IVF and stillbirth: a prospective follow-up study

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1 Human Reproduction, Vol.25, No.5 pp , 2010 Advanced Access publication on February 23, 2010 doi: /humrep/deq023 ORIGINAL ARTICLE Reproductive epidemiology IVF and stillbirth: a prospective follow-up study K. Wisborg 1, *, H.J. Ingerslev 2, and T.B. Henriksen 1 1 Department of Paediatrics, Perinatal Epidemiology Research Unit, Aarhus University Hospital, Brendstrugaardsvej 100, Skejby, DK-8200 Aarhus, Denmark 2 Fertility Clinic, Aarhus University Hospital, Skejby, Aarhus, Denmark *Correspondence address. Tel: þ ; Fax: þ ; kirstenwisborg@dadlnet.dk Submitted on October 3, 2009; resubmitted on January 2, 2010; accepted on January 13, 2010 background: Previous studies have indicated that the risk of stillbirth is increased in singleton pregnancies achieved after assisted reproduction technology (ART). However, no previous study fully accounted for factors with potential influence on the risk of stillbirth. Further, whether fertility treatment, the possible reproductive pathology of the infertile couples or other characteristics related to being subfertile may explain a possible association with stillbirth remains unclear. This study compares the risk of stillbirth in women pregnant after fertility treatment (IVF/ICSI and non-ivf ART) and subfertile women with that in fertile women. methods: We used prospectively collected data from the Aarhus Birth Cohort, Denmark and included information about singleton pregnancies ( ). Outcome measure was stillbirth. results: The risk of stillbirth in women who conceived after IVF/ICSI was 16.2 per thousand ( ) and in women who conceived after non-ivf ART 2.3. In fertile and subfertile women, the risk of stillbirth was 3.7 and 5.4, respectively. Compared with fertile women, women who conceived after IVF/ICSI had more than four times the risk of stillbirth [odds ratio (OR): 4.44, 95% confidence interval (CI): ], and adjustments for maternal age, BMI, education, smoking habits and alcohol and coffee intake during pregnancy had only minor impact on the findings (OR: 4.08; 95% CI: ). The risk of stillbirth in women who conceived after non-ivf ART and in women who conceived spontaneously with a waiting time to pregnancy of a year or more was not significantly different from the risk in women with a shorter time to pregnancy. conclusions: Compared with fertile women, women who conceived by IVF/ICSI had an increased risk of stillbirth that was not explained by confounding. Our results indicate that the increased risk of stillbirth seen after fertility treatment is a result of the fertility treatment or unknown factors pertaining to couples who undergo IVF/ICSI. Key words: assisted reproduction / IVF/ICSI outcome / infertility / stillbirth / epidemiology Introduction Since the first child was born after fertility treatment 30 years ago, the number of assisted pregnancies has increased steadily (Adamson et al., 2006). In European countries, up to 4% of all deliveries now result from fertility treatment (Andersen et al., 2007). Much interest has been put into the efficacy of assisted reproduction technology (ART) (Pandian et al., 2003), but more and more research now focuses on the safety (Ludwig et al., 2006). Safety studies are important not only to be able to provide the couple evidence-based information but also to bring into focus potentially preventable adverse outcomes. Two register-based studies (Gissler et al., 1995; De Neubourg et al., 2006) and several small case control studies (Howe et al., 1990; Tanbo et al., 1995; Verlaenen et al., 1995; Reubinoff et al., 1997; Dhont et al., 1999; Nuojua-Huttunen et al., 1999; Westergaard et al., 1999; Koudstaal et al., 2000a, b; Isaksson et al., 2002) have indicated that the risk of perinatal mortality is increased in singleton pregnancies achieved after ART. However, many previous studies have not had the statistical power to study mortality (Helmerhorst et al., 2004), only a few studies have studied stillbirth (Reubinoff et al., 1997; Koudstaal et al., 2000a, b; Kallen et al., 2005; De Neubourg et al., 2006) and no previous study fully accounted for factors with potential influence on the risk of stillbirth. Thus, whether fertility treatment including hormone stimulation and mechanical procedures, the possible reproductive pathology of the infertile couples or other characteristics related to being subfertile may explain a possible association with stillbirth remains unclear. The aim of this prospective cohort study was to compare the risk of stillbirth in singleton pregnancies in women pregnant after IVF/ICSI with the risk of stillbirth in women who conceived in less than 1 year. To explore the effect of fertility treatment versus the effect of & The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 IVF/ICSI and stillbirth 1313 infertility, we also included information about women who conceived after non-ivf ART and subfertile women with a time to pregnancy of 1 year or more. Study population and methods All women booking for delivery at the Department of Obstetrics and Gynaecology, Aarhus University Hospital, Denmark, are asked to participate in the Aarhus Birth Cohort. The Aarhus Birth Cohort is a longitudinal cohort of unselected pregnant women that are consecutively recruited in early pregnancy through the antenatal healthcare services (Wisborg et al., 2003). Nearly all women in the area comply with the antenatal care programme. Women who agree to participate (75%), complete two questionnaires before the first routine antenatal care visit at 16 weeks of gestation. The first questionnaire provides information for the hospital records and for study purposes, the second questionnaire only for study purposes. Information from these questionnaires is linked, using the women s unique personal identification number, to information about delivery and the newborn. In the present study, we included information on women booking for delivery from 1 August 1989 to 31 October The Danish Data Protection Agency, acting as the ethics committee for studies, granted authorization for the implementation of the project. The first questionnaire provided information on medical and obstetric history, including waiting time to pregnancy and fertility treatment, maternal age, smoking habits before pregnancy and during the first trimester and alcohol intake during pregnancy. The second questionnaire provided information on intake of coffee, marital status, education and any psychological problems. The women were asked whether the pregnancy was planned, and if planned, about waiting time to pregnancy in years and months. We also asked the women to provide information about consultations due to infertility and about infertility treatment. Women who conceived after fertility treatment were categorized into two groups according to treatment (IVF/ICSI and non-ivf ART). The non-ivf ART group included women who conceived after hormone stimulation (n ¼ 352) and insemination (n ¼ 527). No difference in the risk estimate of the outcome of interest was found between these two groups. Women who conceived spontaneously were categorized into two groups according to waiting time to pregnancy, 0 11 months (fertile women) and 12þ months (subfertile women). Women with unplanned pregnancies were categorized as fertile. Information about delivery was obtained from birth registration forms filled in by the attending midwife immediately after delivery. Before data entry, all birth registration forms were manually checked and compared with the medical records by a research midwife. Gestational age, measured in completed weeks, was based on early fetal ultrasound measures or detailed information on the woman s last menstrual period. Information about stillbirths was obtained from the birth registration forms and validated with information from the Danish Medical Birth Register through record linkage, using the mother s unique personal identification number. During the study period, the National Board of Health changed the definition of stillbirth. Until April 2004, stillbirth was defined as delivery of a dead child at 28 completed weeks of gestation or later, and after that time, as delivery of a dead child at 22 completed weeks of gestation or later. The study population was restricted to primiparous, Danishspeaking women with a singleton pregnancy who filled in the first questionnaire (n ¼ ). Women with chronic illnesses (cardiovascular, pulmonary or kidney diseases, diabetes or other metabolic diseases, or epilepsy) (n ¼ 4268) and with missing information on waiting time to pregnancy and infertility treatment (n ¼ 2638) were excluded from the study. Statistical analyses The association between fertility treatment and stillbirth is presented as odds ratio (OR) with 95% confidence interval (CI). Potential confounding factors were coded as in Table I and entered into the multivariate logistic regression analyses as a number of dummy variables equal to the number of categories 2 1. Missing values were included as a separate category for each variable. Interaction was tested by Mantel Haenszel analyses. Statistical significance was defined as a two-sided P-value of,0.05. The study was approved by the Regional Ethics Committee, the Danish National Board of Health and the Danish Data Protection Agency. Results In this study of primiparous, singleton pregnancies, (82%) conceived spontaneously after less than 12 months, 2020 (10%) after more than 1 year of trying, 879 (4%) conceived after non-ivf ART and 742 (4%) conceived after IVF/ICSI. The overall risk of stillbirth was 4.3 (n ¼ 86). Characteristics of fertile women, subfertile women and women who conceived after fertility treatment are shown in Table I. Compared with fertile women, women who conceived after IVF/ICSI were older (P, 0.01), more often cohabiting (P, 0.01), had a higher BMI (P ¼ 0.02), and fewer women who conceived after IVF/ ICSI drank alcohol during pregnancy (P ¼ 0.01). Women who conceived after non-ivf ART were older (P, 0.01), had a higher BMI (P, 0.01) and a higher intake of coffee during pregnancy (P, 0.01). Compared with fertile women, subfertile women were older (P, 0.01), more often cohabiting (P, 0.01), had a higher BMI (P, 0.01) and a shorter education (P, 0.01). There were also more smokers among subfertile women (P, 0.01) and they had a higher intake of alcohol (P, 0.01) and coffee during pregnancy (P, 0.01). The risk of stillbirth was 16.2 in women who conceived after IVF/ ICSI and 2.3 in women who conceived after non-ivf ART. In fertile and subfertile women, the risk was 3.7 and 5.4, respectively (Table II). After adjustment for maternal age, BMI, education, smoking habits and alcohol and coffee intake during pregnancy, we found a significantly increased risk of stillbirth in women who conceived after IVF/ICSI compared with fertile women (OR: 4.08; 95% CI: ). The risk of stillbirth in subfertile women and women who conceived after non-ivf ART was not statistically significantly different from the risk in fertile women. Compared with women pregnant after IVF/ICSI, fertile women (OR: 0.25; 95% CI: ), subfertile (OR: 0.33; 95% CI: ) and women pregnant

3 1314 Wisborg et al. Table I Characteristics of primiparous fertile women, subfertile women and women who conceived after non-ivf ART or IVF/ICSI with singleton pregnancies, Aarhus, Denmark, Fertile* (n ) [n (%)] Subfertile** (n ) [n (%)] Non-IVF ART (n 5 879) [n (%)] IVF/ICSI (n 5 742) [n (%)]... Maternal age (years) (18) 252 (13) 37 (4) 5 (1) (77) 1583 (78) 664 (76) 498 (67) 35þ 827 (5) 185 (9) 178 (20) 239 (32) Marital status Cohabiting (92) 1850 (92) 816 (92) 713 (96) Single 325 (2) 19 (1) 17 (2) 5 (1) Missing 1087 (7) 151 (8) 46 (5) 24 (3) Years of education (7) 188 (9) 51 (6) 44 (6) 11þ (83) 1571 (78) 736 (84) 646 (87) Missing 1667 (10) 261 (13) 92 (11) 52 (7) Cigarettes/day (83) 1531 (76) 737 (84) 633 (85) (10) 262 (13) 85 (10) 62 (8) 10þ 1128 (7) 220 (11) 54 (6) 44 (6) Missing 52 (0.3) 7 (0.3) 3 (0.3) 3 (0.4) Alcohol intake during pregnancy (drinks/week), (78) 1534 (76) 704 (80) 614 (83) (16) 319 (16) 118 (13) 95 (13) 3þ 674 (4) 133 (7) 50 (6) 27 (4) Missing 252 (1) 34 (2) 7 (1) 6 (1) Coffee (cups/day) (76) 1365 (68) 624 (71) 585 (79) 4þ 2210 (13) 381 (19) 155 (18) 105 (14) Missing 1764 (11) 274 (14) 100 (11) 52 (7) Maternal BMI (kg/m 2 ) before pregnancy, (22) 458 (23) 152 (17) 145 (20) (60) 1105 (55) 498 (57) 429 (58) (12) 296 (15) 143 (16) 108 (15) 30þ 688 (4) 122 (6) 66 (8) 44 (6) Missing 330 (2) 39 (2) 20 (2) 16 (2) *Fertile: waiting time to pregnancy,12 months. **Subfertile: waiting time to pregnancy 12þ months. Table II Fertility and risk of stillbirth, Aarhus, Denmark, Fertility Births Stillbirths ( ) Unadjusted OR (95% CI) Adjusted OR (95% CI)*... Fertile (3.7) Reference Reference Subfertile (5.4) 1.48 ( ) 1.33 ( ) Non-IVF ART (2.3) 0.62 ( ) 0.53 ( ) IVF/ICSI (16.2) 4.44 ( ) 4.08 ( ), number of stillbirths per thousand; OR, odds ratio; CI, confidence interval. *Adjusted for maternal age, education, marital status, BMI and intrauterine exposure to tobacco smoke, alcohol and coffee.

4 IVF/ICSI and stillbirth 1315 after non-ivf ART (OR: 0.13; 95% CI: ) all had a statistically significantly lower risk of stillbirth. Mean gestational age at delivery was lower in stillborn infants of IVF pregnant women (32 weeks) compared with stillborn infants of women who conceived spontaneously (36 weeks) (P, 0.05). During the study period, the number of assisted pregnancies increased, and in May 2004, the National Board of Health changed the definition of stillbirth. However, compared with fertile women, we found an increased risk of stillbirth in IVF/ICSI conceptions both before (OR: 4.03; 95% CI: ) and after (OR: 5.55; 95% CI: ) the change in stillbirth definition (test of homogeneity between strata P ¼ 0.65). Discussion In this prospective cohort study, we found that compared with spontaneously conceived singleton pregnancies, singleton IVF/ICSI pregnancies had more than 4-fold increased risk of stillbirth. It has been speculated that the increased risk of adverse outcomes in assisted pregnancies is due to factors related to the underlying infertility of the couples (Romundstad et al., 2008). However, we found that couples with a waiting time to pregnancy of 1 year or more and women who conceived after non-ivf ART had a risk of stillbirth similar to that of fertile couples and statistically significantly lower than women pregnant after IVF/ICSI, which may indicate that the increased risk of stillbirth is not explained by infertility. Confounding In agreement with previous studies (Gissler et al., 1995), we found that women with assisted pregnancies differed from other women in a number of characteristics with potential influence on the outcome of interest. To account for differences in parity and pre-existing disease between women with assisted pregnancies and spontaneously conceived pregnancies, we included only primiparous women with no pre-pregnancy diseases. Furthermore, owing to careful prospective collection of information about a number of factors, we could evaluate variables with potential influence on our results (i.e. maternal age, smoking and socioeconomic factors). None of these factors seemed to explain our results, but residual confounding from crude categorization of variables or confounding from unknown variables cannot be ruled out. IVF and ICSI patients represent a group resistant to lowtechnology infertility treatment and have a longer infertility period and may accordingly be selected by unknown factors associated with an increased risk of stillbirth. Vanishing twins Several previous studies have found that assisted conceptions are at higher risk of adverse outcomes than are spontaneously conceived pregnancies (Helmerhorst et al., 2004; Jackson et al., 2004). However, much of the increased risk is explained by multiple pregnancies in assisted conceptions, and from 1998 to 2005 the average number of embryos transferred decreased from 2.0 to 1.75 in Denmark. In our study, we included only singleton deliveries, but previous studies have shown that 10% of IVF singletons originate from twin gestations because of the transfer of two or more embryos (Pinborg et al., 2005). Compared with singleton conceptions, these pregnancies carry an increased risk of very preterm delivery and low birthweight (Pinborg et al., 2007). The increased risk of stillbirth in singleton IVF/ICSI pregnancies that we found in our study may therefore, to some extent, be explained by a higher number of twin gestations in early pregnancy. However, the risk of stillbirth in non-ivf ART pregnancies was significantly lower than that in IVF/ICSI pregnancies and comparable with the risk in fertile women. As for preterm delivery (Schieve et al., 2002), the vanishing twins are probably not the sole contributor to the increased risk of stillbirth in IVF singletons. Preterm delivery Compared with women who conceive spontaneously, women with pregnancies after IVF/ICSI treatment have an increased risk of preterm delivery which cannot be explained solely by a higher number of twin pregnancies (Jackson et al., 2004; Halliday, 2007). Preterm delivery is associated with a higher risk of morbidity and mortality (Gardosi et al., 1998) and may be one of the reasons for an increased risk of perinatal mortality in IVF pregnancies. It is also possible that in women pregnant after fertility treatment, there is a shared aetiology leading to either stillbirth or delivery of a live born preterm infant. Compared with stillborn infants of women who conceived spontaneously, we found that mean gestational age at stillbirth was lower for infants of women pregnant after fertility treatment, which might indicate different aetiologies of stillbirth. However, despite the size of the study, we had limited possibilities to fully explore the causes of death, and this needs further investigation in even larger datasets. During the study period, the National Board of Health changed the definition of stillbirth. However, analysing data according to the two periods defined by different definitions of stillbirth showed an increased risk of stillbirth in IVF/ICSI conceptions both before and after the change in stillbirth definition. In conclusion, we found that compared with women who conceived spontaneously and women who conceive after non-ivf ART, women who conceived after IVF/ICSI had an increased risk of stillbirth that was not explained by confounding from age, lifestyle habits or socioeconomic factors. Future studies should focus on further exploration of this finding so that the information given to infertile couples seeking treatment can be differentiated to the individual couples. Authors roles The authors qualify for authorship by having contributed substantially to this work, as specified by criteria (a), (b) and (c) of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, and they are able to accept public responsibility for it. They have reviewed the final version of the manuscript and approve it for publication. Ethics Ethical approval not required for this study. The Aarhus Birth Cohort is approved by the Danish Data Protection Agency. Funding The study was supported with grants from the Dagmar Marshall s Fund.

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