Abstract
BackgroundPerinatal characteristics are associated with subsequent risk of several chronic diseases. Previous studies regarding endometriosis were based on small samples and retrospective data and were limited by unmeasured confounding bias, leading to conflicting and inconclusive findings. We investigated the associations of maternal and birth characteristics with risk of endometriosis among Swedish women of reproductive age.MethodsThis total-population register-based cohort study consisted of 628 312 singleton women born in Sweden between 1973 and 1987, who were followed for diagnosed endometriosis from age 15 years until the end of 2012. Multivariable Cox regression was applied to examine associations with perinatal characteristics. Residual unmeasured confounding was assessed through within-family and E-value analyses.ResultsDuring follow-up, 8262 women received an endometriosis diagnosis. There were clear dose−response/linear associations of endometriosis with lower maternal education, endometriosis in the mother [adjusted hazard ratio (aHR): 2.24, 95% confidence interval (CI): 2.04–2.46], maternal smoking during pregnancy (aHR: 1.18, 95% CI: 1.04–1.33 for moderate smoker and aHR: 1.36, 95% CI: 1.18–1.57 for heavy smoker vs non-smoker), lower birthweight, and lower birthweight-for-gestational age (aHR: 0.93 per standard deviation increase, 95% CI: 0.91–0.95). Within-family and E-value analyses suggested that these perinatal characteristics are robust predictors of the incidence of endometriosis. We also found that an estimated 26% of the association between maternal smoking and early-onset endometriosis could be explained by birthweight-for-gestational age.ConclusionThis study finds support for fetal origins of endometriosis, in that exposure to adverse environment or restricted development during the perinatal period may increase the risk. Further research is needed to provide an understanding of the underlying mechanisms.
Highlights
As proposed by the developmental origins of health and disease theory, and supported by many epidemiological studies,[1] the relationship between adverse environmental conditions in prenatal or postnatal periods and poor health in later life has become well established.[2,3] The hypothesis claims that, apart from the predetermined genetic influence, the human body is susceptible to many modifiable factors during early development such as maternal nutrition and intrauterine environment.[4,5] The developmental influence is of particular importance to adult hormonerelated disorders, as alterations in prenatal endocrine status or hormonal milieu may permanently reprogramme the fetus’s postnatal hormone secretion and tissue-specific hormone susceptibility.[2]
The estimated incidence peak of endometriosis is around age 30.8 Considering such a young age, it has been suggested that the programming of endometriosis could occur as early as the perinatal period of life.[9]
Relatively less unmeasured confounding would suffice to explain away the associations of maternal education, region of origin, and women’s birth county with the incidence of endometriosis (Supplementary Table 1, available as Supplementary data at IJE online). In this total-population based cohort of 628 312 women, we found that maternal smoking during pregnancy, lower birthweight and lower birthweight-for-gestational age were all associated with an increase in the incidence of endometriosis during the early to mid-reproductive period
Summary
As proposed by the developmental origins of health and disease theory, and supported by many epidemiological studies,[1] the relationship between adverse environmental conditions in prenatal or postnatal periods and poor health in later life has become well established.[2,3] The hypothesis claims that, apart from the predetermined genetic influence, the human body is susceptible to many modifiable factors during early development such as maternal nutrition and intrauterine environment.[4,5] The developmental influence is of particular importance to adult hormonerelated disorders, as alterations in prenatal endocrine status or hormonal milieu may permanently reprogramme the fetus’s postnatal hormone secretion and tissue-specific hormone susceptibility.[2]. Some studies suggested that preterm birth or lower birthweight predict increased risk of endometriosis in adulthood,[9,15,16,17] whereas others do not find support for the fetal origins of endometriosis.[14,18]. We investigated the associations of maternal and birth characteristics with risk of endometriosis among Swedish women of reproductive age. Conclusion: This study finds support for fetal origins of endometriosis, in that exposure to adverse environment or restricted development during the perinatal period may increase the risk. Further research is needed to provide an understanding of the underlying mechanisms
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