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Potentially Preventable Excess Mortality Among Higher-Order Multiples

Salihu, Hamisu M. MD, PhD; Aliyu, Muktar H. MD, MPH; Rouse, Dwight J. MD, MSPH; Kirby, Russell S. MS, PhD; Alexander, Greg R. MPH, ScD


OBJECTIVE To estimate the level of potentially preventable excess mortality achievable by avoiding the creation of higher-order multiple gestation with assisted reproductive technologies.

METHODS This was a retrospective cohort study of multiple pregnancies delivered in the United States between 1995 and 1997 involving 304,466 twins, 16,068 triplets, 1448 quadruplets, and 180 quintuplets. We used the generalized estimating equation framework to compute adjusted relative risks for combined perinatal and infant mortality (early mortality). We then calculated potentially preventable excess mortality among higher-order gestations, using twins and triplets sequentially as the referent category.

RESULTS Early mortality increased significantly with each additional fetus in a dose-dependent fashion (P < .001), corresponding to relative risks (95% confidence interval) of 2.4 (2.2, 2.6) for triplets, 3.3 (2.5, 4.4) for quadruplets, and 10.3 (5.0, 21.4) for quintuplets. The creation of twin rather than quadruplet pregnancies would be associated with a substantially higher level of preventable excess mortality (70%) than the creation of triplet pregnancies (28%). By contrast, limiting quintuplets to twins or triplets did not exhibit a similar level of difference (89% versus 75%, respectively).

CONCLUSION Our findings support the need for regulating the number of transferred embryos that result in quadruplet and quintuplet pregnancies

Preventing higher-order multiple gestations would be associated with substantial reduction in excess early mortality in the United States.

Departments of Maternal and Child Health, Epidemiology, and Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama.

Address reprint requests to: Hamisu Salihu, MD, PhD, University of Alabama at Birmingham, Department of Maternal and Child Health, 1665 University Boulevard, Room 320, Birmingham, Alabama 35294; E-mail:

Received April 14, 2003. Received in revised form June 15, 2003. Accepted June 26, 2003.

There has been a dramatic rise in the incidence of multiple births in the United States over the last two decades. The frequency of twin births has doubled; that of triplets has increased six-fold, of quadruplets almost 12-fold, and of quintuplets six-fold.1 Two phenomena account for most of this rise: increased maternal age secondary to delayed childbearing, and the use of assisted reproductive technology.2,3

The burden of morbidity and mortality seems to increase substantially with each additional fetus in a multiple gestation. It is known that 90% of triplets are born preterm, and triplets and other higher-order births are 12 times as likely to die during the first year of life compared with singleton infants.4 As a result, there has been growing debate on the need to prevent higher-order multiple pregnancies.5,6 However, surrounding this issue is the lack of population-level information on the potential benefits (in terms of preventable mortality) of the avoidance of higher-order multiple gestation. Prevention of higher-order multiple gestation is feasible chiefly through two methods: transfer of fewer embryos7 and fetal reduction. A third possibility for reducing higher-order multiples is through less intensive ovarian stimulation.8

We do not address fetal reduction in this article, because it is not a primary prevention procedure, involves risks to the ongoing pregnancy,5 and is ethically controversial. Less intensive ovarian stimulation might reduce the occurrence of higher-order multiples, though only to a limited degree and at the expense of overall pregnancy rates.8 Our analysis is therefore based on the possibility of primary prevention by limiting the number of embryos transferred during assisted reproductive technology cycles. Although limiting the number of transferred embryos might result in lower pregnancy success rates, recent studies have demonstrated that when embryos are transferred at the blastocyst stage, the pregnancy success rates are very high.9,10 For instance, the transfer of only two such embryos results in a clinical pregnancy in up to 60% of women.9,10 Based on these high pregnancy success rates and the speculation that the procedure is likely to improve with more experience, we estimated the level of potentially preventable deaths that could occur by limiting the number of embryos transferred to either two or three.

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Data for this analysis were from the “Matched Multiple Birth File” assembled by the National Center for Health Statistics11 covering the period 1995–1997, the most recent for which matched and linked (birth linked to death) data for multiple deliveries in the United States were available. The file contains individual records of live births and fetal deaths involving multiple deliveries. Although the public-access version contains matched and linked information for twins and triplets only, the dataset that was made available to us upon request to the National Center for Health Statistics was matched and linked for higher-order pregnancies as well, with personal identifiers expunged. The completeness of this file is excellent (99%), and the procedures for quality control of the data are explained in detail elsewhere.12

We compared the following maternal sociodemographic characteristics among twin, triplet, quadruplet, and quintuplet pregnancies: maternal age, parity, race or ethnicity, marital status, education, level of prenatal care utilization, and smoking and drinking alcohol during pregnancy. Parity refers to the total number of pregnancies reaching at least 20 weeks that the mother had experienced and was classified into nullipara (0) and multipara (1 or more). Adequacy of prenatal care was determined with the revised graduated index algorithm13,14 and was categorized into adequate and inadequate prenatal care utilization. This index of prenatal care has been found to be more accurate than many others, especially in describing the level of prenatal care utilization among groups that are at high risk and therefore exposed to intense care (eg, multiple pregnancies).15 In this study, inadequate prenatal care utilization refers to women who either had missing prenatal care information, had prenatal care but at a suboptimal level, or had no prenatal care at all. The accuracy of all these aforementioned variables on the birth certificate has been validated in previous studies and found to be accurately reported.16,17

For this study, the main birth outcome of interest was early mortality, the components of which were the following: stillborn fetus (inutero demise at 20 or higher weeks' gestation), neonatal mortality (death of the newborn through the 27th day of life), and infant mortality (death within the first year of life).

The fact that siblings from the same pregnancy are subjected to similar prevailing conditions in the womb and are more or less equally affected by the same attributes that characterize the mother makes the application of conventional statistical techniques inappropriate, because they treat observations as though they are independent. To avoid this bias, we applied the generalized estimating equation18 to our data to adjust for dependence. We used PROC GENMOD 8.2 software (SAS Institute, Cary, NC) to generate random effect estimates that captured sibling correlations. All tests of hypothesis were two-tailed, with a Type 1 error rate fixed at 5%.

We calculated the preventive fraction, namely, the level of excess early mortality that could be prevented if higher-order multiples (quadruplets and quintuplets) were avoided and lower-order births (triplets and twins) created in their stead. The following formula was used19:

where PF = preventable fraction (or excess preventable mortality) and RR = adjusted relative risk (odds ratios). We computed two forms of PF. In one, we assumed a scenario in which higher-order multiples were replaced by twins; in the other, the assumed scenario was that they were replaced by triplets. Finally, we compared the relative benefits of both scenarios (quadruplets-to-twins versus quadruplets-to-triplets and quintuplets-to-twins versus quintuplets-to-triplets) in terms of the potentially preventable excess mortality. This study was approved by the Institutional Review Board of the University of Alabama at Birmingham (protocol number: X030527005).

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The data set contains a total of 326,231 individual multiple deliveries in the United States for the period 1995–1997. Of these, twins, triplets, quadruplets, and quintuplets comprised 94.4%, 5.1%, 0.5%, and 0.07% respectively. Complete matching and linkage was achieved for 322,162 (98.8%) of the records. These represent 304,466 twins, 16,068 triplets, 1448 quadruplets, and 180 quintuplets. The distribution of selected sociodemographic characteristics of the mothers is shown in Table 1.

Table 1

Table 1

Figure 1 displays crude mortality rates for twins, triplets, quadruplets, and quintuplets; the absolute counts of early mortality and its components are shown in Table 2. Table 3 summarizes the adjusted estimates for early mortality and its components with twins used as the referent category. Overall, triplets, quadruplets, and quintuplets had higher risks of mortality than twins. Generally, the twins versus higher-multiple disparity in mortality tended to be lower for stillborn fetuses than for neonatal and infant mortality. The most pronounced discrepancy was for quintuplets, among whom the risk for mortality was 4–15 times that of twins. In contrast to the modest differences in risk levels observed for triplets and quadruplets, quintuplets demonstrated a wide gap between intrauterine and extrauterine mortality risks (Table 3).



Table 2

Table 2

Table 3

Table 3

Table 4 shows the results for the various mortality indices when triplets were used as the referent category and comparisons made with higher-order births, and Table 5 contains the proportion of excess mortality that could be prevented by replacing higher-order multiple gestations with triplets and twins through the restriction of the number of transferred embryos. The proportion of excess mortality that could be prevented among triplets by replacing them with twins ranged from 45% to 64%, with a lower magnitude of preventive fraction for intrauterine demise and higher values for extrauterine death. Among quadruplets, the level of preventable deaths that could be achieved by replacing them with twins was around 70%, with practically no variation across mortality types. The most remarkable benefit of limitation was clearly in the case of quintuplets. If they were replaced by twins, the avoidable excess mortality would be in the range of 74–93%.

Table 4

Table 4

Table 5

Table 5

The right side of Table 5 features the proportion of excess mortality preventable by replacing quadruplets and quintuplets with triplets instead of twins. The level of preventable deaths was still higher for quintuplets (60–81%) compared with that for quadruplets (15–54%).

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This study provides risk estimates for early mortality as well as the magnitude of excess deaths potentially preventable by avoiding higher-order multiple gestation through the restriction of the number of transferred embryos during assisted reproductive technology cycles. We found that the likelihood of stillborn fetus and neonatal and infant mortality increased in a dose-dependent fashion with each additional fetus. In general, there are very limited data on mortality outcomes among higher-order births beyond triplets and quadruplets.20,21 An important limitation in these previous studies is the lack of adjustment for several potentially confounding characteristics, which were considered and controlled for in our study. Thus, it is reasonable to assume that the risk estimates reported in this study provide the most comprehensive and minimally biased risk estimates for stillborn fetus and neonatal and infant mortality among twins, triplets, quadruplets, and quintuplets to date in the United States. To that extent, the results of our study should be useful for counseling women considering infertility treatment options.

An important aspect of this study is the calculated preventive fraction for early mortality. These are adjusted estimates for the numbers of deaths that could be prevented by avoiding the creation of higher-order multiple gestations and replacing them with either twins or triplets. This information should help to inform the current debate regarding the need for averting higher-order multiple gestations by restricting the number of transferred embryos.5

A previous study has used data from the United Kingdom to examine the cost effectiveness of two- versus three-embryo transfers and found the benefits to be comparable.22 A cost–benefit or cost–utility analysis of this nature, especially, for higher multiples in the United States, though clearly beyond the scope of this article, is indicated. Such a study could characterize the costs and benefits of preventing higher-order births through the restriction of the number of transferred embryos, one potential disadvantage of which is a reduced pregnancy success rate. However, the ability to culture embryos to the blastocyst stage23 now permits the transfer of as few as two embryos with pregnancy occurring in up to 60% of women.9,10 Assuming this pregnancy rate to be fixed, then to avoid higher-order multiples, the number of transferred blastocysts could be limited to a maximum of two to three with substantially high pregnancy success rates. Currently, the American Society for Reproductive Medicine recommends the transfer of two good quality embryos for patients with favorable prognosis, three for above-average, four for average, and no more than five for below-average cases.24 In other industrialized countries, the maximum number of transferable embryos is lower than that recommended by the American Society for Reproductive Medicine. The British Fertility Society recommends a maximum of two embryos.25 The European Society for Human Reproduction and Embryology26 advocates either two or three, depending on female age. Other fertility experts have strongly suggested that we should be moving toward the transfer of only one embryo.27 Hence, our recommendation of a maximum of two to three blastocysts based on the analysis above seems reasonable.

A clear limitation in this study is our lack of information on assisted reproduction procedures. This information is not available in the birth record of infants born in the United States. As a result, we were unable to conduct separate analyses for artificially and naturally conceived multiple gestations, However, currently almost all quadruplets and quintuplets are the results of assisted reproduction technology,20 and because the focus of our analysis was mainly on these plurality groups it is unlikely that information on whether these pregnancies were natural or artificial would have influenced our findings. On the other hand, triplets and twins in this study were conceived either spontaneously or through assisted reproductive technology. It is therefore likely that the risk estimates obtained with twins and triplets used as referent categories could have been impacted by this heterogeneous composition.

Another limitation of this study is the lack of information on those multiples that underwent reduction procedures to lower-order multiples. In other words, it is possible that some of the triplets and twins we used as referents were actually the results of reduction procedures of previous higher-order multiples. Currently, the available information suggests that survivors of reduction procedures face either higher-than-expected risks of morbidity or mortality, or, at best, similar risks as twins and triplets that did not result from reduction procedures.28,29 Therefore, it is likely that our computed values for preventive fractions represent conservative estimates.

In summary, our findings, based on comprehensive US data, support that there would be substantial, quantifiable benefit in preventing the occurrence of higher-order multiple gestations and provide a sound rationale for limiting the number of embryos transferred during assisted reproduction procedures.

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© 2003 The American College of Obstetricians and Gynecologists