The relative risk of stillbirth in second-born children with an older brother was 1.08 (0.97–1.20), which was identical to the estimate obtained after excluding the 2256 stillborn firstborn children from the analysis.
The male:female ratio among second-born children born subsequent to a stillborn boy tended to be lower than the ratio among those born subsequent to girls and live-born boys (Table 4).
We found that the delivery of boys compared with girls is associated with an increased risk of stillbirth in subsequent pregnancies.
This study uses an extensive and nearly complete dataset based on the compulsory national registration of births in Denmark. The unique identification number of each person makes it possible to link the pregnancies of a given mother. Misclassification of stillbirths (eg, due to incorrect gestational age) could bias our data, although such misclassification is unlikely to be skewed in relation to the sex of previous births. Skewed distribution of risk factors for stillbirth (such as smoking, alcohol, caffeine intake, body mass index [BMI], socioeconomic status, and ethnicity) in exposed women may confound our findings.11–16 There is no theoretical or empirical evidence of an association between these factors and the sex of prior children. BMI, smoking, and alcohol habits did not differ in relation to sex of previous children in a subsample of more than 25,000 of these women.5
The present study may underreport the number of pregnancy losses caused by factors associated with prior delivery of boys because we defined stillbirth as pregnancy losses after gestational week 28. Previous studies reported that prior birth of a boy is associated with subsequent recurrent miscarriages (including 2nd trimester miscarriages)9,10 and another study defining stillbirth as pregnancy losses after gestational week 20 found that half of all stillbirth occur from gestational week 20 to 28.17
This study is to our knowledge the first to show an association between delivery of boys and subsequent risk of stillbirth. Earlier publications have explored a history of giving birth to boys and subsequent pregnancy outcomes. Delivering boys has been associated with lower birth weights of subsequent siblings.4–8 Two recent studies found that older brothers as well as a twin brother reduce lifetime reproductive success of their siblings.18,19 Furthermore, women who previously have given birth to a boy are more likely subsequently to suffer recurrent miscarriage and have a reduced chance of a subsequent child, compared with women with a first-born girl.9,10
Involvement of the immune system is a plausible physiological explanation for our findings. Maternal immune recognition of male-specific HY-antigens has been described in women following delivery of boys, and HY-specific T-cells can be demonstrated in women up to 22 years after the birth of a boy.1–3 The nonphysiologic situation of stem cell transplantation has demonstrated the impact of this immunity, as cells from a parous donor can attack male recipient cells resulting in graft-versus-host-disease.20–23 Although the immune responses directed against HY-antigens are generally well tolerated in the physiologic situation of pregnancy, we hypothesize that HY-immune responses in a small proportion of pregnant women are poorly tolerated, causing stillbirths.
An alternative explanation for the results of this study could be a shared causal factor increasing both the mothers' risk of complications and the offsprings' sex-ratio (confounding by unobserved time-invariant maternal factors). If this mechanism were to explain our findings, stillbirth would predict the sex ratio of second-borns. This explanation is not supported by our data, as we found no increase in offsprings' sex-ratio following a complicated pregnancy. If anything, the sex-ratio tended to be reduced after stillborn boys.
We observed a tendency toward an increased risk of stillbirth also in girls born subsequent to boys. Determinant spreading, a feature in autoimmune diseases, might be responsible for this finding.26,27 The HY-specific reaction may lose specificity with exposure or time, and become directed toward nonsex-specific proteins on the fetus or trophoblast that have achieved immunogenicity due to the inflammatory process initiated by the anti-HY reaction.
We here report an association between prior delivery of boys and risk of stillbirth. The risk increment is too small to be of clinical significance for a woman with a history of pregnancies with boys, but the associations are not negligible at the population level. Exploring the biologic abnormality behind our finding may provide insight into stillbirth pathogenesis and increase understanding of maternal-fetal interactions during pregnancy.
We thank F. Skovby for critical comments on an earlier draft of the manuscript.
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