University of Medicine and Dentistry of New Jersey (UMDNJ) New Jersey Medical School, Newark, New Jersey

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1 FERTILITY AND STERILITY VOL. 82, NO. 6, DECEMBER 2004 Copyright 2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A. Increased risk of preterm birth in singleton pregnancies resulting from in vitro fertilization embryo transfer or gamete intrafallopian transfer: a meta-analysis Peter G. McGovern, M.D., a Amaury J. Llorens, M.D., a Joan H. Skurnick, Ph.D., b Gerson Weiss, M.D., a and Laura T. Goldsmith, Ph.D. a University of Medicine and Dentistry of New Jersey (UMDNJ) New Jersey Medical School, Newark, New Jersey Received November 5, 2003; revised and accepted June 24, Presented in part at the 49th Annual Meeting of the Society for Gynecological Investigation, Los Angeles, California, March This work was supported by the National Institutes of Health through National Institute of Child Health and Human Development (NICHD) grant no. HD (to G.W. and L.T.G.) and the NICHD National Cooperative Reproductive Medicine Network grant no. 1-U10-HD38999 (to P.G.M.). Reprint requests: Peter G. McGovern, M.D., UMDNJ New Jersey Medical School, Department of Obstetrics, Gynecology and Women s Health, 185 South Orange Avenue, MSB-E506, P.O. Box 1709, Newark, NJ (FAX: ; mcgovepg@umdnj. edu). a Department of Obstetrics, Gynecology and Women s Health. b Department of Preventive Medicine and Community Health /04/$30.00 doi: /j.fertnstert Objective: To perform a systematic review of the literature to determine whether singleton pregnancies resulting from IVF-ET/GIFT are at higher risk for preterm birth ( 37 weeks). Design: Literature search and systematic review. Setting: Medical school. Intervention(s): A MEDLINE search ( ) was performed using the terms premature labor, infertility, pregnancy complications, gonadotropins, pregnancy outcome, preterm delivery, and in vitro fertilization. Criteria for inclusion were English language, original research article, study patients conceived using IVF-ET (with or without intracytoplasmic sperm injection) or GIFT, pregnancy outcome reported compared with a control group (e.g., naturally conceived singletons at their hospital or a national reference), and prematurity clearly defined. Incomplete articles (e.g., abstracts), reports of other studies, and studies that failed to separate multiple from singleton gestations were excluded. Main Outcome Measure(s): Summary of relative risks of preterm birth. Result(s): Twenty-seven articles met all inclusion/exclusion criteria and were analyzed by meta-analysis. The random-effects summary relative risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT was 1.98 (95% confidence interval, ). Conclusion(s): The risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT is twice that of natural conceived pregnancies. (Fertil Steril 2004;82: by American Society for Reproductive Medicine.) Key Words: Gonadotropin stimulation, preterm birth, pregnancy outcome, infertility treatment, assisted reproductive technology, in vitro fertilization Infertility is a growing public health and social problem. According to the latest National Survey of Family Growth (1), in 1995 the number of women with impaired fecundity increased to 10% of the reproductive-age population (6.1 million women), up from 8% in the 1988 survey. More importantly, the number of childless women with impaired fecundity increased dramatically, from 2.2 million in 1988 to 2.8 million in 1995 (a 27% increase). More than 9 million reproductive-age women gave a history of having received infertility services (15% of women aged years). In vitro fertilization embryo transfer and GIFT have become increasingly used treatments for infertile patients. In 1999, more than 86,000 IVF-ET/GIFT cycles were performed in the United States (2), resulting in 30,285 live births. This represents 0.8% of all live births nationally (0.7% in 1998). In a recent survey by Jain et al. (3), the three states that required complete insurance coverage performed almost three times as many IVF-ET/GIFT cycles as states without infertility legislation (3.35 vs cycles per 1,000 women). This suggests that the potential use of this technology is much larger than current numbers suggest and that a federal law requiring infertility insurance coverage (which has been proposed) would greatly increase the number of children born 1514

2 FIGURE 1 Study selection process for systematic review of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT compared with naturally occurring controls. ART assisted reproductive technology. McGovern. Preterm birth after IVF-ET/GIFT. Fertil Steril after these procedures. Almost all IVF-ET/GIFT cycles use gonadotropins to stimulate multiple ovarian follicles. Infants delivered after IVF-ET/GIFT are known to be more likely to be premature, but most of this risk is thought to be explained by the higher frequency of multiple births. Although a number of small series have found an elevated risk of prematurity in singletons after IVF-ET/GIFT, they have usually had limited statistical power. Therefore, a controversy exists as to whether singleton pregnancies are actually more likely to deliver preterm. The hypothesis of this study is that singleton pregnancies conceived after IVF-ET/ GIFT are at increased risk for premature birth. A metaanalysis was performed to answer this question. MATERIALS AND METHODS The study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines (4) for reporting of meta-analyses of observational studies. The University of Medicine and Dentistry of New Jersey Institutional Review Board indicated that approval was not necessary for this study. Publications were identified using MEDLINE ( ) for the English language under the terms premature labor, infertility, pregnancy complications, gonadotropins, pregnancy outcome, preterm delivery, and in vitro fertilization. Other publications were identified by examining the references of these articles and standard textbooks. Criteria for inclusion were English language publication, original work, publication dates , majority ( 85%) of subjects having conceived using IVF-ET or GIFT, prematurity clearly defined, and pregnancy outcome data reporting the incidence of prematurity in comparison with a control group. The control groups accepted were naturally conceived singletons from a hospital database (either age- and/or parity-matched controls or general hospital database) or a national reference. Exclusion criteria were incomplete articles, such as abstracts and reports from other studies, and failure to separate multiple from singleton gestations. This search identified a total of 2,049 references (Fig. 1), and these abstracts were reviewed. Of these, 1,852 were FERTILITY & STERILITY 1515

3 FIGURE 2 Meta-analysis of the relative risk of preterm birth in singleton pregnancies resulting from IVF-ET/GIFT, including relative risks and confidence intervals for each study. RR Relative Risks. McGovern. Preterm birth after IVF-ET/GIFT. Fertil Steril clearly not relevant to the research question. The remaining 197 articles were obtained, and two observers blinded to the journal of publication, authors, and results reviewed the isolated methods sections independently. When the methods section review suggested a relevant study, two observers then examined the complete texts independently, and the results were abstracted and compared. This process excluded 170 articles for the following reasons: no controls (n 31), inclusion of 15% of pregnancies from non-ivf-et/gift treatments (n 40), no singleton obstetrical outcomes (n 62), preterm delivery not defined (n 4), and not an original study (n 33). A final 27 studies met all criteria and were included in the meta-analysis. Statistical analysis was performed using SAS (Cary, NC) and Comprehensive Meta-Analysis (Englewood, NJ) software. Relative risks, 95% confidence intervals (CIs), and P values were extracted when present (three studies). Relative risks were computed from gonadotropin-stimulated and control incidence rates cited in the remaining studies. A 95% CI for the study relative risk was estimated using the binomial distribution or asymptotic estimates of the variance of the logarithm of the relative risk, as justified by sample size and detail of available information. The significance of relative risk 1 was tested in each study by 2 or Fisher s exact test. Although some studies cited the use of matched designs, unmatched estimates were obtained in the absence of sufficient detail for matched-design computations. When national population rate denominators were not available, a conservatively small value of 100,000 was imputed. Summary relative risks and CIs were first estimated using fixed-effect, general inverse variance-based methods (5). Heterogeneity of relative risks within subgroups was tested by 2 based on variance-based methods. In the presence of significant heterogeneity (P.05), random-effects point estimates and CIs were computed (6) using DerSimonian-Laird estimates. RESULTS Relative risks ranged from 0.67 to Combining the relative risks from all 27 studies (Fig. 2) revealed that singleton pregnancies resulting from IVF-ET/GIFT were at a significantly greater risk of delivering prematurely when compared with control groups of spontaneously conceived singletons. The fixed-effects summary relative risk was McGovern et al. Preterm birth after IVF-ET/GIFT Vol. 82, No. 6, December 2004

4 TABLE 1 Summary information from the 27 studies included in the meta-analysis. Reference Study group Controls Study group (n) Study group, % preterm birth Control (n) Control, % preterm birth Relative risk (7) IVF Provincial database , (8) IVF National database 3, ,505, (9) IVF National database 3, ,000 a (10) IVF National database , (11) ICSI only National database , (12) IVF National database ,000 a (13) IVF National database ,000 a (14) IVF or GIFT National database ,000 a (15) ICSI only National database ,000 a (16) IVF or GIFT Matched age (17) IVF or ICSI Matched age parity 1, , (18) IVF Matched age parity (19) ICSI only Matched age parity , (20) IVF Matched age parity (21) IVF or ICSI Matched age parity (22) IVF or GIFT Matched age parity (23) IVF Matched age parity (24) IVF Matched age parity (25) IVF Matched age parity (26) IVF Matched age parity (27) IVF Matched age parity (28) IVF Matched age parity (29) IVF Matched age (30) IVF Hospital database , (31) IVF Hospital database , (32) IVF Hospital database , (33) IVF or GIFT Hospital database , Note: GIFT gamete intrafallopian transfer; ICSI intracytoplasmic sperm injection. a The article did not specify the control n, and a conservative n of 100,000 was assumed for statistical purposes. McGovern. Preterm birth after IVF-ET/GIFT. Fertil Steril (95% CI, ). A 2 test for heterogeneity was highly significant (P.0001). To attempt to explain heterogeneity, articles were classified (Table 1) according to type of control group (the major difference among studies): local hospital-based controls, national or regional database controls, or matched controls (usually age and parity). Four studies with hospital-based controls whose relative risks ranged from 1.78 to 2.71 had a fixed-effects summary relative risk of 2.58 (95% CI, ). Nine studies with controls from a national or regional database had relative risks ranging from 1.50 to 3.14, with a fixed-effects summary relative risk of 2.23 (95% CI, ). Fourteen studies with controls matched by age and/or parity had relative risks ranging from 0.67 to 8.00, with a fixed-effects summary relative risk of 1.52 (95% CI, ). However, within the second and third subgroups (national/regional database or matched controls) there was significant heterogeneity among their relative risks. Finally, a random-effects analysis that included all the studies produced a summary relative risk of 1.98 (95% CI, ). Six of the included studies contained additional information about the incidence of extremely preterm birth ( 32 weeks). Analysis of these six articles revealed a randomeffects summary relative risk of extremely premature birth after IVF-ET/GIFT of 2.49 (95% CI, ) that was not significantly different from 1. The wide confidence bands reflect the heterogeneity of the results (relative risks ranged from 0.4 to 19.0). DISCUSSION This meta-analysis demonstrates a highly significant twofold (1.98) relative risk for preterm birth in singleton pregnancies resulting from IVF-ET/GIFT when compared with naturally conceived singletons. The strength of this finding led us to a further analysis of the risk of extreme prematurity ( 32 weeks). A trend toward an excess risk for extreme prematurity was found in singleton pregnancies resulting from IVF-ET/GIFT when compared with naturally conceived singletons (relative risk, 2.49). Unfortunately, be- FERTILITY & STERILITY 1517

5 cause only six studies provided information about delivery before 32 weeks, our analysis was limited and therefore remains inconclusive. Although births before 32 weeks are less common events, even a slight increase in deliveries at this age would have dramatic effects upon healthcare costs and childhood health. Prematurity is the single largest preventable cause of perinatal morbidity and mortality and continues to increase despite considerable efforts to reverse this trend (34). Of the $10.2 billion spent in the United States annually for initial hospital care of newborns, 57% is spent on the 9% of infants who deliver before 37 weeks (35). Therefore, a 1% increase in prematurity would increase national healthcare expenditures by more than $642 million. For initial hospital care, a term infant costs about $1,197, whereas a preterm infant costs approximately $16,305 (35). We believe that publication bias did not influence the results because of [1] the great interest in studying all aspects of pregnancies derived from these new technologies and [2] the interest of physicians performing these procedures to publish data verifying their safety (which would produce significant investigator effort to publish negative results). Publication dates of studies included in our analysis ranged from 1985 through Clearly, over this period, IVF-ET/ GIFT went from being investigational to being established. To confirm our hypothesis, we examined and found no correlations among the years of patients studied, the years of publication, the risks of prematurity in either the IVF-ET/ GIFT or control groups, and the relative risks of prematurity reported in the article (data not shown). This does not suggest a systematic publication bias as these procedures became more established or a general change in the diagnosis of prematurity over time. This analysis also does not allow us to determine precisely whether the elevated prematurity risk is related to gonadotropin stimulation or some other aspect of IVF-ET/GIFT. Virtually all IVF-ET/GIFT cycles involve the stimulation of multiple ovarian follicles with injectable gonadotropins, and therefore the resulting pregnancies are associated with multiple corpora lutea (36). Relaxin, a peptide hormone produced by the corpus luteum of pregnancy (37), is a potent stimulator of collagen breakdown. Relaxin stimulates procollagenase (MMP-1) and prostromelysin-1 (MMP-3) production while decreasing tissue inhibitor of metalloproteinase-1 (TIMP-1) production (38). In human pregnancy, collagen breakdown normally plays an important role in the increased elasticity necessary for cervical effacement and dilatation during labor. The increased relaxin levels observed in gonadotropinstimulated pregnancies do not fall after the first trimester but persist for the duration of pregnancy (39). These excess levels of relaxin may well lead to premature cervical change and premature delivery. Although other luteal products are also important, relaxin provides a plausible link between excess luteal function and premature cervical change and delivery. In a study of pregnancies after gonadotropin stimulation (40), it was demonstrated that elevated levels of relaxin were an independent risk factor for prematurity. Because relaxin levels were more closely linked to the number of corpora lutea than to the presence of twins or triplets, all pregnancies resulting from gonadotropin stimulation would be at risk, not just multiple pregnancies. There could be many differences between spontaneously conceived singleton pregnancies in healthy couples and singleton pregnancies in infertile couples that have been treated with IVF-ET/GIFT. It is possible that the couples themselves have a reproductive pathology, which would result in premature delivery even in treatment-independent pregnancies. An interesting study published after the dates selected for the systematic review (41) addresses this question. These investigators compared the incidence of prematurity in three groups of singleton pregnancies: IVF-ET/GIFT patients, insemination patients (many of whom used minimal gonadotropin stimulation), and normal controls. A very large sample size ( 1,000 pregnancies in each of the three arms) adds considerable strength to their analysis. They found a significant gradation of prematurity risk, with 12.5%, 8.5%, and 5.5% preterm births, respectively, in the three groups. Joffe and Li (42) used a large birth database to compare the incidence of prematurity with the time needed to achieve pregnancy (a surrogate indicator of infertility). Their data reveal an incidence of prematurity of 12.6% in infertile couples (took longer than 12 months to conceive), vs. 9.3% in couples who conceived within 6 months. Taken together, these studies support the concept that, although infertility itself may slightly increase the prematurity risk above the normal population, gonadotropin stimulation and IVF-ET/ GIFT further elevate this risk. It is possible that some of the excess prematurity in gonadotropin singletons is iatrogenic because of either altered management (early delivery) of a premium pregnancy or necessary medical interventions secondary to other obstetrical complications. Both singleton and multiple pregnancies resulting from assisted reproductive technologies have been shown to be at increased risk for a variety of obstetrical complications (22, 26, 28, 43), which can be associated with the need for early delivery. It has also been suggested that IVF-ET/GIFT pregnancies may have gestational age calculations that are incorrectly estimated to be several days early, leading to a falsely elevated incidence of preterm birth. Although the day of ovulation is known with great certainty, concerns have been expressed that the process of developing embryos in vitro may delay the early stages of implantation. If the increased prematurity of IVF-ET/GIFT infants was a result of mathematical error, then these children would be born at normal or greater-than-normal weights for their miscalculated gestational ages. This is clearly not the case, and multiple studies 1518 McGovern et al. Preterm birth after IVF-ET/GIFT Vol. 82, No. 6, December 2004

6 document lower birth weights in infants born after IVF-ET/ GIFT (22, 23, 44). It should be emphasized that the reproductive problems of the infertile couple are not resolved at conception. The twofold risks of preterm and extremely preterm birth in singleton pregnancies after IVF-ET/GIFT argue strongly for further study and heightened clinical vigilance during these pregnancies. Obstetricians and patients alike should be aware of this risk so that they can maintain an increased awareness for the signs and symptoms of premature labor. Our results reveal that the problem of prematurity is not limited to multiple pregnancies but rather exists as a risk for singleton pregnancies resulting from IVF-ET/GIFT. If true, they suggest that the current strategy of making infertility treatments safer by trying to limit the occurrence of multiple pregnancies may be expected to have only partial success. 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