title: Increased risk of precocious puberty in internationally adopted children in Denmark.
abstract: BACKGROUND
  Studies have indicated that internationally adopted children have an increased risk of developing precocious puberty, but no epidemiologic risk estimates have previously been calculated. We aimed to assess the risk of developing precocious puberty in intercountry adoptees, children immigrating with their family, and descendants of immigrants living in Denmark.
  
  
  METHODS
  Patients who were registered with the diagnosis of precocious puberty during the period 1993-2001 were identified through the national patient registry. The background population of children born from 1983 to 2001 were identified through the unique Danish Civil Registration System and subsequently categorized as being Danish (N = 1,062,333), adopted (N = 10,997), immigrating with their family (N = 72,181), or being descendants of immigrants (N = 128,152). The incidence rate ratio of precocious puberty was estimated by log-linear Poisson regression. All rate ratios were adjusted for age and its interaction with gender and calendar year. P values were based on likelihood ratio tests, and 95% confidence intervals were calculated by Wald's test.
  
  
  RESULTS
  In the study period, 655 children developed precocious puberty during 5,627,763 person-years at risk. Adopted children were followed during 39,978 person-years at risk, during which 45 girls and 6 boys developed precocious puberty. The risk of developing precocious puberty was significantly increased 10 to 20 times in adopted girls compared with girls with Danish background. The risk of developing precocious puberty depended on the country of origin. In children immigrating with their family, the risk of developing precocious puberty was only marginally increased. Older age at adoption significantly increased the risk of precocious puberty in adoptees independent of region of origin. The incidence rate ratio was significantly higher in children adopted after the age of 2. In children immigrating with their family, we found no effect of age at migration.
  
  
  CONCLUSIONS
  In this large, nationwide, register-based study including 655 cases of precocious puberty, we found that intercountry boys and girls were 10 to 20 times more likely to develop precocious puberty compared with the Danish reference group. Older age at adoption significantly increased the risk of precocious puberty. Uncertainty of the exact age is a well-known problem in adopted children, and systematic underestimation of age might bias the result. However, using the worst-case scenario that all children who according to the Danish Civil Registration System were adopted after 2 years of age were in fact 1 year older, we still observed a highly increased risk of precocious puberty associated with adoption and especially with adoption after 2 years of age. Surprisingly, the risk of precocious puberty was not increased in the large group of children adopted from Korea. One case of precocious puberty was identified among Korean children, whereas > 20 cases of precocious puberty would have been expected if the risk for a Korean child was at the same level as observed among adopted children from India and South America. In the study population, 99% of Korean children were adopted before 2 years of age, which may contribute to explaining our finding. In Korea, children appointed for adoption are often living in foster care settings from birth to adoption, whereas most other countries are reported to take care of the children in orphanages before adoption. It can only be speculated whether a relation between preadoption living conditions and later risk of precocious puberty exists. Genetic factors play a key role in the timing of puberty, and large variations in age at menarche are observed worldwide. Age at menarche is reported to be in the same age range in South Korea as in well-off populations in other parts of the world, indicating that the different risk of precocious puberty observed between Korean and other adoptees probably cannot be explained by genetic factors alone. The finding that the risk of precocious puberty was significantly increased among adoptees in contrast to what was seen in children immigrating with their families contradicts a direct effect of migration. An increasing number of studies have shown long-term effects of certain prenatal and postnatal growth patterns, including advancement in pubertal maturation after poor intrauterine growth and catch-up growth during childhood. Different growth patterns and dietary habits between adoptees and children immigrating with their families might contribute to explain our findings. It has been hypothesized that stressful psychosocial factors in infancy and childhood may lead to earlier pubertal maturation. In general, adoptees have experienced several traumatic life events, and it may be speculated that these events alter the susceptibility for developing precocious puberty.
  
  
  CONCLUSIONS
  Foreign-adopted children originating from regions other than Korea had a 15- to 20-fold increased risk of precocious puberty compared with Danish-born children, whereas adoptees originating from Korea had no increased risk of precocious puberty. In addition, children immigrating with their families had no increased risk of precocious puberty. The effect of country of origin might be explained by genetic factors or by different environmental exposures and living conditions in the different countries. Older age at adoption increased the risk for premature onset of puberty, which may suggest that environmental factors influence the risk of precocious pubertal development in adopted children.
authors.affiliation: Department of Growth and Reproduction GR, University Hospital of Copenhagen, Rigshospitalet, DK-2100 Copenhagen 0, Denmark. gteilmann@rh.dk
authors.forename: Grete
authors.initials: G
authors.lastname: Teilmann
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Pedersen
authors.forename: Niels E
authors.initials: NE
authors.lastname: Skakkebaek
authors.forename: Tina Kold
authors.initials: TK
authors.lastname: Jensen
mesh_terms: D000300:Adoption; D000367:Age Factors; D001208:Asia / Q000208:ethnology; D001315:Australia / Q000208:ethnology; D002648:Child; D015331:Cohort Studies; D003718:Denmark / Q000453:epidemiology; D004641:Emigration and Immigration / Q000706:statistics & numerical data*; D005060:Europe / Q000208:ethnology; D005260:Female; D006801:Humans; D015994:Incidence; D007194:India / Q000208:ethnology; D007723:Korea / Q000208:ethnology; D008297:Male; D008877:Middle East / Q000208:ethnology; D011629:Puberty, Precocious / Q000208:ethnology*; D012042:Registries; D012306:Risk; D013020:South America / Q000208:ethnology