In the United States and worldwide, assisted reproductive technologies (ARTs) are increasingly used to overcome infertility.1 In 2000, close to 100,000 procedures were performed in the United States, resulting in more than 35,000 infants, nearly 1% of the U.S. birth cohort.1 Although ART is thus providing benefits to thousands of couples, adverse outcomes associated with these procedures have been reported. In addition to the known risk for multiple gestation and multiple birth resulting from high-order embryo transfer, recent studies also suggest that singleton infants may be at increased risk for adverse outcome compared with naturally conceived singleton infants. A series of studies reported that singletons conceived through ART are at increased risk for low birth weight (LBW), very low birth weight (VLBW), preterm delivery, and fetal growth restriction.2–13
We recently reported increased risks for LBW and VLBW among singletons recorded in the U.S. population-based registry of ART procedures maintained by the Centers for Disease Control and Prevention (CDC). Our analysis included more than 18,000 infants conceived with ART in 1996 and 1997.2 We found an increased risk for LBW and VLBW among ART singletons compared with the general U.S. population of singletons. The risks remained elevated after restricting analyses to subgroups conceived with presumably healthy gametes or carried by a presumably healthy woman, suggesting that the increased risks were, at least in part, due to a treatment effect.
Recent evidence from Finland suggests that the risk for LBW and preterm delivery among ART infants may have declined in that country.3 For singleton infants, adjusted odds ratios for the association between ART and LBW declined from 2.4 in 1991–1993 to 1.7 in 1998–1999. The authors suggested that this finding may have been related to improved antenatal care for women who conceived with ART.
Both ART treatment and patient care after treatment may have changed in the United States since our initial study of this issue. To determine whether the risk of LBW or preterm delivery among ART infants has declined in the United States, we have expanded on our earlier work. We examined secular trends from 1996 to 2000 for LBW, VLBW, preterm delivery, preterm LBW, and term LBW among singleton infants conceived with ART in the United States. We further examined the risks for each of these outcomes in greater detail among a subset of infants conceived in the most recent year, 2000.
MATERIALS AND METHODS
Clinics and medical practices in the United States are mandated to report data for every ART procedure to the CDC (Fertility Clinic Success Rate and Certification Act of 1992 [FCSRCA], Public Law No. 102–493, October 24, 1992). Assisted reproductive technology is defined as infertility treatments in which both oocytes and sperm are handled outside the body. These include in vitro fertilization-transcervical embryo transfer (IVF-ET), gamete and zygote intrafallopian transfer (GIFT and ZIFT), frozen embryo transfer, and donor embryo transfer. Data abstracted from patient records and submitted to the CDC include patient demographics, medical history, and clinical information about the ART procedure and resultant pregnancies and births. Five to seven percent of clinics do not report data each year. Most of these are known to be small practices; thus, we estimate the data reported represent more than 95% of all ART procedures performed. For the present study, we selected ART procedures that were performed during the period 1996–2000 and resulted in a singleton live-birth delivery. The total study population included 62,551 infants, with a range of 9,078–16,422 per year.
We defined LBW and VLBW as 2,500 g or less and less than 1,500 g, respectively. We defined preterm delivery as gestational age less than 37 completed weeks. We calculated gestational age as date of birth minus date of oocyte retrieval (and fertilization). If date of retrieval was missing, and for all frozen embryo procedures, gestational age was calculated as date of birth minus date of embryo transfer. For comparability with the general population, we adjusted for date of theoretical last menstrual period (LMP) by adding 14 days to our gestational age estimate. Preterm LBW was defined as gestational age less than 37 weeks and birth weight of 2,500 g or less. Term LBW was defined as gestational age 37 weeks or greater and birth weight of 2,500 g or less.
Data used to calculate gestational age were collected in a comparable manner in all years of the study. Data collection for birth weight underwent revision between the 1998 and 1999 data collection periods. From 1996 to 1998, birth weight was collected as a categorical variable in 500-g increments up to 2,500 g and an additional category of greater than 2,500 g. In 1999 and 2000, birth weight was collected as a continuous variable, with options for entering grams, pounds, and ounces, or ounces only. For this analysis, all birth weights collected in 1999 and 2000 were converted to grams. We considered the possibility that changing the variable from categorical to continuous might have impacted its validity over time. We examined data from a separate study underway in which birth certificate data were obtained for ART infants born to Massachusetts resident mothers in 1997–2000. Preliminary analyses suggest high (> 90%) concordance rates between singleton birth weights reported in the ART registry and those reported on the birth certificate in both early (1997–1998) and late (1999–2000) time periods (unpublished data).
We examined secular trends for LBW, VLBW, preterm, preterm LBW, and term LBW among all ART singleton infants reported to the registry for 1996 to 2000 and among subsets based on the type of ART procedure. Procedure type was classified as 1) transferred embryos created from the patient's oocytes fertilized during the current procedure (fresh, nondonor), 2) transferred embryos created using oocytes from a woman serving as an egg donor fertilized during the current procedure (fresh, donor), and 3) transferred embryos previously fertilized (using either patient or donor oocytes) and frozen until the current procedure (thawed). Within each group we calculated the relative change in each outcome from 1996 to 2000 and the χ2 test for trend.
More detailed analyses of the risks for each outcome among a subset of the infants born after an ART treatment in 2000 were performed. These analyses included stratification on maternal and ART treatment characteristics, and comparison of observed numbers of adverse outcomes among ART singletons with expected numbers based on the general U.S. population of singleton births, with adjustment for potential confounding factors. For these analyses, our original study population was 16,422 infants from 380 clinics. We restricted the sample to ensure complete data for key outcome and adjustment factors and homogeneity in ART type. Because maternal race/ethnicity was an important adjustment factor but was incompletely reported in some clinics, we first selected infants from clinics with less than 20% missing data for this variable (N = 9,145 infants from 294 clinics). We further limited the sample to infants conceived using fresh, nondonor embryos, IVF-ET (ie, procedures with transfer to the fallopian tubes were excluded),and gestation by the intended mother (ie, procedures using a gestational surrogate were excluded). This further restriction to obtain a more homogeneous subset of ART births reduced our sample to 6,709. Finally, we excluded infants with maternal age less than 20 or more than 44 years (n = 12), missing or out-of-range birth weight data (n = 23), missing or out-of-range gestational age data (n = 101), missing maternal parity (n = 4), and missing maternal race (n = 192). Our final ART study population was 6,377 infants.
For each of the 5 outcomes of interest, we assessed variations in risk by maternal, treatment, and pregnancy factors. Factors evaluated included maternal age, parity, race/ethnicity, parental infertility diagnosis, use of intracytoplasmic sperm injection (ICSI), use of assisted hatching, number of days in embryo culture, supernumerary embryos cryopreserved for future use (a marker for high embryo quality independent of embryos transferred), and number of fetal hearts observed on early ultrasound (ie, pregnancy plurality). Intracytoplasmic sperm injection, which is used often in male-factor infertility, involves injecting a single sperm directly into the oocyte. Assisted hatching includes various treatments in which chemicals, lasers, or mechanical means are used to create an opening in the zona pellucida of the embryo so that the implantation potential might be increased.
We compared the observed numbers for each outcome among infants in our final ART study population with expected numbers. Expected numbers were calculated using a referent population from the 2000 U.S. natality public use computer file.14 From this file we selected singleton births with a maternal age between 20 and 44 years, maternal race/ethnicity of non-Hispanic white, non-Hispanic black, Hispanic, or Asian, and no missing data for parity. Maternal age, race/ethnicity, and parity were our primary adjustment factors. The restrictions to specific groups of age and race were made because of small samples in other categories for either the natality file (age above 44) or the ART study population (age below 20 and other race/ethnicity groups, such as Native American). To provide comparability in gestational age estimates between the referent population and the ART population, we also limited our selection of births from the natality file to those with maternal initiation of prenatal care in the first trimester and a gestational age estimate based on LMP. From this referent group of births, we computed rates for each of the 5 outcomes within strata based on maternal age, race/ethnicity, and parity (48 strata in all). These rates were applied to the distribution of the ART study population on these same factors to compute expected numbers. We computed standardized risk ratios for each outcome and calculated 95% confidence intervals for each estimate.
Slight differences between the natality and ART registry files in data definitions, collection, and categorization for the 3 adjustment factors should be noted. Maternal age was based on age at delivery in the natality file and age at conception (ART treatment) in the ART registry. Parity was based on previous live births in the natality file and previous births (both live and stillbirths) in the ART registry. Maternal race and Hispanic origin were separately collected on birth certificates and then combined as a single variable. In the ART registry, race/ethnicity was collected as a single categorical variable. We do not believe these differences in collection and classification had an appreciable effect on the calculation of expected numbers.
We also calculated risk ratios for selected subsets of our ART study population. Because it is plausible that ART singletons were more likely than singletons in the general population to have been from pregnancies that originated as multiple gestations with subsequent reduction of one or more fetuses, we separately examined the subset of ART singletons with only one fetal heart documented in early pregnancy. We also examined subsets based on the 2 most common parental infertility diagnoses, tubal factor and male factor. For both of these subsets, we selected infants with only a single diagnosis reported. The tubal factor group was considered the most likely ART subset to have been conceived with healthy gametes (ie, no reports of ovarian abnormalities, diminished ovarian reserve, or male factor infertility). The male factor group was considered the most likely subset to have been gestated by a woman without an underlying infertility abnormality. Finally, we examined several subsets based on specific treatment characteristics to disentangle some of the heterogeneity in ART treatment. Accordingly, we separately evaluated infants conceived with IVF only, ie, without the more invasive ICSI and assisted hatching procedures. We also separately evaluated infants conceived in ICSI procedures (a group of special interest because of the rapid growth of this treatment), procedures with supernumerary embryos cryopreserved (an indication that the embryos transferred were deemed of good quality), procedures with embryo culture for 3 days (the current standard of care for embryo culture), and procedures with embryo culture for 5 days (extended culture to the blastocyst stage).
This study was approved by the Institutional Review Board at CDC.
The number of singleton infants reported to the ART registry increased each year from 1996 to 2000; the total increase was 81% (Table 1). Increases were observed among all procedure types. The rise in ART singletons paralleled increases in total ART procedures performed and associated live-birth deliveries during the same time period (data not shown). The proportion of singletons born LBW and term LBW declined for all ART types (Table 1). Overall, LBW declined 31%, from 13.3% to 9.2%, and term LBW declined 64%, from 6.6% to 2.4%. The percent VLBW declined 12% overall, although one ART type (thawed embryos) had a nonsignificant 42% increase. There was little change in the proportion of singletons born preterm (13.8% versus 14.1% in 1996 and 2000, respectively) or both preterm and LBW (6.6% versus 6.7%), except for the subset conceived with thawed embryos. For this group, the trends were similar to that observed with VLBW.
Singleton infants in our final ART study population selected for in-depth analysis (n = 6,377) were comparable with the total population of singleton infants reported from fresh, nondonor ART procedures in 2000 on maternal and treatment variables (Table 2). For the vast majority of infants in both groups, maternal age was 30 to 39 years, there were no prior births, and maternal race was non-Hispanic white. The most common single infertility conditions were tubal factor and male factor; additionally multiple diagnoses were commonly reported. For over half of the infants, ICSI had been used for fertilization, and approximately 40% were conceived from treatments involving assisted hatching of transferred embryos. For about 70%, embryos were cultured for 3 days before transfer. Supernumerary embryos were available and cryopreserved in about one third of the procedures from which these infants were conceived. For over 97% (data not shown), 2 or more embryos had been transferred; however, only 9% had more than 1 fetal heart in early pregnancy. The risks for the perinatal outcomes of interest were also comparable between the total population of singletons conceived in fresh, nondonor ART in 2000 (Table 1) and our final study population (Table 3).
In comparison with the singletons in the referent population, ART singletons had increased risks for all 5 perinatal outcomes (Table 3). We observed some variation in risk across ART infant subgroups based on maternal and treatment characteristics; however, risks in specific subgroups were nonetheless increased in comparison with the referent population. In general, there was little variation in risk of any outcome according to maternal age. Lower risks were observed with a parity of 1 and a maternal race/ethnicity of non-Hispanic white. The variation by parity and race is in keeping with known variation in the general U.S. population and was, thus, also observed in the referent population (data not shown).
Among ART infants significant variations in risks of preterm delivery and preterm LBW were also observed according to parental infertility diagnosis; the lowest risks were observed in the male-factor subgroup (Table 3). In keeping with these results, infants from ICSI procedures had decreased risks for all outcomes but term LBW. Infants from procedures with presumed high-quality embryos (ie, supernumerary embryos were cryopreserved) had an increased risk for LBW. Infants from pregnancies with more than 1 fetal heart had substantially higher risks for all outcomes, although the difference did not reach statistical significance for VLBW.
After adjustment for maternal age, parity, and race/ethnicity, infants from the ART study population had significantly elevated risks for all outcomes—LBW, VLBW, preterm delivery, preterm LBW, and term LBW (Table 4). Risk ratios for each of these 5 outcomes remained elevated when the analysis was restricted to infants with only 1 fetal heart in early pregnancy, parental infertility diagnosis of male factor, parental infertility diagnosis of tubal factor, conception using IVF with no ICSI or assisted hatching, conception with ICSI, conception in a procedure with supernumerary embryos cryopreserved, embryo culture for 3 days, and embryo culture for 5 days. However, in 5 (of 45) subsets with smaller sample sizes, confidence intervals overlapped 1.0.
We previously reported that singletons conceived with ART in 1996 and 1997 had a greater than 2-fold increase in term LBW compared with the expected rate adjusted for age and parity.2 The present study demonstrates that, by 2000, the absolute risk for term LBW among ART singletons had declined by 64%. Moreover, although the risk for term LBW was still significantly increased above expected rates, the magnitude of the increase was less than that previously reported. In 2000, term LBW was moderately increased (40%) among ART singletons compared with the expected rate adjusted for age, parity, and race/ethnicity.
The reasons for the decline in term LBW are unclear. A similar trend was observed for all ART types. Moreover, detailed analyses of the 2000 data do not reveal any subset based on patient or treatment characteristics that approach the high rate of term LBW (6.6%) observed in 1996. Thus, the available data do not illuminate a particular change in either the patient population undergoing ART or the specific aspects of this population's treatment that are responsible for the change in risk. However, the ART registry captures only limited patient and treatment variables. For example, the ART registry does not include data on some maternal characteristics that are strongly associated with fetal growth, such as maternal body mass index and weight gain.15 Additionally, several changes in ART treatment have occurred over the time period of interest that we were not able to evaluate. One example is the increased focus on techniques such as ultrasound-guided embryo transfer. Several randomized studies have demonstrated that ultrasound-guided transfer results in increased implantation and pregnancy rates.16 It is conceivable that more optimal embryo placement might lead to a more optimal site for implantation and placentation, which could lead to improvements in fetal growth. Previous studies have demonstrated that placentas from ART pregnancies had increased pathologic features compared with naturally conceived pregnancies.17,18 Finally, the trend might in part reflect a change in obstetric practice, such as closer monitoring and intervention before term for pregnancies with an indication of fetal growth restriction. A recent Canadian study suggests this may be related to the increase in average birth weight among term infants in that country.19
Although term LBW declined, the risk for preterm LBW was stable and remained increased in comparison with expected rates. The greater risks for LBW and preterm delivery among singletons conceived with ART have been hypothesized to be related to the underlying infertility among women using ART.20 Our results of slightly reduced risks for the subset of infants born to couples with male factor as the only infertility diagnosis suggest that part of the association between ART and preterm delivery might be explained by maternal infertility. However, risks in the male-factor subset were still elevated in comparison with the general population of singletons born to nonteenaged mothers in the United States, which served as our referent population. Thus, it appears that part, but not all, of the elevated preterm risk is explained by the underlying infertility, and part remains unexplained and may be related to a treatment effect. As in other analyses, the risk ratios in the male-factor subset were most pronounced for the most restrictive preterm outcomes, preterm LBW and VLBW, rather than for the more general category of preterm delivery (which included many normal birth weight [50%] infants).
We were unable in this analysis to identify a specific treatment factor that may underlie the preterm risk. Infants conceived with freshly fertilized embryos, thawed embryos, maternal oocytes, donor oocytes, ICSI, IVF without ICSI, 3 days in embryo culture, and 5 days in embryo culture were all at increased risk for preterm delivery, preterm LBW, and VLBW. It is possible that the risk is related to some aspect of treatment common to all or most ART procedures. ART pregnancies may be different from naturally conceived pregnancies in several ways. Ovarian hyperstimulation and administration of hCG and/or progesterone for luteal support may result in nonphysiological levels of estrogen, progesterone, and relaxin, which in turn may have effects on endometrial and cervical tissues and placentation and/or may impair embryo-endometrial synchronization.21–26 The in vitro environment in which embryos develop can affect various embryo parameters27 and might also impact subsequent in vivo development of the embryo and fetus.
It is feasible that part of the preterm risk in ART singletons is related to maternal exposures such as cigarette smoking, maternal stress, subclinical pelvic infection, deficiencies in micronutrients such as folate, or environmental exposures such as pesticides. To explain the excess preterm risk associated with ART, such a factor would need to be increased, not only among women with a diagnosis of infertility, but also among women who sought ART because their partners had male-factor infertility. This is plausible with many of the above factors; however, the data are not collected in the ART registry.
Finally, the possibility exists that increased monitoring and intervention among ART pregnancies may lead to a higher rate of medically indicated preterm deliveries and that these births are accounting for the preterm excess. We cannot evaluate this hypothesis directly because the ART registry does not capture detail on type of preterm birth, induction or cesarean delivery. However, as noted above, the increase in preterm risk among ART singletons is not solely attributable to moderately preterm births but is actually greatest among very preterm infants.
This study had many strengths, most notably the large sample that allowed us to adjust for important potential confounders and to examine specific infertility and treatment subsets. This study also must be interpreted in the context of certain limitations. We lacked data needed to explore specific mechanisms for the effects observed, including data on maternal progesterone, estrogen and relaxin levels, embryo culture constituents, embryo quality grade, maternal exposures associated with preterm delivery, and type of preterm delivery. Because the ART registry data set is based on ART procedures performed each year and patients undergoing more than one procedure cannot be linked, our evaluation of secular trends may not be based on completely independent samples of births across years.
This study provides evidence that, from 1996 to 2000, there was little change in the risk for preterm LBW among singletons born after assisted reproductive technology; however, term LBW declined. Nonetheless, ART singletons had greater than expected risks for all adverse perinatal outcomes evaluated, including term LBW. Further study of the mechanisms for these effects may help to clarify the exact roles of the underlying infertility, other maternal-fetal exposures, obstetric practice, and direct effects stemming from the ART treatment, which are responsible for this risk.
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© 2004 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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