fetal genotype, as well as genetic associations in additional racial and ethnic groups.

References

1. Annells, M.F., et al., Interleukins-1, -4, -6, -10, tumor necrosis factor, transforming growth factor-beta, FAS, and mannose-binding protein C gene polymorphisms in Australian women: Risk of preterm birth. Am J Obstet Gynecol, 2004. 191(6): p. 2056-67.
2. Clausson, B., P. Lichtenstein, and S. Cnattingius, Genetic influence on birthweight and gestational length determined by studies in offspring of twins. Bjog, 2000. 107(3): p. 375-381.
3. Treloar, S.A., et al., Genetic influences on premature parturition in an Australian twin sample. Twin Res, 2000. 3(2): p. 80-82.
4. Porter, T.F., et al., The risk of preterm birth across generations. Obstet Gynecol, 1997. 90(1): p. 63-67.
5. Bakketeig, L.S., H.J. Hoffman, and E.E. Harley, The tendency to repeat gestational age and birth weight in successive births. Am J Obstet Gynecol, 1979. 135(8): p. 1086-1103.
6. Li, D.K., Changing paternity and the risk of preterm delivery in the subsequent pregnancy. Epidemiology, 1999. 10(2): p. 148-152.
7. Hao, K., et al., Power estimation of multiple SNP association test of case-control study and application. Genet Epidemiol, 2004. 26(1): p. 22-30.
8. Macones, G.A., et al., A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol, 2004. 190(6): p. 1504-1508.
9. Kalish, R.B., et al., Interleukin-4 and -10 gene polymorphisms and spontaneous preterm birth in multifetal gestations. Am J Obstet Gynecol, 2004. 190(3): p. 702-706.
10. Romero, R., et al., Bacterial vaginosis, the inflammatory response and the risk of preterm birth: a role for genetic epidemiology in the prevention of preterm birth. Am J Obstet Gynecol, 2004. 190(6): p. 1509-1519.