Share this article on:

Sex of Prior Children and Risk of Stillbirth in Subsequent Pregnancies

Nielsen, Henriette Svarrea,b; Mortensen, Laust H.a; Nygaard, Ulrikkac; Schnor, Olea; Christiansen, Ole Bjarneb; Andersen, Anne-Marie N.d

doi: 10.1097/EDE.0b013e3181c04dcf
Perinatal: Brief Report

Background: Delivery of a boy has been reported to increase a woman's risk of recurrent miscarriage in subsequent pregnancies. We explored whether delivery of boys similarly increases the risk of a subsequent stillbirth.

Methods: We identified all Danish women delivering their first child (singleton) between 1980 and 1998 (n = 499,731) using the Danish Birth Registry. These women had subsequent singleton births through 2004 (n = 558,314). We assessed the risk of stillbirth conditional on sex of prior children.

Results: The risk of stillbirth was increased by 12% after deliver of boys compared with girls (relative risk = 1.12 [95% confidence interval = 1.02–1.23]). This association did not appear to be explained by maternal confounders.

Conclusion: Stillbirth risk appears to be slightly higher among the pregnancies of women who have previously delivered a boy. One possible mechanism is maternal immune response to male-specific minor histocompatibility antigens initiated during pregnancies with boys.

From the aThe National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; bThe Fertility Clinic, and cDepartment of Neonatology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; and dDivision of Epidemiology, University of Southern Denmark, Odense, Denmark.

Submitted 14 December 2008; accepted 3 March 2009; posted 9 November 2009.

Supported by a research grant from the Copenhagen University Hospital, Rigshospitalet (to H.S.N.).

Correspondence: Henriette S. Nielsen, The Fertility Clinic, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen Ø, Denmark. E-mail:

Women who have delivered boys, possesses long-lasting immunity against male-specific minor histocompatibility (H-Y) antigens.1–3 This H-Y immunity is generally well tolerated by subsequent pregnancies, as half of all newborns are boys. Nontolerated H-Y immunity has, however, recently been hypothesized to account for adverse pregnancy outcomes found more frequently in pregnancies subsequent to boys compared with girls. Two population-based studies4,5 and 3 smaller cohort studies6–8 found a lower birth weight among children with an older brother compared with a sister. Furthermore, women with firstborn boys are subsequently more likely to suffer recurrent miscarriage than women with firstborn girls.9,10 We use an epidemiologic approach to test whether prior birth of boys is followed by an increased risk of stillbirth, which would be consistent with a biologic hypothesis of nontolerated maternal immune responses against H-Y antigens.

Back to Top | Article Outline


The Danish Birth Registry was the source of our data. The registry is based on compulsory notification of all births in Denmark. Every person living in Denmark has a unique identification number, which allows a woman's births to be linked using the mother's number. We identified all primipara women who gave birth to a singleton (excluding women with multiple birth) from 1 January 1980 to 31 December 1998, (n = 499,731). Subsequent singleton births to the women were identified through 2004 (n = 558,314). There were 101,593 women (20%) who did not have subsequent births in the follow-up period and therefore are not included here. The remaining women gave birth to 558,314 second- to fifth-born singletons, including 1952 stillborn children; stillbirth rates by parity are shown in Table 1. Until 2005, the Danish definition of stillbirth did not include pregnancy loss before gestational week 28, which was considered miscarriage. Thus, our cohort included all live births and stillbirths with a gestational age of 28 weeks or more. Permission to perform this register-based study was given by the National Data Protection Agency according to Danish legislation.



Back to Top | Article Outline


To test the association of sex of prior children on subsequent stillbirth risk, we looked at all second- through fifth-born children. For each child we counted the number of preceding brothers. This variable was dichotomized (prior boys = 1, no prior boys = 0). We used multilevel logistic regression to estimate the relative risk (RR) of stillbirth and its associated confidence interval (CI). This model was adopted to take into account serial dependency (a woman could contribute up to 4 pregnancies). We used the STATA/SE 10.0 (StataCorp LP, College Station, TX) estimation routine xtmelogit, with an independent covariance structure. The point estimates obtained from the multilevel logistic regression were virtually identical to those of an ordinary logistic regression, with slightly wider confidence intervals. The analysis was adjusted for sex of the child at risk, number of older siblings, and interpregnancy interval. All analyses were repeated for each sex of the child at risk because we had an a priori expectation that previous boys would affect girls differently from boys. We tested for confounding by unobserved time-invariant maternal factors that could affect both offspring sex and risk of stillbirth by comparing the male:female ratios among second-born children subsequent to a firstborn stillborn child to the ratios following a live-born first child. If an association between delivery of a boy and a subsequent increased risk of stillbirth were confounded by time-invariant maternal factors, then stillbirth will predict the sex ratio of later-borns (because the 2 share a common ancestor).

Back to Top | Article Outline


The unadjusted relative risk of stillbirth subsequent to the delivery of boys was 1.17 (95% CI = 1.06–1.28), compared with the risk in pregnancies preceded only by girl(s). The adjusted relative risk of stillbirth was 1.12 (1.02–1.23) (Table 2). Stratification by sex of the child at risk showed an increased risk of stillbirth in both sexes, but the risk increment was greater among boys (Table 3). Increasing number of preceding boys did not seem to increase the risk of stillbirth (in test of linear trend, P = 0.88).





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).



Back to Top | Article Outline


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.

Cesarean section is known to be more common in pregnancies with boys than girls,24 and cesarean section has been found to be associated with an increased risk of complications in subsequent pregnancies.25 It is possible that cesarean section could mediate the results presented here.

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.

Back to Top | Article Outline


We thank F. Skovby for critical comments on an earlier draft of the manuscript.

Back to Top | Article Outline


1. James E, Chai JG, Dewchand H, Macchiarulo E, Dazzi F, Simpson E. Multiparity induces priming to male-specific minor histocompatibility antigen, HY, in mice and humans. Blood. 2003;102:388–393.
2. Piper KP, McLarnon A, Arrazi J, et al. Functional HY-specific CD8+ T cells are found in a high proportion of women following pregnancy with a male fetus. Biol Reprod. 2007;76:96–101.
3. Verdijk RM, Kloosterman A, Pool J, et al. Pregnancy induces minor histocompatibility antigen-specific cytotoxic T cells: implications for stem cell transplantation and immunotherapy. Blood. 2004;103:1961–1964.
4. Magnus P, Berg K, Bjerkedal T. The association of parity and birth weight: testing the sensitization hypothesis. Early Hum Dev. 1985;12:49–54.
5. Nielsen HS, Mortensen L, Nygaard U, Schnor O, Christiansen OB, Andersen AM. Brothers and reduction of the birth weight of later-born siblings. Am J Epidemiol. 2008;167:480–484.
6. Blanchard R, Ellis L. Birth weight, sexual orientation and the sex of preceding siblings. J Biosoc Sci. 2001;33:451–467.
7. Cote K, Blanchard R, Lalumiere ML. The influence of birth order on birth weight: does the sex of preceding siblings matter? J Biosoc Sci. 2003;35:455–462.
8. Trotnow S, Bregulla K, Flugel K. Studies on the birth-weight and the size of the new-born child with reference to the parity of the mother [in German]. Geburtshilfe Frauenheilkd. 1976;36:744–750.
9. Christiansen OB, Pedersen B, Nielsen HS, Nybo Andersen AM. Impact of the sex of first child on the prognosis in secondary recurrent miscarriage. Hum Reprod. 2004;19:2946–2951.
10. Nielsen HS, Andersen AM, Kolte AM, Christiansen OB. A firstborn boy is suggestive of a strong prognostic factor in secondary recurrent miscarriage: a confirmatory study. Fertil Steril. 2008;89:907–911.
11. Stephansson O, Dickman PW, Cnattingius S. The influence of interpregnancy interval on the subsequent risk of stillbirth and early neonatal death. Obstet Gynecol. 2003;102:101–108.
12. Baeten JM, Bukusi EA, Lambe M. Pregnancy complications and outcomes among overweight and obese nulliparous women. Am J Public Health. 2001;91:436–440.
13. Kramer MS, Seguin L, Lydon J, Goulet L. Socio-economic disparities in pregnancy outcome: why do the poor fare so poorly? Paediatr Perinat Epidemiol. 2000;14:194–210.
14. Little RE, Weinberg CR. Risk factors for antepartum and intrapartum stillbirth. Am J Epidemiol. 1993;137:1177–1189.
15. Naeye RL. Weight gain and the outcome of pregnancy. Am J Obstet Gynecol. 1979;135:3–9.
16. Wisborg K, Kesmodel U, Henriksen TB, Olsen SF, Secher NJ. Exposure to tobacco smoke in utero and the risk of stillbirth and death in the first year of life. Am J Epidemiol. 2001;154:322–327.
17. Copper RL, Goldenberg RL, Dubard MB, Davis RO; Collaborative Group on Preterm Birth Prevention. Risk factors for fetal death in white, black, and Hispanic women. Obstet Gynecol. 1994;84:490–495.
18. Lummaa V, Pettay JE, Russell AF. Male twins reduce fitness of female co-twins in humans. Proc Natl Acad Sci USA. 2007;104:10915–10920.
19. Rickard IJ, Russell AF, Lummaa V. Producing sons reduces lifetime reproductive success of subsequent offspring in pre-industrial Finns. Proc Biol Sci. 2007;274:2981–2988.
20. Adams KM, Holmberg LA, Leisenring W, et al. Risk factors for syngeneic graft-versus-host disease after adult hematopoietic cell transplantation. Blood. 2004;104:1894–1897.
21. Atkinson K, Farrell C, Chapman G, Downs K, Penny R, Biggs J. Female marrow donors increase the risk of acute graft-versus-host disease: effect of donor age and parity and analysis of cell subpopulations in the donor marrow inoculum. Br J Haematol. 1986;63:231–239.
22. Flowers ME, Pepe MS, Longton G, et al. Previous donor pregnancy as a risk factor for acute graft-versus-host disease in patients with aplastic anaemia treated by allogeneic marrow transplantation. Br J Haematol. 1990;74:492–496.
23. Gratwohl A, Hermans J, Niederwieser D, van BA, van Houwelingen HC, Apperley J. Female donors influence transplant-related mortality and relapse incidence in male recipients of sibling blood and marrow transplants. Hematol J. 2001;2:363–370.
24. Ingemarsson I. Gender aspects of preterm birth. BJOG. 2003;110(suppl 20):34–38.
25. Daltveit AK, Tollanes MC, Pihlstrom H, Irgens LM. Cesarean delivery and subsequent pregnancies. Obstet Gynecol. 2008;111:1327–1334.
26. Lehmann PV, Sercarz EE, Forsthuber T, Dayan CM, Gammon G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol Today. 1993;14:203–208.
27. Ott PA, Dittrich MT, Herzog BA, et al. T cells recognize multiple GAD65 and proinsulin epitopes in human type 1 diabetes, suggesting determinant spreading. J Clin Immunol. 2004;24:327–339.
© 2010 Lippincott Williams & Wilkins, Inc.