Overall, 97 infants died between the 8th and the 365th day after birth: 77 born of fertile couples, and 9 and 11 born of infertile couples conceiving without and with infertility treatment, respectively. Compared with infants of fertile couples, the ORs adjusted for maternal age and body mass index were 1.07 (95% CI 0.53–2.14) and 1.83 (95% CI 0.96–3.49) for those born of infertile couples conceiving without and with infertility treatment, respectively. The small number of cases did not permit analysis of infant death by treatment procedures. Among untreated couples, we saw no trend between time to pregnancy and death between the 8th and 365th day of life (Table 3, infant deaths: crude and first column of adjusted ORs).
Further adjustment for parity did not substantially change the above estimates (Tables 2 and 3). We saw no interactions in the risk of perinatal and infant death between parity and categories of infertility or time to pregnancy (P=.48∼.88, Wald test for slope for categories of time to pregnancy as a continuous variable). Restricting the analyses to primiparas yielded estimates similar to those adjusted for parity in Tables 2 and 3. Our analyses included neonates born alive at any gestation but, during the time of the study, delivery of a dead fetus before the 28th week was considered a miscarriage and thus not recorded in the Birth Register. However, the estimates did not change after excluding the 115 neonates born alive before 28 weeks.
Compared with singletons born of fertile couples, those born of infertile couples had an increased risk of SGA, regardless of treatment or adjustment (Table 4, reference Group A: crude and first column of adjusted ORs). Compared with singletons born of infertile couples conceiving naturally, those born after treatment had a slightly higher risk of SGA (Table 4, reference Group B: crude and first column of adjusted ORs).
Analyses among naturally conceived babies showed a statistically significant trend between time to pregnancy and the risk of SGA (Table 3, small-for-gestational-age: crude and first column of adjusted ORs).
Adjustment for parity resulted in attenuated estimates but a similar conclusion, except that the overall difference between treated and untreated couples was no longer statistically significant (Tables 3 and 4). We detected no interaction in the risk of SGA between categories of infertility or time to pregnancy and parity (P=.62∼.87, Wald test for slope for categories of time to pregnancy as a continuous variable), and restricting the analyses to primiparas resulted in estimates similar to those adjusted for parity in Tables 3 and 4.
Before adjustment, we saw a small shift in the birth weight distribution of neonates born to infertile couples, regardless of treatment (Fig. 1). The linear regression model not including parity suggested differences in birth weight of −42.7 grams (95% CI −54.9 to −30.4) and −96.1 grams (95% CI −110.1 to −82.1) among neonates born of infertile couples conceiving naturally and after treatment, respectively. Including parity in the model suggested a more modest reduction in birth weight (−21.2 grams [95% CI −33.3 to −9.1] and −34.5 grams [95% CI: −48.6 to −20.4] for neonates born of infertile couples conceiving naturally and after infertility treatment, respectively). All the following estimates were adjusted for parity. Restricting to infertile couples resulted in a small borderline significant effect of treatment (−17.6 grams [95% CI −36.1 to 0.9]). Compared with neonates born of infertile couples conceiving naturally, neonates born after IUI (−37.8 grams [95% CI −65.2 to −10.5]) and HT (−35.8 grams [95% CI −65.4 to −6.3]) were smaller, but not neonates born after ICSI (−3.6 grams [95% CI −50.0 to 42.9]) or IVF (11.9 grams [95% CI −14.6 to 38.5]).
Figure 2 shows the unadjusted birth weight distributions as a function of time to pregnancy. After adjustment and compared with neonates with time to pregnancy of 0–2 months, the differences in birth weight were 0.6 (95% CI −8.5 to 9.7), −13.2 (95% CI −23.3 to −3.1), and −24.3 grams (95% CI −36.9 to −11.7) for neonates with time to pregnancy of 3–5, 6–12, and more than 12 months, respectively.
Singletons born of infertile couples were slightly more likely to be small-for-gestation than singletons born of fertile couples, and time to pregnancy correlated with the risk among spontaneously conceived babies. Estimates were similar between treated and untreated infertile couples, suggesting that part of the increased risk may be due to the underlying infertility or its determinants, rather than to treatment. The crude increased relative risk of perinatal mortality among babies born of infertile couples was in part explained by older maternal age, higher body mass index, and primiparity.
Infertile couples not receiving treatment may have a less severe form of infertility than infertile couples recurring to treatment. However, use of this group as the reference for assessing the side effects of treatment reduces the potential for confounding by indication.
In this population-based cohort, information on birth outcome was collected from national registers and was virtually complete. Although time to pregnancy and treatment were retrospectively collected during pregnancy, they were reported before the occurrence of the outcomes under study. Thus, differential recall and differential loss to follow-up are not likely sources of bias in this study. Although participants in the Danish National Birth Cohort were somewhat healthier than mothers in the general population (eg, fewer smokers), the effect of nonparticipation on our estimates is expected to be small, as showed in a validation study.19 The 21,771 singletons excluded from this analysis because of unplanned and partly planned pregnancies had a risk of perinatal and infant (8–365 days) death (5.6 and 1.6 per 1,000 births, respectively) comparable to that of singletons born of fertile couples. The risk of SGA was slightly higher (5.1%), but not significantly different after adjustment for maternal age, parity, and smoking (OR 1.04, 95% CI 0.97–1.12).
The validity of time to pregnancy reported by women has been found to be high even after more than a decade.20 Participants in this cohort had to recall the time to pregnancy of the current pregnancy, thus with a short time lag. Excluding pregnancies reported as conceived right away (labeled as a time to pregnancy of 0) did not change our results (data not shown). Long or irregular cycles may result in a time to pregnancy of longer than 12 months, which could cause bias if associated with the studied outcomes. However, excluding all women reporting long (more than 33 days) or irregular cycles (15%) resulted in slightly stronger estimates (with a change of less than 20%).
Women reporting a time to pregnancy of less than 6 months were not asked about treatment for infertility, but we expect only a small proportion of treated couples to have been wrongly classified as untreated. About 45% of women with a time to pregnancy longer than12 months reported treatment, whereas only 7% of women with a time to pregnancy of 6–12 months reported treatment. Treatment type was also self-reported, but most women would be aware of the treatment they received, especially since the time period of recall was relatively short. Among women reporting more than one procedure, we prioritized the treatment based on an a priori assessment of potential risk to the baby. Analyses restricted to women who reported only one procedure (79%) yielded estimates similar to those presented. Additionally, our previous findings for twinning and congenital malformations in relation to infertility treatment suggest that the reporting of treatment procedures was, overall, reasonably accurate.10,21
The rates of stillbirth and infant mortality in our study population (0.3% and 0.4%) were comparable with the national figures between 1997 and 2001 (0.3–0.4% and 0.4%–0.5%, respectively) (homepage of the Danish Society of Obstetrics and Gynecology: http://www.dsog.dk/). We used SGA defined as the lowest 5% of the distribution of birth weight by sex and gestational age, instead of 10%, to increase specificity. Babies defined as SGA in this study had a rate of infant death (0–365 days of life) of 1.90%, compared with 0.28% in non-SGA babies. Among the several options to determine gestational age, we used the one that we considered the best estimate. Using only gestational age recorded in the Medical Birth Register (likely based on ultrasound estimates) yielded similar results (data not shown).
In a case-control study, Draper and colleagues6 found that history of infertility and untreated infertility were associated with an increased risk of perinatal mortality, but recall bias could not be ruled out. Some authors have reported an increased risk of perinatal mortality among children born after ART compared with naturally conceived children.1,2,22 Our findings suggest that the increased risk may be due to the characteristics of infertile women, consistent with two large studies showing no significant difference between singletons born after IVF or ovarian stimulation and population controls, after adjustment for covariates including maternal age and parity.23,24 Due to the limited number of cases in our study, we cannot, however, rule out a small to moderate increased risk of perinatal mortality.
Several studies reported an association between a long time to pregnancy and low birth weight or preterm birth.4,7–9 One, however, reported no association with these outcomes and SGA.25 Participants in the study were enrolled between 1959 and 1966, a time period characterized by limited availability of effective contraception. The small proportion of pregnancies with a known time to pregnancy (15%) may reflect a selected low-risk group. Our finding of a higher risk of SGA in singletons born after infertility treatment is in line with previous studies reporting a 40–60% excess risk of SGA in ART children.1,2,22,26 The increased risk, however, may be at least partly due to the underlying infertility or, more likely, to its determinants, although some evidence suggests otherwise.27 Intrauterine insemination was associated with a slightly increased risk of SGA, which may be explained by the indication for treatment (type or severity of infertility. In vitro fertilization, including ICSI, usually involves selection of embryos, which may reduce the excess risk of SGA induced by treatment. When analyzing the entire birth weight distribution, however, we saw a small effect, possibly due to residual confounding. If our results reflect a true association, it is possible that only specific types (or causes) of infertility are associated with elevated risk. Studies with detailed clinical diagnoses are necessary for understanding the mechanisms by which infertility may correlate with fetal growth disruption.
Using a segment of the Danish National Birth Cohort including births between 1998 and 2001, we previously reported an increased risk of neonatal death with increasing time to pregnancy among primiparas.5 However, we could not replicate this finding with the data for the whole period, although the estimates were in the same direction. Compared with primiparas with a time to pregnancy of 0–2 months, we found adjusted ORs of 1.21 (95% CI 0.63–2.35) and 1.46 (95% CI 0.76–2.79) for untreated and treated infertile couples, respectively. The discrepancy with the previous analysis may have resulted from a higher rate of neonatal deaths among women with a time to pregnancy of 0–2 months (used as the reference category) in 2002–2003 compared with the previous years. The number of neonatal deaths was too small to further examine this difference. On the other hand, we still saw an elevated risk of preterm birth among infertile women.4 Compared with primiparas with a time to pregnancy of 0–2 months, we saw adjusted ORs of 1.26 (95% CI 1.05–1.52) and 1.49 (95% CI 1.23–1.81) for untreated and treated infertile couples, respectively.
Infertility is a result of environmental/lifestyle exposures and/or of genetic predisposition, and several of these factors, in women as well as men, may also affect fetal growth. Male factors may be more present in some groups, such as couples treated with ICSI. Maternal factors may, however, play a more direct role during pregnancy. In our data, primiparity, advanced maternal age, and smoking were associated with a higher risk of SGA. The association between time to pregnancy and SGA was reduced after adjustment for these factors. Advanced maternal age, inherently linked to ovarian aging and decreased fertility,28 may explain part of the increased risk of perinatal mortality among infertile couples. Maternal chronic conditions such as preexisting hypertension or metabolic diseases did not affect our estimates, consistent with previous findings.25
A long time to pregnancy may be associated with reduced fetal growth. The reported increased risk of SGA in singletons born after infertility treatment could be, in part, due to the underlying infertility or to its determinants. Treatment procedures per se may have little effect on fetal growth in singletons.
1. Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328:261.
2. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal outcomes in singletons following in vitro fertilization: a meta-analysis. Obstet Gynecol 2004;103:551–63.
3. Hansen M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects–a systematic review. Hum Reprod 2005;20:328–38.
4. Basso O, Baird DD. Infertility and preterm delivery, birthweight, and Caesarean section: a study within the Danish National Birth Cohort. Hum Reprod 2003;18:2478–84.
5. Basso O, Olsen J. Subfecundity and neonatal mortality: longitudinal study within the Danish national birth cohort. BMJ 2005;330:393–4.
6. Draper ES, Kurinczuk JJ, Abrams KR, Clarke M. Assessment of separate contributions to perinatal mortality of infertility history and treatment: a case-control analysis. Lancet 1999;353:1746–9.
7. Henriksen TB, Baird DD, Olsen J, Hedegaard M, Secher NJ, Wilcox AJ. Time to pregnancy and preterm delivery. Obstet Gynecol 1997;89:594–9.
8. Joffe M, Li Z. Association of time to pregnancy and the outcome of pregnancy. Fertil Steril 1994;62:71–5.
9. Williams MA, Goldman MB, Mittendorf R, Monson RR. Subfertility and the risk of low birth weight. Fertil Steril 1991;56:668–71.
10. Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ 2006;333:679.
11. Hay WW. Catz CS, Grave GD, Yaffe SJ. Workshop summary: fetal growth: its regulation and disorders. Pediatrics 1997;99:585–91.
12. Resnik R. Intrauterine growth restriction. Obstet Gynecol 2002;99:490–6.
13. Tan TY, Yeo GS. Intrauterine growth restriction. Curr Opin Obstet Gynecol 2005;17:135–42.
14. Olsen J, Melbye M, Olsen SF, Sørensen TI, Aaby P, Andersen AM, et al. The Danish National Birth Cohort-its background, structure and aim. Scand J Public Health 2001;29:300–7.
15. Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull 1998;45:320–3.
16. Henriksen TB, Wilcox AJ, Hedegaard M, Secher NJ. Bias in studies of preterm and postterm delivery due to ultrasound assessment of gestational age. Epidemiology 1995;6:533–7.
17. Zhu JL, Hjollund NH, Olsen J. Shift work, duration of pregnancy, and birth weight: the National Birth Cohort in Denmark. Am J Obstet Gynecol 2004;191:285–91.
18. Hosmer DW, Lemeshow S. Applied logistic regression.
New York (NY): John Wiley & Sons; 2000.
19. Nohr EA, Frydenberg M, Henriksen TB, Olsen J. Does low participation in cohort studies induce bias? Epidemiology 2006;17:413–8.
20. Joffe M, Villard L, Li Z, Plowman R, Vessey M. A time to pregnancy questionnaire designed for long term recall: validity in Oxford, England. J Epidemiol Community Health 1995;49:314–9.
21. Zhu JL, Basso O, Obel C, Christensen K, Olsen J. Infertility, infertility treatment and twinning: the Danish National Birth Cohort. Hum Reprod 2007;22:1086–90.
22. McDonald SD, Murphy K, Beyene J, Ohlsson A. Perinatel outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Obstet Gynaecol Can 2005;27:449–59.
23. Ombelet W, Martens G, De Sutter P, Gerris J, Bosmans E, Ruyssinck G, et al. Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study. Hum Reprod 2006;21:1025–32.
24. Klemetti R, Sevón T, Gissler M, Hemminki E. Health of children born as a result of in vitro fertilization. Pediatrics 2006;118:1819–27.
25. Cooney MA, Buck Louis GM, Sun W, Rice MM, Klebanoff MA. Is conception delay a risk factor for reduced gestation or birthweight? Paediatr Perinat Epidemiol 2006;20:201–9.
26. Westergaard HB, Johansen AM, Erb K, Andersen AN. Danish National IVF Registry 1994 and 1995. Treatment, pregnancy outcome and complications during pregnancy. Acta Obstet Gynecol Scand 2000;79:384–9.
27. Kapiteijn K, de Bruijn CS, de Boer E, de Craen AJ, Burger CW, van Leeuwen FE, et al. Does subfertility explain the risk of poor perinatal outcome after IVF and ovarian hyperstimulation? Hum Reprod 2006;21:3228–34.
© 2007 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
28. Swanton A, Child T. Reproduction and ovarian ageing. J Br Menopause Soc 2005;11:126–31.