Although a statistically significant increase in the incidence of gestational hypertension in patients undergoing IVF and in the incidence of gestational diabetes in patients undergoing ovulation induction was noted, these findings did not meet criteria for achieving clinical significance, because the odds ratios were less than 2.0.
Despite the widespread and increasing use of assisted reproductive technologies, there are few prospective studies published addressing the obstetric and pediatric outcomes with these therapies. Additionally, studies suggesting an increase in adverse outcomes such as congenital malformations are limited by small numbers and limited information on confounding variables.9 A recent meta-analysis of a large number of IVF pregnancies suggested that such pregnancies are at increased risk for adverse perinatal outcome, including preterm delivery, low birthweight, placenta previa, gestational diabetes, preeclampsia, and neonatal intensive care admission.9 The main strength of our study is that it incorporated a large number of ART pregnancies and collected prospectively from the general population, with appropriate controls. Our findings corroborate those of the recent meta-analysis, demonstrating a significant increase in hypertensive disorders, placental abnormalities such as placenta previa and placental abruption, and the incidence of cesarean delivery.
We estimated a 2.7-fold increased risk of preeclampsia in IVF pregnancies compared with controls. This association between IVF and preeclampsia has also been noted by other authors, including Jackson et al9 in 2004, Wang et al14 in 2002, Maman et al15 in 1998, and Tan et al11 in 1992. We have also shown an increased incidence of abnormal placentation with IVF use, including a 2.4-fold increased risk of placental abruption and a 6.0-fold increased risk of placenta previa noted in IVF pregnancies compared with controls. This has also been substantiated by other authors, including Verlaenen et al16 in 1995, Li et al17 in 1996, Tan et al12 in 1992, and Jackson et al9 in 2004. Preeclampsia, placental abruption, and placenta previa are all related to abnormalities of location and function of the placenta. Therefore, when pregnancy and the formation of the chorion are initiated in vitro, an inherent difference in the nature of the placenta itself may predispose the patient to develop these conditions during gestation.
Previous authors have suggested an association between IVF use and increased cesarean delivery rate.13,18 We found greater than a two-fold increase in the incidence of cesarean delivery in patients undergoing IVF. Although studies have linked advancing maternal age to the risk of cesarean delivery, this increase remained significant in our study after adjustment for maternal age and parity. Infertile women have been reported to be more anxious about the outcome of their pregnancies compared with women who conceive spontaneously.19 It is possible, therefore, that the apparent increase in cesarean delivery rates may reflect patient and physician choice, rather than an inherent biologic abnormality in such pregnancies.
We did not observe an increased incidence of congenital malformations or fetal aneuploidy in the women who used ART to conceive. A recent study by Zadori et al6 in 2003 reviewed outcomes of 301 neonates born as a result of IVF in a population of more than 12,900 deliveries and found no significant increase in the number of major birth defects. Additionally, in the United States, the Society for Assisted Reproductive Technology reported a prevalence of congenital malformations of 1.9% among patients undergoing IVF, which was similar to that seen in the general population. Retzloff and Hornstein3 in 2003 performed an analysis of 11 major studies from 1996 to 2002 and concluded that the vast majority showed neither an increase in malformations nor clustering of any single specific major malformation in ICSI pregnancies. This finding is complemented by the work done by Bonduelle et al20 in 2002, who studied 2,840 ICSI children and 2,955 IVF children in Brussels. This study found no significant difference in the malformation rate between ICSI and IVF pregnancies. However, our study contradicts the work of Hansen et al7 in 2002, which found an increased incidence of major birth defects in IVF pregnancies with an overall adjusted odds ratio of 2.0. This study found that infants conceived with ART were more likely to have multiple major defects and were also more likely to have chromosomal abnormalities. However, increased diagnostic vigilance of the study population may have resulted in ascertainment bias given the low-risk nature of the control population.21
Additionally, prior work has suggested an association between use of ICSI and an increase in both autosomal and sex chromosome abnormalities.22,23 This apparent association may be due to the known increase in prevalence of chromosomal abnormalities in both azoospermic and oligospermic men.3 It is possible that any association between IVF use and fetal chromosomal abnormalities may be confined only to the subgroup of patients using ICSI. Although our study found no association between ART use overall and fetal chromosomal abnormalities, we had insufficient numbers of patients using ICSI to evaluate this subgroup individually. Also, not all of the FASTER infants had a chromosome analysis performed, so it is possible that there are FASTER infants who have a sex chromosome abnormality but do not know it. In fact, most cases of sex chromosome abnormalities go undiagnosed.
A report from the Centers for Disease Control and Prevention of IVF pregnancies from 1996 to 1997 suggested a 1.8-fold increased risk of low birth weight infants.4 This study attempted to control for the confounding effects of multiple gestation on incidence of low birth weight, and the analysis was restricted to those singletons born of pregnancies that did not originate as multiple gestations. Similar findings for IVF singletons were also reported by Bergh et al24 in 1999, who compared 5,856 ART children to 1,505,742 children born in the general population and found an odds ratio of 4.4 for delivery of a very low birth weight singleton. However, most recently, Schieve et al11 in 2004 found that despite the report of their findings in 2002, from 1996–2000 in 62,551 infants born of IVF, the risk for term low birth weight was found to decline, with an overall standardized risk ratio of 1.62. Our study failed to demonstrate any association between ART and low birth weight. Our population of IVF pregnancies may not have been sufficiently large to detect a difference in birth weight. Alternatively, it is possible that earlier larger studies may have demonstrated statistical significance, but without clinical significance.
The current study objectively addresses the outcome of a subgroup of patients with “subfertility,” requiring only ovulation induction rather than IVF. Nuojua-Huttunen et al25 in 1999 studied 111 patients who underwent ovulation induction and found no change in obstetric or perinatal risk compared with controls. However, in another report by Gaudoin et al26 in 2003, ovulation induction patients were 4.85 times more likely to have a LBW infant compared with controls. Although we did not find an increased incidence of low birthweight in this population, patients undergoing ovulation induction were 2.4 times more likely to have a placental abruption, and 2.1 times more likely to suffer a fetal loss after 24 weeks. In a study undertaken by Maman et al15 in 1998, patients undergoing ovulation induction were also found to have a greater incidence of gestational diabetes, which may reflect an increased prevalence of polycystic ovary syndrome (PCOS) requiring therapy. This underlying metabolic instability may be linked to risk of abnormal placentation (abruption) and of fetal loss. Due to limitations of data collection regarding specific underlying causes for infertility in patients requiring ovulation induction, we cannot distinguish whether some of the abnormal outcomes seen here represent a preexisting disease process, such as PCOS, or are secondary to the ovulation induction therapy itself.27 Despite the fact that there is a slight increase in adverse outcome for patients undergoing ovulation induction, as evidenced by the increase in fetal loss after 24 weeks, there still is a striking difference between complications rates between this group and patients undergoing IVF. This might imply that perhaps the state of subfertility or infertility itself may not be the cause of these adverse outcomes, but that these risks may be related to the process of in vitro fertilization itself.
It is unlikely that a single pathophysiologic approach is responsible for the wide range of adverse obstetric outcomes noted in this study, because the causes of infertility, both identified and unidentified, are broad. Some of the risks apparently associated with ART may be confounded by the nature and presence of infertility itself or by other associated underlying conditions, such as PCOS. A limitation of our study is that no data were collected on the particular cause of infertility, and therefore we cannot comment on how these different causes may affect outcomes. However, we feel that knowledge of an association between overall ART use and adverse pregnancy outcome will be useful for practitioners. The odds remain strong that infertile couples seeking to conceive through the use of assisted reproductive technology will have relatively uncomplicated pregnancies and healthy children. Clearly, however, there is an increased risk of adverse events in a subgroup of these patients, and the information provided here should prove useful when counseling prospective patients before embarking on fertility therapy.
Additionally, an increase in antenatal surveillance may be warranted in this population, including assessment for hypertensive complications and sonographic evaluation of the placenta. The possible associations between infertility, or its therapies, with a range of adverse obstetric outcomes should be discussed with prospective patients before embarking on fertility therapy. Clinicians caring for such patients should be aware of these possible associated adverse outcomes and may need to be vigilant for additional signs or symptoms of complications during antenatal care. However, we cannot conclude from our data whether any particular program of fetal surveillance is warranted or would cause any adverse outcome. It is important, however, for patients and clinicians to realize that although an extra level of surveillance may be warranted given the additional degree of risk, their chances of having a healthy child through ART are overall extremely high.
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The authors acknowledge the work of the members of the FASTER Research Consortium: K. Welch, MS, R. Denchy, MS (Columbia University, New York, NY); R. Ball, MD, L. Cannon, BS, K. Nelson, BSN, C. Loucks, RNC, A. Yoshimura (University of Utah, and Intermountain Health Care Perinatal Centers, Salt Lake City, Provo, and Ogden, UT); D. Nyberg, MD, S. Coe, MS (Swedish Medical Center, Seattle, WA); D. Schmidt, J. Esler, BS (William Beaumont Medical Center, Royal Oak, MI); G. Saade, MD, R. Bukowski, MD, J. Lee, MS, (University of Texas Medical Branch, Galveston, TX); R. Berkowitz, MD, Y. Kharbutli, MS (Mount Sinai Medical Center, New York, NY); S. Gross, MD, I. Merkatz, MD, S. Carter, MS (Montefiore Medical Center, Bronx, NY); J. Hobbins, MD, L. Schultz, RN (University of Colorado Health Science Center, Denver, CO); M. Paidas, MD, J. Borsuk, MS (New York University Medical Center, New York, NY); B. Isquith, MS (Tufts University, Boston, MA) J. Canick, PhD, G. Messerlian, PhD, C. Duquette, RDMS (Brown University, Providence, RI); R. Baughman, MS (University of North Carolina, Chapel Hill, NC); and K. Traister, MS, K. Dukes, PhD, T. Tripp, MA, D. Emig, MPH, N. Tibbetts, L. Sullivan, PhD (DM-STAT, Inc., Medford, MA).