| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
ORIGINAL RESEARCH |
From the Departments of Research and Development, Obstetrics and Gynecology, and Reproductive Endocrinology, Kaiser Permanente; The Department of Preventive Medicine and Biometrics, the University of Colorado Health Sciences Center; and the Colorado Department of Public Health and Environment, Denver, Colorado.
Address reprint requests to: Robert McDuffie, Jr, MD Department of Obstetrics and Gynecology 20th Street Medical Campus 2045 Franklin Street Denver, CO 80205
 |
Abstract |
|---|
Top
 Abstract Materials and MethodsResultsDiscussionReferences |
|---|
Methods: This historic prospective study was conducted in a cohort of 13,151 women who delivered after 20 weeks’ gestation between October 1996 and December 1999. The study setting was a Colorado health maintenance organization. Cases were women who were pregnant as a result of exposure to treatment with either assisted reproductive technologies or ovulation induction in the absence of assisted reproductive technologies. The main outcome measure was multiple birth.
Results: There was a significant association between assisted conception and multiple birth. Compared with women with naturally conceived pregnancies, there was a 25-fold likelihood (95% confidence interval 18, 35, P < .001) of multiple birth among women exposed to any of those treatments. In the total cohort the proportion of multiple births attributable to those treatments was 33%. After adjusting for the use of assisted conception and other covariates, we found no association between advanced maternal age and multiple birth.
Conclusion: In this cohort, assisted reproductive interventions were strongly associated with multiple birth. Although a higher proportion of older women sought assisted reproductive technologies, we did not find an independent relationship between advanced maternal age and multiple birth. The increasing number of multiple births attributable to assisted conception raises public health concerns regarding multiple gestation-related maternal and infant morbidities.
The number of twins born in the United States has increased by 42% since 1980. Higher-order births (triplets or more) have more than doubled, from 81.4 per 100,000 in 1991 to 173.6 per 100,000 in 1997.1 Similar trends have been reported in Great Britain2,3 and elsewhere.4 Colorado’s vital statistics showed a 60% increase in multiple births between 1975 and 1997.5 Twins and higher-order births contribute disproportionately to neonatal mortality and morbidity rates. Recent United States data suggest that multiple births are almost six times more likely than singletons to be born preterm and approximately ten times more likely than singletons to be of low birth weight (LBW).1 In Colorado, approximately 20% of all LBW infants were associated with multiple gestation.6 Compared with singletons, the relative risk (RR) of severe handicap among the postneonatal survivors of twin and triplet births has been reported to be 1.7 and 2.9 respectively.7
Multiple births have been reported to occur with greater frequency in older women.8 Race,9 parity,10 and genetic factors11 have also been reported as risk factors for multiple births. However, delay in child bearing, first observed in the post-World War II baby boom generation,12 cannot fully explain the steep increase in incidence of multiple births. It is thought that the increase in multiple births is largely a result of the use of ovulation-inducing agents and assisted reproductive technologies.13 Introduced in the late 1960s and 1970s, respectively, these interventions have provided new opportunities to achieve pregnancy in subfertile women and their partners.
The epidemiology of the factors contributing to multiple birth has thus changed in the past 3 decades primarily because of the availability of fertility-enhancing drugs and assisted reproductive technologies. There is, however, a paucity of literature that describes and explains the magnitude of the relative, attributable, and population-attributable risks of reproductive interventions for multiple pregnancy in recent birth cohorts. In the United States, birth certificate data currently do not contain information about whether a pregnancy was conceived spontaneously or was assisted.14 Although reporting of pregnancy success rates by clinics specializing in assisted reproductive technologies to the Society for Assisted Reproductive Technology15 has improved in the past decade, these data are limited to iatrogenic pregnancies resulting from assisted reproductive technologies. There is no comprehensive system of surveillance of pregnancies resulting from ovulation induction. Consequently, the overall public health impact of assisted conception in population-based cohorts is poorly understood.
We initiated this study in a cohort of 13,151 deliveries from a Colorado-based group model health maintenance organization. The objective of the study was to determine (using several measures of association) the contribution of ovulation induction and assisted reproductive technologies to multiple birth.
|
Materials and Methods |
|---|
|
Top
AbstractMaterials and MethodsResultsDiscussionReferences |
|---|
The study’s research questions were addressed using a retrospective study design.17 The outcome was multiple birth (twins or a higher-order birth). Cases (Table 1
) were defined as women who were pregnant as a result of exposure to treatment with either assisted reproductive technologies or ovulation induction in the absence of assisted reproductive technologies. For the purpose of this study, assisted reproductive technologies were defined as procedures that involved the laboratory handling of human oocytes or embryos.18 Most pregnancies resulting from assisted reproductive technologies were the consequence of in vitro fertilization (IVF). A small proportion resulted from gamete intrafallopian transfer and other assisted reproductive technology-related procedures. Clomiphene citrate and the human menopausal gonadotropins ([hMG] LH and FSH or FSH only) were the ovulation-inducing drugs studied. Controls were defined as women who were not exposed to these fertility treatments during this pregnancy (Table 1). Covariates included in the analysis were categorized as shown in Table 2.
|
|
2 or Fisher exact test. Statistics are presented with 95% confidence intervals (CI).
Multivariable logistic regression was used to determine the adjusted odds ratio (OR) of the primary explanatory variables (clomiphene citrate, hMG, and assisted reproductive technologies) for multiple pregnancy and to test for significant confounding. The OR was used as an approximation of the RR. Initially, a full multivariable logistic regression model was constructed with the covariates and the variable "any assisted reproductive treatment" defined as treatment with clomiphene citrate, hMG, or assisted reproductive technologies. As the three treatments were independent of one another (ie, each subject had only one of these treatments in this pregnancy), the adjusted ORs of the primary explanatory variables for multiple birth were then calculated in individual models containing one primary explanatory variables and the covariates shown in Table 3. To assess confounding we reintroduced each variable into the model with the primary explanatory variable. A change in the parameter estimate of the primary explanatory variable of greater than 10% was considered evidence of confounding.
|
|
Results |
|---|
|
Top
AbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Proportions of mothers who had assisted compared with unassisted births are shown in Table 1
. Among the multiple births, 88 (36%) were iatrogenic and 156 (64%) were spontaneous. The mean maternal age ± standard deviation [SD] of the cohort was 28 ± 6 years. The mean maternal age (33 ± 6 years) was higher among iatrogenic multiple births compared with the mean maternal age (28 ± 6 years) among spontaneous multiple births. It is of interest that the mean maternal age of women who received assisted reproductive technologies was 37 ± 5 years compared with a mean maternal age of 31 ± 5 years for clomiphene citrate and 33 ± 4 years for hMG users. In this study 14% of all women were over 35 years. In 1997, Colorado vital statistics reported that 14.3% of women in Colorado were over 35 years of age.5 The mean parity in the study population was low at 0.9 ± 1. Only 6.5% of the cohort had a parity of three or greater.
Regardless of whether subjects were cases or controls, there was a striking contrast in the use of assisted reproductive interventions among mothers who had a multiple compared with a singleton birth. Clomiphene citrate, hMG, and assisted reproductive technologies were used in 16%, 5.3%, and 14.8% of multiple pregnancies, respectively. In contrast, the rate of clomiphene citrate, hMG, and assisted reproductive technology use among mothers of singleton deliveries was 1.8%, 0.3%, and 0.3%, respectively. These differences were significant (P = .001). Adverse pregnancy outcomes were also reported more often for multiple births compared with singleton births. Preterm delivery (before 37 weeks’ gestation), LBW (under 2500 g) and pregnancy-induced hypertension were found in 57%, 61%, and 12% of multiple births compared with 7.7%, 6.6%, and 3.2% of singleton births, respectively (P = .001).
The RR, attributable risk, and population attributable risk percentage for clomiphene citrate, hMG, and assisted reproductive technology for multiple pregnancy are shown in Table 1. The RR shows a highly significant relationship between these three primary explanatory variables and multiple birth. The attributable risk ranged from 13% for clomiphene citrate to 48% for assisted reproductive technologies. In the entire cohort of 13,151 women, 33% of multiple births was associated with any form of assisted reproductive intervention (population attributable risk percentage).
The full multivariable logistic regression model containing any assisted reproductive treatment and other selected covariates is shown in Table 2. In this model, treatment with any of these forms of assisted conception was significantly associated with multiple pregnancy (OR 25, 95% CI 18, 35, P < .001). The strong relationship between the clomiphene citrate, hMG, and assisted reproductive technologies and multiple pregnancy was confirmed in each model separately (Table 3). The adjusted OR for maternal age was not associated with a significantly higher risk of multiple pregnancy in any model (Tables 2 and 3) (among women who were not exposed to assisted pregnancy treatments [n = 12,768] there was no association between age, examined as a continuous variable, and multiple birth [OR 1, 95% CI 0.9, 1; P = .2]). However, we found that a high proportion (69%) of women who received assisted reproductive technologies were over 35 years of age. In contrast 35% of women who were treated with hMG were over 35 years, and 23% of clomiphene citrate users were over 35 years of age. Compared with nulliparas, women with higher parities had a higher risk of multiple birth (Tables 2 and 3). As shown in the clomiphene citrate, hMG, and assisted reproductive technology models, subjects with parities between one and three had significantly higher risk of multiple birth. Although the increase in OR continued for parity three or greater, it was significant only in the clomiphene citrate model, which could be due to small numbers in that group. In the individual models, maternal race and marital status were not significant risk factors for multiple birth; their adjusted ORs were close to one, so their results are not shown in Table 3. None of the covariates in Table 2 met our criteria for a significant confounding variable.
|
Discussion |
|---|
|
Top
AbstractMaterials and MethodsResultsDiscussionReferences |
|---|
The number of multiple pregnancies that can be attributed to assisted reproduction has been poorly described in population-based cohorts. Estimates are wide ranging. One recent study reported that 38% of the recent increase in triplet and higher-order gestations was due to assisted reproductive technologies.21 Corchia et al22 conducted a case-control study in Italy and found that the proportion of multiple births attributable to ovulation-inducing drugs was 9.7%.
We measured the association between assisted reproductive interventions and multiple pregnancy in several ways. We determined the strength of the relationship between three assisted reproductive interventions and multiple birth by calculating the RR. We found that clomiphene citrate, hMG, and assisted reproductive technologies each was strongly associated with multiple birth (Tables 1–3). The impact of assisted conception interventions on our cohort was then assessed using the attributable risk and the population attributable risk percentage. The attributable risk of a multiple birth among subjects who had any of those forms of assisted conception was 22%. It is noteworthy that among women exposed to assisted reproductive technologies, the attributable risk of a multiple birth was 48%.
The population attributable risk percentage (Table 1) shows that one-third of multiple births in the cohort were attributable to any form of assisted conception, with 14% attributable to assisted reproductive technologies. However, treatment with clomiphene citrate or hMG was responsible for just under 20% of the multiple births. This important contribution of ovulation-inducing drugs to multiple birth is an observation that has been obscured recently by the more intensive surveillance of pregnancies that result from assisted reproductive technologies. This high population attributable risk percentage for ovulation-inducing drugs supports recent findings by British3 and American investigators.23
Thus, a small subcohort (less than 3% of this cohort) of women who receive a reproductive intervention are driving the rising multiple birth rates. The public health implications are far reaching. In this study population for whom care was accessible and of good quality, there were high rates of prematurity and LBW among multiple births. This trend has important implications for health and human service policies. Survivors of these adverse neonatal outcomes often have long-term medical, educational, and occupational needs.24 Increasing rates of multiple pregnancy also raise concerns for multiple gestation–related maternal morbidities.25 In this study there was a higher prevalence of pregnancy-induced hypertension among women with multiple gestations compared with those with singletons.
More older women in this cohort sought assisted reproductive technologies and obtained the technology at specialized infertility clinics outside the health maintenance organization. Although 69% of women who had assisted reproductive technology were over 35 years of age, their advanced maternal age was not a significant independent risk factor for multiple birth. As shown in Tables 2 and 3, the crude (unadjusted) OR of women in the three upper strata of maternal age suggested a slight increase in risk of multiple birth. This association was reduced after adjustment for the exposures and other covariates. In addition, we did not find any association between maternal age and multiple birth among spontaneously conceived pregnancies. The mother’s exposure to assisted reproductive treatment was the most important contributing factor for multiple birth. Advanced maternal age traditionally has been viewed as a risk factor for multiple gestation. Our results regarding age do not support those studies.8 We believe it is most likely that older women seek infertility treatments. It is possible that our observations reflect changes in reproductive patterns (delayed child bearing, assisted conception) and behaviors (eg, multiple sex partners leading to a greater incidence of pelvic inflammatory disease) which have evolved during the past century.
In agreement with other studies10 and despite the low number of women with high parity in this cohort, we found that, compared with nulliparas, women of higher parity were at a slightly higher risk of multiple birth (we did not know whether earlier births were iatrogenic or spontaneously conceived). In fact, the multivariable logistic regression analysis (Tables 2 and 3) suggested that the crude ORs were an underestimate of the relationship between parity and multiple birth.
We regard this study as an opportunity to define the association between assisted reproductive interventions and multiple pregnancy in this cohort. The demographic and maternal age distribution were comparable to those reported in Colorado’s vital statistics (1997), suggesting that the study’s results can be generalized to the state of Colorado. There are limitations that should be mentioned here. We did not exclude from the cohort women who might have delivered more than once during the study period. Although the strength of the association between these treatments and multiple birth was highly significant, a larger number of subjects exposed to fertility treatments would have assured us of the precision of our estimates. The OR was not a good estimate of the RR in the hMG and assisted reproductive technology models (Table 3) because of low numbers and a high frequency of the outcome in the exposed group (Table 1). Further, several variables were uncontrolled, including maternal educational status, infertility history, previous fertility treatments, and dosage of ovulation-inducing drugs. There is also a possibility of misclassification bias among the spontaneously conceived pregnancies, because we relied on the mother’s report as to her pregnancy-related treatments. Nevertheless, this study provided valuable information about the magnitude of the association between assisted conception and multiple birth.
|
Footnotes |
|---|
Received June 5, 2000. Received in revised form August 28, 2000. Accepted September 13, 2000.
|
References |
|---|
|
Top
AbstractMaterials and MethodsResultsDiscussionReferences |
|---|
2. Botting BJ, MacDonald Davies I, MacFarlane AJ. Recent trends in the incidence of multiple births and associated mortality. Arch Dis Child 1987;62:941–50.[Abstract]
3. Levene MI, Wild J, Steer P. Higher multiple births and the modern management of infertility in Britain. Br J Obstet Gynaecol 1992;99: 607–13.[Medline]
4. Westergaard T, Wohlfahrt J, Aaby P, Melbye M. Population based study of rates of multiple pregnancies in Denmark, 1980–94. BMJ 1997;314:775–9.
5. Colorado Department of Public Health and Environment. Colorado Vital Statistics 1997. Denver Colorado: Colorado Department of Public Health and Environment, 1999.
6. Colorado Department of Public Health and Environment. Tipping the scales: Weighing in on Colorado’s low birth weight problem. Denver Colorado: Colorado Department of Public Health and Environment, 2000.
7. Luke B, Keith LG. The contribution of singletons, twins and triplets to low birth weight, infant mortality and handicap in the United States. J Reprod Med 1992;37:661–6.[Medline]
8. Waterhouse JAH. Twinning in twin pedigrees. Br J Soc Med 1950;4:197–216.
9. Pritchard JA, MacDonald PC, Gant NF. Williams obstetrics. 17th ed. Norwalk, Connecticut: Appleton-Century-Crofts. 1985;504–6.
10. Pettersson F, Smedby B, Lindmark G. Outcome of twin birth. Review of 1636 children born in twin birth. Acta Paediatr Scand 1976;65:473–9.[Medline]
11. White C, Wyshak G. Inheritance in human dizygotic twinning.N Engl J Med 1964;271:1003–5.
12. Stein ZA. A woman’s age: Childbearing and childrearing. Am Epidemiol 1985;3:327–42.
13. Keith L, Oleszezuk J. Iatrogenic multiple birth, multiple pregnancy and assisted reproductive technologies. Int J Gynaecol Obstet 1999;64:11–25.[Medline]
14. Luke B, Keith LG. The 1989 United States standard certificate of live birth: A critical commentary. J Reprod Med 1991;36:587–91.[Medline]
15. Meilkle SF, Danel I, Wilcox LS. Surveillance of assisted reproductive technology in the United States. An update. Int J Technol Assess Health Care 1999;15:11–4.[Medline]
16. Meikle SF, Lyons E, Hulac P, Orleans M. Rehospitalizations and outpatient contacts of mothers and neonates after hospital discharge after vaginal delivery. Am J Obstet Gynecol 1998;179:166–71.[Medline]
17. Elwood JM. Study designs which can demonstrate and test causation. Elwood JM, ed. Causal relationships in medicine: A practical system for critical appraisal. New York: Oxford University Press, 1988;12–3.
18. American Fertility Society. Revised minimum standards for in vitro fertilization, gamete intrafallopian transfer, and related procedures. Fertil Steril 1990;53:255–6.
19. Elwood JM. The results obtained from studies of causation. Elwood JM, ed. Causal relationships in medicine: A practical system for critical appraisal. New York: Oxford University Press, 1988;25–32.
20. Hennekens CH, Buring JE. Measures of disease frequency. In: Mayrent SL, ed. Epidemiology in medicine. 1st ed. Boston: Little, Brown, and Company, 1987:87–96.
21. Wilcox LS, Kiely JL, Melvin CL, Martin MC. Assisted reproductive technologies: Estimates of their contribution to multiple births and newborn hospital days in the United States. Fertil Steril 1996;65: 361–6.[Medline]
22. Corchia C, Mastroiacovo P, Lanni R, Mannazzu R, Curro V, Fabris C. What proporion of multiple births are due to ovulation induction? A register-based study in Italy. Am J Public Health 1996;86: 851–4.
23. Oleszczuk JJ, Keith D, Keith LG. Projections of population-based twinning rates through the year 2100. J Reprod Med 1999;44:913–21.[Medline]
24. Levene MI. Assisted reproduction and its implication for paediatrics. Arch Dis Child 1991;66:1–3.[Medline]
25. Gall SA, ed. Multiple pregnancy and delivery. St. Louis, Missouri: Mosby-Year Book Inc, 1996:18–20.
This article has been cited by other articles:
|
|
 |
|
  A. Pinborg IVF/ICSI twin pregnancies: risks and prevention Hum. Reprod. Update, November 1, 2005; 11(6): 575 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Carmichael, G. M. Shaw, C. Laurent, M. S. Croughan, R. S. Olney, E. J. Lammer, and for the National Birth Defects Prevention Study Maternal Progestin Intake and Risk of Hypospadias Arch Pediatr Adolesc Med, October 1, 2005; 159(10): 957 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Dabelea, J. K. Snell-Bergeon, C. L. Hartsfield, K. J. Bischoff, R. F. Hamman, and R. S. McDuffie Increasing Prevalence of Gestational Diabetes Mellitus (GDM) Over Time and by Birth Cohort: Kaiser Permanente of Colorado GDM Screening Program Diabetes Care, March 1, 2005; 28(3): 579 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Smulian, C. V. Ananth, W. L. Kinzler, E. Kontopoulos, and A. M. Vintzileos Twin Deliveries in the United States Over Three Decades: An Age-Period-Cohort Analysis Obstet. Gynecol., August 1, 2004; 104(2): 278 - 285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tiitinen, L. Unkila-Kallio, M. Halttunen, and C. Hyden-Granskog Impact of elective single embryo transfer on the twin pregnancy rate Hum. Reprod., July 1, 2003; 18(7): 1449 - 1453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Reefhuis, M. A. Honein, G. M. Shaw, and P. A. Romitti Fertility Treatments and Craniosynostosis: California, Georgia, and Iowa, 1993-1997 Pediatrics, May 1, 2003; 111(5): 1163 - 1166. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kallen, P. O. Olausson, and K. G. Nygren Neonatal Outcome in Pregnancies From Ovarian Stimulation Obstet. Gynecol., September 1, 2002; 100(3): 414 - 419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lynch, R. McDuffie Jr, J. Murphy, K. Faber, and M. Orleans Preeclampsia in Multiple Gestation: The Role of Assisted Reproductive Technologies Obstet. Gynecol., March 1, 2002; 99(3): 445 - 451. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
