Background The increased risk of low birth weight associatedwith the use of assisted reproductive technology has been attributedlargely to the higher rate of multiple gestations associatedwith such technology. It is uncertain, however, whether singletoninfants conceived with the use of assisted reproductive technologymay also have a higher risk of low birth weight than those whoare conceived spontaneously.
Methods We used population-based data to compare the rates oflow birth weight (2500 g) and very low birth weight (<1500g) among infants conceived with assisted reproductive technologywith the rates in the general population.
Results We studied 42,463 infants who were born in 1996 and1997 and conceived with assisted reproductive technology andused as a comparison group 3,389,098 infants born in the UnitedStates in 1997. Among singleton infants born at 37 weeks ofgestation or later, those conceived with assisted reproductivetechnology had a risk of low birth weight that was 2.6 timesthat in the general population (95 percent confidence interval,2.4 to 2.7). The use of assisted reproductive technology wasassociated with an increased rate of multiple gestations; however,its use was not associated with a further increase in the riskof low birth weight in multiple births. Among twins, the ratioof the rate of low birth weight after the use of assisted reproductivetechnology to the rate in the general population was 1.0 (95percent confidence interval, 1.0 to 1.1). Infants conceivedwith assisted reproductive technology accounted for 0.6 percentof all infants born to mothers who were 20 years of age or olderin 1997, but for 3.5 percent of low-birth-weight and 4.3 percentof very-low-birth-weight infants.
Conclusions The use of assisted reproductive technology accountsfor a disproportionate number of low-birth-weight and very-low-birth-weightinfants in the United States, in part because of absolute increasesin multiple gestations and in part because of higher rates oflow birth weight among singleton infants conceived with thistechnology.
Infants who have low birth weight, either because of early deliveryor because of fetal growth restriction, are at increased riskfor short- and long-term disabilities and death.1,2 The useof assisted reproductive technology is an important contributorto the rate of low birth weight in the United States becauseit is associated with a higher rate of multiple birth,3,4 which,in turn, is associated with low birth weight.5 By 1997, theuse of assisted reproductive technology accounted for more than40 percent of triplets born in the United States.4 In addition,studies have suggested that there is a higher rate of low birthweight among singleton infants conceived with assisted reproductivetechnology than among naturally conceived singleton infants6,7,8or among all infants in the general population.9,10,11,12,13However, these studies had methodologic limitations. In particular,they did not address the issue of whether infants born as singletonswere conceived as part of a multiple gestation that was laterreduced either medically or spontaneously to a singleton pregnancy.
In addition, it remains unclear whether the risk of low birthweight among singleton infants conceived with assisted reproductivetechnology is a direct effect of the procedure involving suchtechnology14,15 or reflects some other factor related to theunderlying infertility of the couples who conceive using theseprocedures.16,17,18 Studies have been limited by small samplesizes and lack of data regarding such potentially confoundingvariables as the factors causing infertility and their severity.
We used population-based data from records of procedures performedwith assisted reproductive technology in the United States tocompare the risk of low birth weight among infants conceivedwith assisted reproductive technology with that found in thegeneral population. The large sample and detailed data on theprocedures and resulting pregnancies provided an opportunityto analyze outcomes according to several important factors,including the number of infants born, the number of fetusesearly in the pregnancy, cause of infertility, and factors involvedin treatment.
Methods
Study Population
Clinics and medical practices in the United States are requiredto report data on every procedure involving assisted reproductivetechnology to the Centers for Disease Control and Prevention(CDC).19 Each year, the Society for Assisted Reproductive Technologycollects data on such procedures performed in clinics in theUnited States and provides these data to the CDC. Proceduresinvolving assisted reproductive technology are defined as proceduresfor the treatment of infertility in which both oocytes and spermare handled outside the body; these include in vitro fertilizationwith transcervical embryo transfer, gamete and zygote intrafallopiantransfer (in which gametes or zygotes are transferred into thefallopian tube rather than the uterus), frozen-embryo transfer,and donor-embryo transfer. Data abstracted from patients' recordsand submitted to the CDC include each patient's demographiccharacteristics and medical history, as well as clinical informationon the procedures performed and resultant pregnancies and births.In 1996, 300 clinics reported more than 60,000 procedures; in1997, 335 clinics reported more than 70,000 procedures. Fiveto 7 percent of clinics that were in operation during theseyears did not report data, despite the federal requirement;because most of these were known to be small practices, we estimatethat the data reported represent more than 95 percent of allprocedures performed with the use of assisted reproductive technology.
We included in the present analysis infants conceived throughprocedures performed in 1996 and 1997 in which the mother wasbetween 20 and 60 years of age. Of 136,972 procedures, 23 percent(31,767) resulted in the delivery of one or more liveborn infants.Because some of these were multiple-birth deliveries, the totalnumber of infants was 45,886. Although a delivery could includeboth liveborn and stillborn infants, we excluded from our analysisthe 182 stillborn infants. A total of 3241 infants with missingdata on birth weight were also excluded. Our final sample included42,463 infants conceived with assisted reproductive technology.
Internal Comparisons
We classified infants according to the number at birth (singleton,twin, triplet, or quadruplet or higher-order birth). Althoughonly liveborn infants were included in this study, the assignmentof the number born was based on the total number of livebornand stillborn infants delivered. Within each birth-number groupwe examined the risk of low and very low birth weight. Birthweight was recorded as a categorical variable in 500-g strata.We defined low birth weight as 2500 g or less and very low birthweight as less than 1500 g.
We assessed variations in risk according to maternal and treatment-relatedfactors, using stratification and multivariable logistic regression.The factors we evaluated included the number of fetal heartsobserved on early ultrasonography (i.e., the number of fetusesin the pregnancy), maternal age, parity, primary cause of infertility,previous procedures involving assisted reproductive technology,and the type of procedure that resulted in the current conception.Procedures were classified according to whether the embryoshad been fertilized during the current procedure (i.e., werefresh) or had been previously fertilized and frozen until thecurrent procedure and whether the source of the oocytes wasthe mother herself (nondonor) or another woman serving as anoocyte or embryo donor. In addition, procedures in which a womanother than the mother served as a gestational carrier or surrogatewere classified separately. Thus, the procedure was categorizedas involving fresh embryos and nondonor oocytes, frozen embryosand nondonor oocytes, fresh embryos and donor oocytes, frozenembryos and donor oocytes, or a gestational carrier. We consideredseparately whether intracytoplasmic sperm injection (a procedurein which a single sperm is injected directly into the oocyte)was used in procedures involving fresh embryos and nondonoroocytes and those involving fresh embryos and donor oocytes.
External Comparison
We compared the observed numbers of low-birth-weight and very-low-birth-weightinfants conceived with assisted reproductive technology withexpected numbers. Expected numbers were calculated with theuse of the public-use computer file containing the 1997 birth-certificatedata for the United States (on 3,389,098 infants born to womenwho were 20 years of age or older)20 and were adjusted to matchthe age and parity distributions for women who conceived withassisted reproductive technology. We computed standardized ratiosfor low birth weight and very low birth weight by dividing theobserved numbers by the expected numbers and calculated 95 percentconfidence intervals for each estimate.21
To rule out the possibility that the reduction of gestationsthat had initially involved multiple fetuses might explain ahigher rate of low birth weight in singletons, we performedsecondary analyses that included only those births in whichthe number of fetal hearts noted on ultrasonography did notexceed the number of infants who were born. (Data were not availableto permit the differentiation of spontaneous reductions frommedically induced reductions.) To separate the effects of treatmentfrom underlying characteristics of the patients or embryos,we performed several additional analyses in this subsample.In one analysis, we restricted the sample to infants conceivedwith the use of donor oocytes among couples without a diagnosisof male-factor infertility, since these infants were consideredmost likely to have been conceived with healthy gametes. Ina second analysis, we restricted the sample to infants bornto couples with a diagnosis of male-factor infertility, sincewomen in this subgroup were considered unlikely to have uterineor other infertility-related disease. And in a third analysis,we restricted the sample to infants who had been carried bya gestational surrogate, since these surrogates were presumablyhealthy women.
Analyses were conducted separately for singletons and twins.In addition, we subdivided low-birth-weight infants into termand preterm infants. Preterm delivery was defined as deliveryat less than 37 completed weeks of gestation. We calculatedgestational age as the interval from the date of oocyte retrievaland fertilization to the date of birth. For procedures performedwith the use of frozen embryos and for other procedures forwhich the date of oocyte retrieval was missing, the gestationalage was calculated as the interval from the date of embryo transferto the date of birth. To make the estimates comparable withthose in the general population, we computed the estimated postmenstrualage (the age according to the last menstrual period) as thegestational age in days plus 14. Term low birth weight was definedas a weight of 2500 g or less with delivery at term; pretermlow birth weight was defined as a weight of 2500 g or less withpreterm delivery.
To assess the contribution of the use of assisted reproductivetechnology to low birth weight in the United States, we examined20,369 infants from our study population who were born in 1997;some had been conceived with assisted reproductive technologyin 1996 and some in 1997. For singleton infants, twins, andinfants from higher-order multiple births, we divided the numberof low-birth-weight and very-low-birth-weight infants conceivedwith assisted reproductive technology by the total number oflow-birth-weight and very-low-birth-weight infants born to women20 years of age or older in the United States in 1997.
This study was approved by the institutional review board ofthe CDC; in accordance with federal regulations, the requirementto obtain informed consent was waived for this retrospectiveanalysis.
Results
The study population was similar to the total population ofwomen treated with assisted reproductive technology in termsof the characteristics of the women and the infertility treatmentthey received (Table 1). However, some factors associated withhigher success rates for assisted reproductive technology —an age of less than 35 years, previous deliveries, no previousprocedures involving assisted reproductive technology, and theuse of fresh embryos (particularly fresh donor embryos) —were slightly more common among the study population.
Table 1. Maternal Characteristics and Characteristics of Assisted Reproductive Technology Used.
A total of 43 percent of the infants in the study populationwere singletons, 43 percent were twins, 12 percent were triplets,and 1 percent were quadruplets or higher-order multiples. Thepercentage of infants with low birth weight varied from 13.2percent among singletons to almost 100 percent among quadrupletsor higher-order multiples. The percentage of infants with lowbirth weight varied with maternal characteristics and treatment-relatedfactors (Table 2). Singletons were more likely to have low birthweight if there had been more than one fetal heart on earlyultrasonography, and twins were more likely to have low birthweight if there had been more than two fetal hearts.
Table 2. Percentage of Infants with Low Birth Weight (2500 g) among Singletons, Twins, and Triplets Conceived with Assisted Reproductive Technology in 1996 and 1997.
The rate of low birth weight was also higher among singletonsand twins born to nulliparous women and women who had no previousprocedures involving assisted reproductive technology (Table 2).Low birth weight was less common in infants conceived bycouples with male-factor infertility, conceived with intracytoplasmicsperm injection, or carried by a gestational surrogate. Amongtriplets, 90 percent or more of the infants had low birth weight,regardless of maternal characteristics or treatment-relatedfactors. The percentages of quadruplets and higher-order multipleswith low birth weight are not shown in Table 2 but were nearly100 percent in all groups. The results for singletons and twinswere materially unchanged after multivariable adjustment forthe maternal characteristics and treatment factors listed inTable 2.
The rate of very low birth weight ranged from 2.6 percent forsingletons to 66.9 percent for quadruplets or higher-order multiples.The rate of very low birth weight also varied with maternaland treatment-related factors, but to a lesser degree than therate of low birth weight did (data not shown).
As compared with all singleton infants born in the United Statesto women 20 years of age or older in 1997, singletons conceivedwith assisted reproductive technology in 1996 or 1997 were atincreased risk for low and very low birth weight (Table 3).When the analysis was restricted to infants who were carriedby a gestational surrogate the risk was no longer significantlyincreased, but there were relatively few infants in this group.
Table 3. Observed and Expected Cases of Low Birth Weight and Very Low Birth Weight among Singleton Infants Conceived with Assisted Reproductive Technology in 1996 and 1997.
We stratified low-birth-weight infants according to whetherthey were born at term or were preterm (Table 4). Singletoninfants conceived with assisted reproductive technology hada risk of term low birth weight that was more than twice thatof singleton infants in the general population, and they hada smaller but still significant increase in the risk of pretermlow birth weight. The risk of term low birth weight remainedelevated in analyses restricted to subgroups of the study populationconceived with presumably healthy gametes or carried by a presumablyhealthy woman. The risk of preterm low birth weight was no longerincreased in analyses restricted to study infants who had beencarried by presumably healthy women.
Table 4. Observed and Expected Cases of Low Birth Weight among Term and Preterm Singleton Infants Conceived with Assisted Reproductive Technology in 1996 and 1997.
Singletons conceived with assisted reproductive technology anddelivered at term tended to be born slightly earlier than singletonsin the general population (mean gestational age, 39.1 vs. 39.5weeks). We therefore further adjusted our analyses for the weekof gestation at delivery (37 to 41 or more) in addition to maternalage and parity. This adjustment did not substantially changeour findings (adjusted term-low-birth-weight ratio, 2.4; 95percent confidence interval, 2.3 to 2.6).
Among twins conceived with assisted reproductive technology,the risks of both term and preterm low birth weight were similarto those in the general population of twins. The ratio of therate of low birth weight at term among twins conceived withassisted reproductive technology to the rate among all twinsborn at term was 1.0 (95 percent confidence interval, 1.0 to1.1).
The 20,369 infants conceived with assisted reproductive technologyand born in 1997 represented 0.6 percent of the 3,389,098 infantsborn to women 20 years of age or older in the United Statesin that year. However, we estimate that the use of assistedreproductive technology accounted for 3.5 percent of the infantswith low birth weight and 4.3 percent of the infants with verylow birth weight born to women in this age group. The excesseswere due in large part to the increased number of infants frommultiple births who were conceived with assisted reproductivetechnology. However, the increased rates of low birth weightamong singletons conceived with assisted reproductive technologyalso played a small part (0.6 percent of low-birth-weight singletonswere conceived with assisted reproductive technology, as comparedwith the 0.2 percent that would have been expected).
Discussion
Singleton infants conceived with assisted reproductive technologywere at increased risk for low birth weight at term relativeto singletons in the general population of the United States.This risk was not explained by known differences between thetwo populations in the distribution of maternal age, maternalparity, or gestational age at delivery. In addition, there wasan increased risk even in analyses in which the sample was restrictedto infants from pregnancies that had not originated as multiplegestations, infants conceived with gametes from apparently fertilepersons, and infants from pregnancies carried by women who wereunlikely to have an underlying uterine or other infertility-relateddisease. Thus, this study suggests that the increased risk oflow birth weight in singleton infants born at term who wereconceived with assisted reproductive technology may be directlyrelated to such treatments for infertility.
Singletons who were conceived with assisted reproductive technologyalso had a moderately elevated rate of preterm low birth weight.However, increased risks were not observed among all subgroups;in particular, the risk was not increased among infants deliveredby a gestational carrier rather than the mother. These subgroupanalyses involved greatly reduced samples and must thereforebe interpreted cautiously. However, a possible explanation isthat the risk of preterm low birth weight associated with assistedreproductive technology may be related to some underlying conditionin the women who undergo procedures involving such technologyrather than to the procedures themselves.
The mechanisms underlying the association between the use ofassisted reproductive technology and low birth weight amonginfants born at term remain unclear and warrant further research.The use of human menopausal gonadotropin as part of proceduresinvolving assisted reproductive technology has been associatedwith increases in insulin-like growth factor–binding protein1; this protein has been linked to intrauterine growth restriction.22During pregnancies initiated with assisted reproductive technology,altered levels of other endometrial proteins and increased ratesof structural abnormalities of the placenta have also been found.23,24These factors may also contribute to growth restriction. A lessdirect mechanism is also possible. The use of assisted reproductivetechnology has been linked to such maternal complications aspregnancy-induced hypertension.25,26,27
Studies also suggest that women who have conceived with assistedreproductive technology are more likely to undergo electivecesarean section, resulting in deliveries that occur earlierthan those following spontaneous pregnancies.6,7,25,26,27 Wedid not have data on complications of pregnancy or type of delivery,but we did find that singletons conceived with assisted reproductivetechnology and born at term were delivered slightly earlierthan term singletons in the general population. Adjustment forthe week of gestation at delivery did not substantially reducethe risk ratio for low birth weight at term. We observed anexcess risk of low birth weight among the singletons conceivedwith assisted reproductive technology who were born at everyweek of gestation between 37 and 41 weeks.
Twins conceived with assisted reproductive technology and bornat term were not at higher risk of low birth weight than twinsin the general population. It is possible that the additionalrisk associated with the use of assisted reproductive technologyis negligible in twin pregnancies, which are already at highrisk. Twins conceived with the use of medications for ovarianstimulation but without assisted reproductive technology mayalso be at increased risk for low birth weight and may haveaccounted for a sizable proportion of twins in the general population.We do not have data on the use of these medications among themothers of the general birth cohort.
We did not compare the birth weights of triplets and higher-ordermultiples in our study population with those in the generalpopulation. More than 40 percent of the triplets and higher-ordermultiples in the general population were conceived with assistedreproductive technology, and the risk of low birth weight wasgreater than 90 percent among such infants in both groups.
We estimate that more than 3 percent of the low-birth-weightinfants and more than 4 percent of the very-low-birth-weightinfants born in 1997 were conceived with assisted reproductivetechnology — six times the proportions that would be expectedon the basis of the frequency of these procedures. These higher-than-expectedproportions are largely explained by the increased rate of multiplebirths. Although the use of assisted reproductive technologydid not appear to increase the already high risk of low birthweight among infants from multiple gestations, the increasedrisk of low birth weight among singletons conceived with assistedreproductive technology and delivered at term indicates thatinfants from both singleton and multiple births must be consideredin assessing the effect of assisted reproductive technologyon the rate of low birth weight in the United States.
We are indebted to the Society for Assisted Reproductive Technology(SART) for the use of its data-reporting system; and to SART,the American Society for Reproductive Medicine, and Resolve,the National Infertility Association, for their support.
Source Information
From the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta.
Address reprint requests to Dr. Schieve at the Division of Reproductive Health, Centers for Disease Control and Prevention, Mailstop K-34, 4770 Buford Hwy., NE, Atlanta, GA 30341, or at LJS9{at}cdc.gov.
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2500 g) and very low birth weight (<1500 g) among infants conceived with assisted reproductive technology with the rates in the general population. 
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