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ORIGINAL RESEARCH |
From the Epidemiology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
Address reprint requests to: Jun Zhang, PhD, MD, National Institutes of Health, National Institute of Child Health and Human Development, Epidemiology Branch, Building 6100, Room 7B03, Bethesda, MD 20892-7510; E-mail: jim_zhang{at}nih.gov.
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ABSTRACT |
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METHODS: We used the Matched Multiple Birth File from the US National Center for Health Statistics, which included 152,233 sets of twins and 5356 sets of triplets registered from 1995 to 1997. The Cox proportional hazards model was used to estimate the adjusted relative risk of death before age 1 year for remaining twins and triplets.
RESULTS: Fetal death at 20 weeks’ gestation or later was uncommon, occurring in 2.6% of twin and 4.3% of triplet gestations. After adjustment for confounders, the survival of the remaining fetuses was inversely related to the time of the first fetal demise. Same-sex twins were two times more likely than opposite-sex twins to die after an intrauterine demise at 25–32 weeks’ gestation and were more than three times more likely to die after a death at 33 weeks’ gestation or more.
CONCLUSION: After a fetal death in a multifetal pregnancy at 20 weeks’ gestation or later, the survival of the remaining fetuses is inversely related to the time the death occurred. Among twins, survival also depends on sex concordance, with opposite-sex twins more likely than same-sex twins to survive.
Fetuses in a multifetal gestation are more likely than singletons to die in utero.1,2 When a single fetal demise occurs in a multifetal pregnancy, the survival of the remaining fetus or fetuses is in jeopardy. The magnitude of the risk to surviving fetuses is unclear, as most published reports have been based on relatively few cases.
The "vanishing twin syndrome," a term often used to describe the death of one fetus of a multifetal gestation during the first trimester of pregnancy, occurs in up to one-quarter of all recognized multifetal pregnancies, and is much more common among monozygotic twins with monochorionic placentation.3,4 However, the reported incidence of single fetal demise after the first trimester among recognized multifetal gestations is much lower, approximately 0.5–6.8%.3,5–8 It is often difficult to determine the cause of a fetal demise; however, cord entanglement, twin-twin transfusion syndrome, abruptio placenta, chronic placental insufficiency, and congenital anomalies have been reported as causes.3,5,9–13
The prognosis for the surviving fetuses after one fetus dies appears to vary widely according to the cause of the death and the time at which the death occurred. For instance, the survival of a fetus may be unaffected by the death of a twin or triplet early in pregnancy from a congenital anomaly. In contrast, the death of a monochorionic twin at 20–28 weeks’ gestation can lead to renal cortical necrosis, major central nervous system damage, or death of the remaining fetus or fetuses.14 Fetuses with monochorionic placentation appear to be at higher risk after the death of a twin in utero than those with dichorionic placentation.11
Given the heterogeneity of the small number of cases that have been reviewed in the literature to date, obstetricians have had limited evidence to guide their counseling of patients after a fetal demise. We used the population-based Matched Multiple Birth File from the US National Center for Health Statistics to estimate the frequency of fetal death in multifetal pregnancies and the probability of survival to age 1 year for fetuses and infants who were the products of twin or triplet pregnancies in which at least one fetal death occurred at 20 weeks’ gestation or more.
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MATERIALS AND METHODS |
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). After the exclusion of 5394 sets of twins and 525 sets of triplets, there were 150,386 sets of twins (97%) and 5240 sets of triplets (91%) available for analysis.
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). A total of 3599 (96%) of the 3735 sets of twins and 211 (95%) of the 222 sets of triplets met this inclusion criterion and were retained for further study. In the majority of subjects, gestational age was based on the clinical estimate of gestation at the time of birth or fetal death; however, in approximately 13% of twins and 11% of triplets, where the clinical estimate was unavailable, we used the gestational age calculated from the mother’s last menstrual period. The gestational age at the time the first fetus died was categorized as 20–24 weeks, 25–28 weeks, 29–32 weeks, 33–36 weeks, and 37 weeks or later. For triplets, we combined the last two categories, as most of the triplets were delivered before 37 weeks’ gestation. Gestational age was categorized to reduce the amount of misclassification caused by errors in gestational age assessment. Among twins, we further stratified by sex concordance as a crude approximation for zygosity and chorionicity; among triplets, the numbers were too small to perform a similar stratification. The percent distribution of outcomes among remaining twins and triplets are presented with 95% confidence intervals.
To estimate the adjusted relative risk of dying before age 1 for remaining twins and triplets given the time of the first fetal demise, we used the Cox proportional hazards model.16 For triplets, we calculated the adjusted relative risk of at least one of the remaining triplets dying, given the time of the first death. The estimates are presented as relative risks with 95% confidence intervals.
Among infants who died before age 1, survival times were calculated by adding the number of days of survival after birth to the gestational age at birth. For instance, an infant who was delivered at 37 weeks’ gestation and then survived for 10 days was assigned a survival time of 38.4 weeks. For infants known to have survived to at least 1 year, we considered them to be censored at a time equal to their gestational age at birth plus 52 weeks. Among triplets, if at least one of the remaining triplets died, the survival time was based on the next death to occur after the initial demise. We used Stata Statistical Software (StataCorp 2001, College Station, TX) for all of the analyses.
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RESULTS |
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compares selected demographic characteristics of mothers of twins or triplets from 1995 to 1997 with mothers of singletons in the United States in 1996. The mothers with twin gestations were similar to those women with singleton gestations with respect to age and parity; however, they were slightly more likely to be non-Hispanic white and to have a graduate school education. Compared with the mothers of singletons and the mothers of twins, the mothers of triplets were slightly older and were much more likely to be non-Hispanic white, nulliparous, and to have a graduate school education.
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presents the reported vital status of twin and triplet pregnancies that survived to at least 20 weeks’ gestation in the United States from 1995 to 1997. Of these twin pregnancies, 93.7% resulted in two liveborn infants who survived at least 1 year; 87.1% of triplet pregnancies resulted in all of the infants being liveborn and surviving to 1 year; and 2.6% of twin gestations and 4.3% of triplet gestations that survived to at least 20 weeks’ gestation ended with the death of at least one of the fetuses.
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shows the outcomes of remaining fetuses after one fetus died in utero for same-sex twins, opposite-sex twins, and triplets. Among the 3599 twin gestations complicated by intrauterine fetal demise, 2855 (79%) involved same-sex twin pairs. The probability of survival for the remaining fetuses improved dramatically with increasing gestational age at the time of the fetal death. Overall, remaining twins of opposite-sex twin pairs were more likely to survive than remaining twins of same-sex twin pairs. Remaining triplets had a pattern of survival that was similar to that of remaining twins of opposite-sex twin pairs.
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presents the relative risks of death for remaining fetuses after adjustment for maternal age, race/ethnicity, educational attainment, marital status, parity, prenatal care, and smoking status during pregnancy. The results confirm the unadjusted relations presented in Table 3. The risk of death for remaining fetuses was found to be inversely related to the time of the initial demise, with twins whose cotwin died at 20–24 weeks’ gestation having a risk of death that was approximately 130 times that of twins whose cotwin perished at 37 weeks or later. The adjusted probability of survival for remaining triplets was also found to be inversely related to the time of the first fetal death, although the effect was less pronounced.
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DISCUSSION |
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The survival pattern of remaining triplets after an intrauterine fetal demise was similar to that of remaining twins of opposite-sex twin pairs and better than that of same-sex twin pairs. Although the Matched Multiple Birth File does not contain information regarding infertility treatment, it has been estimated that approximately 80% of the mothers of triplets and higher-order multiples born in the United States in 1996 and 1997 used assisted reproductive technologies or ovulation-stimulating drugs.17 Therefore, the majority of the triplets in our study were likely to have been trizygotic.18 After adjustment for confounders, the time of the initial fetal demise had less of an effect on the survival of remaining triplets than it did on remaining twins, perhaps as a result of the fact that the lungs of triplets are thought to mature more quickly than the lungs of twins.19
Our study has several deficiencies that should be noted. First, it is often impossible to pinpoint the exact time that a fetal death has occurred, particularly in a multifetal pregnancy. We relied on the clinical estimate of gestational age at the time of death, but the accuracy of these estimates has not been validated. To reduce the effect of this uncertainty, we divided the gestational age at death into 4- and 5-week categories. The magnitude of any resulting misclassification is probably small, as the majority of mothers in this study received early and frequent prenatal care (every 2 weeks on average, in late pregnancy).
Our study was limited to completely matched sets of twins and triplets in which all of the fetuses survived to at least 20 weeks’ gestation. We chose to exclude incomplete sets because they likely included pregnancies in which a death occurred before 20 weeks’ gestation, as most of the vital statistics reporting areas do not require the reporting of these early deaths.20 By excluding both incomplete sets and sets in which a death occurred before 20 weeks’ gestation, we were able to eliminate the bias associated with differential reporting requirements.
Another limitation is that early fetal deaths, particularly those that occurred at or before 24 weeks’ gestation, may have been under-reported; therefore, the percentage of multifetal pregnancies in which at least one death occurred may be underestimated. This should not have affected the estimated probability of survival for remaining fetuses after an intrauterine demise, however, as we only included pregnancies with complete records. Similarly, the coding of fetal death versus neonatal death is somewhat arbitrary, which could have resulted in some misclassification of those outcomes. The Matched Multiple Birth File does not contain information about the cause of fetal death or infant morbidity, nor was information on clinical management or selective reduction available for detailed analysis. The effects of maternal medical conditions were also not examined, as they are not well reported on vital records.21
To assess the risk associated with monochorionic placentation, we stratified the twin pairs by sex concordance as a rough approximation for zygosity and chorionicity.5 By definition, opposite-sex twin pairs are dizygotic and dichorionic. Same-sex twin pairs can be either monozygotic or dizygotic. Because it is assumed that dizygotic twinning results in an equal number of same-sex and opposite-sex twin pairs, the number of monozygotic twin pairs in a population can be approximated by the total number of twin pairs in a population minus two times the number of opposite-sex twin pairs.22 Following this logic, approximately 70% (2011) of the same-sex twin pairs in our study in which at least one fetus died were likely to have been monozygotic. Further, our study population likely included a disproportionate share of twins with monochorionic placentation, as they are at higher risk of death overall compared with dichorionic twins.23,24 Thus, the probabilities of survival for the remaining twins of same-sex twin pairs represent the weighted average of the survival of twins with monochorionic placentation and those with dichorionic placentation and, as such, the probabilities of survival for monochorionic same-sex twin pairs may be overestimated.
Despite the deficiencies, this study provides population-based estimates of the probability of survival to 1 year for remaining twins and triplets after the intrauterine demise of one fetus. Physicians may use these estimates to counsel patients, after a fetal demise in a multifetal gestation.
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Footnotes |
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Received October 23, 2001. Received in revised form January 11, 2002. Accepted January 31, 2002.
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REFERENCES |
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