Infertility treatment use in relation to selected adverse birth outcomes

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1 Infertility treatment use in relation to selected adverse birth outcomes Diana B. Welmerink, M.P.H., a,b Lynda F. Voigt, Ph.D., a,c Janet R. Daling, Ph.D., a,c and Beth A. Mueller, Dr.P.H. a,c a Department of Epidemiology, University of Washington, Seattle, WA; b School of Social Work, University of Michigan, Ann Arbor, Michigan; and c Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington Objective: To determine whether maternal infertility treatment is associated with adverse outcomes. Design: Population-based cohort study using linked birth certificate-hospital discharge data. Setting: Washington State. Patient(s): Live-born singleton infants conceived with infertility treatment between 2003 and 2006 (n ¼ 2,182) and a random sample of live-born singleton infants conceived spontaneously, frequency matched by birth year (n ¼ 10,989). Intervention(s): None. Main Outcome Measure(s): Mantel-Haenszel adjusted relative risks (RRs) and 95% confidence intervals (CIs) were computed for low birth weight, delivery at <37 weeks, small for gestational age infants, any malformation, placenta previa, and placenta abruptio. Result(s): Women with infertility treatment were at increased risk of placental abnormalities, including placenta abruptio (RR, 1.6; 95% CI, ) and placenta previa (RR, 3.0; 95% CI, ). Their infants were more likely to be delivered at <37 weeks (RR, 1.7; 95% CI, ) or weigh <2500 g (RR, 1.4; 95% CI, ); however, they were not at increased risk of being small for gestational age. An increased risk of malformations was observed in infants born to older women with infertility treatment, but not to younger women. Conclusion(s): Women using infertility treatment are at increased risk for delivering preterm, placenta previa, and placenta abruptio. Studies with measurement of specific infertility treatments will help identify the mechanisms. (Fertil Steril Ò 2010;94: Ó2010 by American Society for Reproductive Medicine.) Key Words: Infertility treatment, placenta previa, premature birth, pregnancy outcomes, birth certificates In 2002, an estimated 7.2 million women of child-bearing age in the United States were subfecund or subfertile; 8.3% ever received medical help to become pregnant, and 1.9% reported at least one medical visit in the past year for help becoming pregnant (1). Treatment for infertility has been available for more than 50 years (2), first in the form of oral prescription medications and later in the form of assisted reproductive technology (ART), including IVF-ET. In 2004, approximately 1% of all infants born in the United States were the result of a pregnancy assisted by fertility treatment, with a similar proportion occurring in Washington State (3). Between 1980 and 1998, the twin birth rate increased approximately 50%, and triplet and higher-order births increased more than 400% (4). These increases have been attributed primarily to increased maternal age at conception and increased use of infertility treatments (5). Regardless of the use of infertility treatment, preterm birth, low birth weight, and infant death occur at increased rates in multiple gestations (4). However, recent studies have reported an increased occurrence of adverse outcomes among singleton pregnancies conceived after ART, including malformations (6 9), low birth weight (10 13), small for gestational age (SGA) (14, 15), and placental anomalies (11, 16, 17). Infants born too early or with Received March 5, 2009; revised February 26, 2010; accepted March 1, 2010; published online April 30, D.B.W. has nothing to disclose. L.F.V. has nothing to disclose. J.R.D. has nothing to disclose. B.A.M. has nothing to disclose. Reprint Requests: Beth A. Mueller, Dr.P.H., Fred Hutchinson Cancer Research Center, P.O. Box 19024, Mailstop: M4-C308, Seattle, WA (TEL: ; FAX: ; bmueller@fhcrc.org). malformations require extensive hospital care, resulting in longer term cost (18) and considerable distress to the family. Placenta previa and placenta abruptio cause serious morbidity and mortality in infants (19). The number of births resulting from infertility treatment will continue to increase as new technologies are developed and refined. The majority of studies that have evaluated pregnancy outcomes after infertility treatment have been clinic-based, had relatively small numbers, or had inadequate comparison groups. We conducted a population-based cohort study using linked birth certificate-hospital discharge data to describe delivery and personal characteristics of all women with and without infertility treatment who delivered infants in a recent time period, and to determine whether infertility treatment is associated with malformation, low birth weight, SGA, premature delivery, placenta previa, or placenta abruptio among singleton deliveries. MATERIALS AND METHODS Human Subjects Protection Committee approval was received from the University of Washington Institutional Review Board before beginning this study, which used electronic birth and hospital registry data from Washington State. Washington State birth certificates collect information regarding parental characteristics, maternal health, course of pregnancy, labor and delivery details, and infant outcomes. The Comprehensive Hospital Abstract Reporting System (CHARS), containing hospital discharge information from all nonfederal hospitals in Washington State, was instituted by the Washington State Department of Health in The CHARS is linked by the University of Washington Epidemiology Department to birth certificate data for the delivery hospitalization of both mothers and infants. Much of the information included on the birth certificate and in CHARS data is taken from labor and delivery records and the mother s and infant s medical records Fertility and Sterility â Vol. 94, No. 7, December /$36.00 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 Subjects were identified from Washington State birth and fetal death records for Use of infertility treatment in the current pregnancy was first indicated by a check box in the 2003 revision of the Washington State birth and fetal death certificates. The statement reads, Pregnancy resulted from infertility treatment. Infertility treatment is defined to include: fertility-enhancing drugs, artificial insemination, intrauterine insemination, and all ART techniques. The health care worker completing the certificate uses the maternal medical or prenatal care records to determine maternal exposure. To describe all women delivering after infertility treatment, birth and fetal death certificates were screened to identify all women with deliveries conceived as a result of infertility treatment (n ¼ 2,835 women, with 3,506 live-born singleton infants and fetal deaths). A random sample of all deliveries not conceived via infertility treatment, regardless of plurality, were selected and frequency matched in a ratio of 5:1 by delivery year (n ¼ 14,172). Specifically, for each birth year we randomly selected five women without infertility treatment for each woman with infertility treatment. Live-born singleton infants and fetal deaths in this comparison group were then maternally linked to identify twins, triplets, and so on, delivered to the comparison women, resulting in a total of 14,356 comparison live-born singleton infants and fetal deaths. The final ratio of exposed to unexposed infants/fetal deaths is not 5:1, because of the high number of multiple gestations occurring in women using infertility treatment. To compare the relative occurrence of maternal and infant outcomes among singletons, all live-born singleton infants conceived as a result of infertility treatment were identified from birth certificates (n ¼ 2,182). Singletons not conceived via infertility treatment, constituting the comparison group, were randomly selected and frequency matched in a ratio of 5:1 by birth year (n ¼ 10,989), as described in the previous paragraph. Outcome information was obtained from both birth certificates and hospital discharge records. Birth weight was categorized as <1500, , , and R4000 g. Gestational length was categorized as <37, 37 41, and R42 weeks. Infants were classified as SGA if they were in the lowest 10% of the distribution of birth weights for each week of gestational age, according to Washington State live births from Congenital malformations were identified on the birth certificate (by check box) or in the infant s linked CHARS record (International Classification of Disease Ninth Revision [ICD-9] codes ). The presence of any malformation was treated as a dichotomous variable. An occurrence of placenta previa (ICD or 641.1), or placenta abruptio (ICD ) was identified by screening the mother s linked hospital discharge record. We computed Mantel-Haenszel adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationships of interest and stratified by selected variables. All analyses were conducted using Stata 10 (StataCorp, College Station, TX). Variables examined for their potential effects on the associations were: maternal age (<30, 30 34, 35 39, R40 years), race/ethnicity (white, black, Native American, Asian/Pacific Islander, Hispanic), education (< high school, high school graduate, some college, college graduate), marital status (married, not married), body mass index (BMI; <25.0, , , R35.0), prenatal smoking (no, yes), prior pregnancies (0, 1þ), prior births (0, 1þ), previous poor birth outcome (no, yes), and previous cesarean delivery (no, yes). Race/ethnicity was later collapsed into two groups (white and nonwhite) because of the small number of women in other racial/ethnic groups in the study population. Previous poor birth outcome (defined as previous perinatal death or an SGA infant), previous preterm delivery, and previous cesarean delivery were evaluated only among women with prior deliveries. Women with a previous cesarean delivery were identified from a longitudinal search of maternally linked birth records (20) for earlier years from The Kotelchuck Summary Index was used to describe the adequacy of prenatal care (21). Adjustments were made in the analyses for variables that altered the RR more than 10%. All analyses were adjusted for birth year (the frequency matching variable), maternal age, and parity. Missing data were excluded from relevant analyses. Data on maternal age was missing for <0.1% of singleton births. Parity was missing for 0.5% of singleton infants conceived after infertility treatment and 2.7% of infants conceived spontaneously. Most other variables were missing data for <5% of singleton births. A few variables were missing data for more than 25% of all singleton births (maternal race, BMI, and Kotelchuck Summary Index). Little data was missing for birth weight (0.3%), gestational age (0.3%), and size for gestational age (2.4%). Data on infant malformations and placental anomalies were missing for approximately 6% of women with infertility treatment and 9% of women conceiving spontaneously. RESULTS Twenty-two percent of women who received infertility treatment delivered multiple gestations, compared with 1% of women conceiving spontaneously (Table 1). Characteristics of women with infertility treatment who delivered singletons were similar to those of all women with infertility treatment. Women delivering infants after infertility treatment were more likely to be older, white, highly educated, and married than were women conceiving naturally. Only 1% of women using infertility treatment smoked prenatally, compared with 11% of women conceiving spontaneously. BMI was similar in both groups. Women with infertility treatment were more likely to have had no prior pregnancies or deliveries. Among women with prior deliveries, women with infertility treatment were also more likely to have had a previous preterm birth or a poor birth outcome. Infertile women were more likely to have received adequate or intensive prenatal care and to have the delivery hospitalization billed to a private insurance company. All subsequent results refer to singleton deliveries only. Singletons born to women who had received infertility treatment were almost twice as likely to weigh <1500 g and had a 40% increased risk of weighing ,499 g, but were not at increased risk to be SGA (Table 2). Women with infertility treatment had a 70% increased risk for delivering at <37 weeks gestation. Because infertile women with and without a prior delivery can vary greatly, we evaluated birth weight and gestational length separately among each group (data not shown). Nulliparous women with infertility treatment had an increased risk of delivering an infant weighing <2500 g (RR, 1.6; 95% CI, ), but this appeared to be due to prematurity because these women were not at increased risk for delivering an SGA infant. Parous women were not at increased risk of delivering an infant weighing <2500 g (RR, 1.2; 95% CI, ). Both nulliparous and parous women with infertility treatment were at increased risk for delivering prematurely (data not shown). Overall, infants of infertile women were not at increased risk of having a malformation (Table 2), but this risk varied by maternal age (data not shown). Infants born to older infertile mothers (R35 years old) were at increased risk of malformations (RR, 1.4; 95% CI, ) relative to older mothers who were not infertile, but infants born to younger mothers (<35 years old) were not (RR, 1.1; 95% CI, ). When all infants with missing data from both the birth certificate and hospitalization records regarding malformations (accounting for 85% of missing data for this variable) were considered to have no congenital malformations, there was no change in the RR (data not shown). Women receiving infertility treatment were at significantly increased risk of placental anomalies (Table 2), including placenta abruptio (RR, 1.6; 95% CI, ) and placenta previa (RR, 3.0; 95% CI, ). The risk of placenta previa decreased with increasing maternal age. Women <35 years old using infertility treatment were at four times the risk (RR, 4.0; 95% CI, ), and women R35 years old were at greater than two times the risk (RR, 2.6; 95% CI, ) of placenta previa, compared with similarly aged women without infertility treatment (data not shown). The adjusted relative risk of placenta previa was increased among both nulliparous and parous women (RR, 3.2; 95% CI, ; Fertility and Sterility â 2581

3 2582 Welmerink et al. Infertility treatment, adverse outcomes Vol. 94, No. 7, December 2010 TABLE 1 Selected characteristics of women with and without infertility treatment with deliveries in Washington State, a All infants Singleton infants only Conceived after infertility treatment Conceived spontaneously Conceived after infertility treatment Conceived spontaneously N [ 2,835 N [ 14,172 N [ 2,182 N [ 10,989 n % n % n % n % Plurality, twins or more n/a n/a Mother s age (y) < , , , , , , R Father s age (y) < , , , , , , R , , White mother 2, , , , Mother s education <High school , , High school graduate , , Some college , , College graduate or greater 2, , , , Married 2, , , , BMI < , , , R30.0 1, , , Smoked prenatally , , No prior pregnancies 1, , , Nulliparous 1, , , , Previous preterm birth b Previous poor birth outcome b Kotelchuck summary index Inadequate , , Intermediate , , Adequate or Intensive 1, , , , Mother s primary payer Government , , Private 1, , , Other , , a Numbers may not add to total because of missing data. b Among multiparous women (all deliveries: 952 exposed, 8,129 unexposed; singleton infants only: 726 exposed, 6,351 unexposed). Welmerink. Infertility treatment, adverse outcomes. Fertil Steril 2010.

4 TABLE 2 Infant and maternal outcomes comparing women delivering a live-born singleton infant after infertility treatment with women delivering a live-born singleton infant after spontaneous conception in Washington State, a Conceived after infertility treatment N [ 2,182 Conceived spontaneously N [ 10,989 Adjusted RR b Outcome n % n % (95% CI) Birth weight (g) <1, ( ) 1,500 2, ( ) 2,500 3,999 1, , (ref) R4, , ( ) Gestational age (wk) < ( ) , , (ref) R ( ) Size for gestational age Small ( ) Normal 1, , (ref) Large ( ) Any malformation ( ) No malformation 1, , (ref) Placenta previa ( ) No placenta previa 2, , (ref) Placenta abruptio ( ) No placenta abruptio 2, , (ref) a Numbers may not add to total because of missing data. b All RRs are adjusted for birth year, maternal age, and parity. Welmerink. Infertility treatment, adverse outcomes. Fertil Steril and RR, 3.4; 95% CI, , respectively; data not shown). To examine whether a prior cesarean delivery modified this relationship among parous women, we stratified our results. Insufficient numbers precluded calculation of adjusted RRs; however, 10 of 358 (2.8%) parous women with infertility treatment and 16 of 3,541 (0.5%) parous women without infertility treatment had placenta previa (P < 0.001, Fisher s exact test). Among parous women with a prior cesarean delivery, 7 of 174 (4.0%) of women with infertility treatment and 12 of 920 (1.6%) of women without infertility treatment had placenta previa (P¼0.07, Fisher s exact test). DISCUSSION This population-based study used information from the new revision of the U.S. birth certificate to describe women with and without infertility treatment, and to evaluate maternal and infant outcomes among singleton pregnancies. Women who deliver after infertility treatment compose a selected subpopulation of all women giving birth, with characteristics that differ from those of women who conceive naturally. Among singleton deliveries, it is reassuring to observe no increased risks for associated malformations. However, infertility treatment appears associated with an increased risk of certain adverse outcomes and conditions, such as preterm delivery and placental abnormalities. An increased risk of placenta previa was observed in previous studies of singleton infants conceived after ART. In a small metaanalysis of 39 events in 1,610 pregnancies, women conceiving after IVF-ET were 2.87 times (95% CI, ) more likely to have placenta previa than women conceiving naturally (11). More recent studies have indicated a 4- to 6-fold increased risk of placenta previa after ART in singleton deliveries (16, 17). Our results suggest a similar increase in placenta previa risk, even in a population of women conceiving after both non-art and ART methods. One concern is whether the infertility treatment or some inherent characteristic causing infertility is the cause of adverse outcomes. A matched study (16) compared the outcomes of women with consecutive singleton pregnancies achieved naturally and subsequently by ART treatment, or vice versa, with each woman acting as her own control. After adjusting for maternal age, parity, and previous cesarean delivery, placenta previa was nearly three times more likely after the ART-conceived pregnancy than after the spontaneously conceived pregnancy, regardless of the sequence of ART treatment (first or second pregnancy), suggesting that the infertility treatment is associated with an increased risk of placenta previa. Surgical procedures, including previous cesarean delivery (22, 23) and induced abortions (23) can increase the risk of placenta previa, possibly owing to pathologic changes that occur in the endometrium after surgery (22). IVF-ET can also induce endometrial changes. Therefore, an increased risk of placenta previa, such as what we observed, might be expected even among women with no prior history of abdominal surgery (e.g., nulliparous women). Technical aspects of the ART procedure might provide another explanation for this finding. Embryos are likely to implant in the same area in which they are transferred (24). Implantation in a suboptimal spot has been shown to affect the placenta and umbilical cord, possibly leading to complications at birth (25). If implantation is too close to the cervical os, placenta previa might be more likely. This is especially worrisome because transferring embryos lower in the uterine cavity has been suggested to improve implantation success rates (26, 27). Fertility and Sterility â 2583

5 The risk of low birth weight we observed among singletons born after infertility treatment appears to be due to prematurity. A recent metaanalysis reported that infants conceived by IVF-ET were at increased risk of low birth weight or being delivered at <37 weeks gestation (11). A more recent study observed a twofold increase in the risk of having a low birth weight infant among women conceiving after ART treatment (12), but this was calculated using expected numbers of low birth weight infants born in the general population. The only population-based study to date in the United States observed an increased risk of ART pregnancies being delivered preterm (RR, 1.8; 95% CI, ) and delivering a low birth weight infant (RR, 1.5; 95% CI, ), but no increased risk of delivering a very low birth weight infant (28). A Swedish study observed a 50% increased risk of preterm birth in women delivering after IVF-ET, even after controlling for maternal age, parity, and duration of infertility (29); a slightly increased risk for delivering a low birth weight infant was observed. Similar results were also observed in a Finnish study (13). Our risk estimates are similar to those obtained in other studies of the effects of ART, despite the fact that our exposed infants included those conceived after both ART and non-art procedures. Again, the question arises of whether qualities inherent to the infertile couple or specific aspects of the infertility treatment are responsible for women with infertility treatment delivering an infant too early. Two studies may provide some clues owing to unique aspects of their study design. A study comparing women receiving infertility treatment to subfecund women awaiting infertility treatment reported a twofold greater risk of delivering preterm in women with infertility treatment and a 3.5-fold increased risk in women conceiving after ovulation stimulation (10). There was no increased risk of delivering a very low birth weight or preterm infant. A subanalysis of a population-based study excluded groups that rarely receive ART treatment and women with complicated pregnancies, and it was observed that singletons conceived after ART were at increased risk of being delivered preterm or at low birth weight compared with the general population (28). The results of these studies suggest that some specific aspect of infertility treatment might lead to infants being born too early, although the specific mechanism for this relationship is still unclear. However, we cannot exclude the possibility that a characteristic inherent to the infertile couple is the underlying cause for an increased risk of delivering prematurely. Subfertile women not using infertility treatment were more likely to deliver a preterm infant than were women with normal fertility (30), and subfertile women were also at increased risk of spontaneous abortion (odds ratio [OR], 1.7; 95% CI, ) (31). It is possible that the same characteristics that decrease the chance of successful implantation or carrying a fetus to term are also responsible for ending established pregnancies prematurely. A study comparing the outcomes of women with consecutive singleton pregnancies achieved naturally and subsequently by ART treatment, or vice versa, observed no increased risk of premature birth or an SGA infant after ART, regardless of the sequence of ART treatment (first or second pregnancy) (32). When comparing outcomes for the ART population with the general population, this study observed results for preterm birth and SGA infants similar to our study. Thus, unlike the persistent increased risk of placenta previa regardless of ART sequence in a similarly designed study (16), it appears that premature birth may in fact be due to characteristics of the infertile couple. Finally, singletons born after infertility treatment are no more likely than those conceived naturally to have malformations. A previous metaanalysis reported that infants delivered following ART were more likely to have a malformation than those spontaneously conceived (OR, 1.4; 95% CI, ) (6). A more recent study in the United States observed a slightly increased risk of major birth defects (OR, 1.3; 95% CI, ), which may, however, have been due to chance (8). We observed a similar increased risk among women R35 years old with infertility treatment, but no increased risk among younger women with infertility treatment. This might be because younger infertile women are more likely to terminate a pregnancy with a malformed infant than are older infertile women. It was recently reported that major structural defects were 2.1- to 4.5 times more likely in a population of live-born singleton infants, fetal deaths, and pregnancy terminations conceived by ART (33); the latter two outcomes were not included in our study. A study using the Swedish Medical Birth Registry and the Registry of Congenital Malformation (29) observed a slightly increased risk of congenital malformations in singleton infants born after IVF-ET (RR, 1.25; 95% CI, ), but no adjustment was made for maternal age or parity. In addition, the expected number of infants with congenital malformations in the general population was used because of differences in registration between delivery units. Our overall results might differ from those previously reported because our study population contained women conceiving by both ART and non-art methods. Small studies have shown that non-art techniques do not confer an increased risk of malformations (34 36), meaning that a mixed population would temper any association. The type of infertility treatment used generally depends on whether male or female factors, or both, are the cause of the infertility. Intracytoplasmic sperm injection (ICSI) is typically used to treat male-factor infertility. Studies suggest that de novo mutations can increase in infants conceived after the use of ICSI to treat couples with low sperm quality (37 39). It has also recently been suggested that the culture medium used to foster fertilization and cell division can have harmful effects on the embryo, although this has not yet been studied in humans (40, 41). Unfortunately, Washington State birth certificates do not provide information on the type of infertility treatment or specifics of malformations beyond a general category of chromosomal abnormalities. Most prior studies examined the ART and non-art techniques separately, because the potential mechanism for adverse birth outcomes may differ. However, the first step in many of these procedures is ovulation stimulation using medication. Extremely high concentrations of E 2 and P achieved during ovulation stimulation may set off a chain reaction between growth factors, cell adhesion molecules, and steroid receptors in the endometrium that influence the receptivity of the endometrium (10, 12, 42), possibly affecting implantation and placentation (10) or leading to preterm delivery (43, 44). If only ART is associated with increased risk of these adverse outcomes, our results would likely be biased to the null. It is difficult to say how much bias a population with mixed treatment type would confer, because the proportion of women who conceive via non- ART methods is unknown. However, we still observe increased risks for several outcomes and the mix of infertility treatments in our study represents the general population, rather than women treated only at specialty clinics. Our study may also be limited by the fact that our measurement of malformations is likely incomplete. Even though our data only captured malformations noted at the birth hospitalization, it is likely that the most serious malformations were identified and reported at this time. Although multiple gestations are more common among women with infertility treatment than women conceiving spontaneously, vanishing twin syndrome can affect between 10% and 30% of multiple gestations, causing these pregnancies to end in a singleton birth (45, 46). Singleton survivors of a pregnancy with a vanishing twin have been shown 2584 Welmerink et al. Infertility treatment, adverse outcomes Vol. 94, No. 7, December 2010

6 to have increased odds of low birth weight, preterm delivery, being SGA, and neurologic sequelae (45, 47). Assuming that a similar percentage of multiple gestations in Washington State are affected, a small number of infants surviving vanishing twin syndome would have been misclassified as singleton infants and considered eligible for this study. However, because this number is low, and we have randomly selected only 4% of the total number of singleton births during the time, it is unlikely that these survivors will have a large effect on our risk estimates. Finally, the women delivering after infertility treatment in this study included those with pregnancies resulting in live births, a subset of women with infertility treatment. Heightened monitoring of pregnancies of women with infertility treatments might result in more vigilant prenatal care or greater likelihood of diagnosing malformations. Birth certificates accurately capture birth weight information (48 50); however, gestational age may be less accurate (49, 50). Although studies have indicated that placenta abruptio and placenta previa are less accurately reported on the birth certificate (49 51), a validation study in Washington State indicated that using linked birth certificate-hospital discharge data, as we have done, increased the reporting accuracy for these conditions (52). We also used linked hospital discharge records, in combination with birth certificate data, to identify malformations, which likely increased our accuracy of reporting (53). We were unable to evaluate the accuracy of reporting regarding use of infertility treatment, because there are no estimates of the number of women using non-art methods to become pregnant. However, in completing this section of the birth certificate, the certifier is directed to consult the mother s medical records for information (54). 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