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ORIGINAL RESEARCH |
From the *Departments of Maternal and Child Health and Health Behavior, University of Alabama at Birmingham, Birmingham, Alabama.
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ABSTRACT |
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METHODS: Retrospective cohort study of triplets delivered in the United States from 1995 through 1998. Four triplet clusters were identified: cluster A (all members anomaly-free); cluster B (1 anomalous member); cluster C (2 anomalous members), and cluster D (all 3 members anomalous). We compared the risk for stillbirth and infant mortality among nonanomalous fetuses in clusters A, B, and C after adjusting for intracluster correlations.
RESULTS: A total of 7,560 triplet clusters (98.9%) were analyzed after excluding cluster D (1.1%). The total stillbirth rate was 20.9 (cluster A), 61.0 (cluster B), and 81.1 (cluster C) per 1,000 (P for trend < .001), and infant mortality rate was 56.4 (cluster A), 108.8 (cluster B), and 196.1 (cluster C) per 1,000 (P for trend < .001). Using cluster A as the referent category, the risk for stillbirth among anomaly-free clustermates climbed with increase in the number of siblings with anomalies in a dose-response pattern (adjusted odds ratio, 95% confidence interval 1.5, 0.7–3.1, for cluster B; and 5.2, 1.4–18.8, for cluster C; P for trend = .03). For infant mortality, the only rise in risk was in cluster C (3.3, 1.6–6.7), whereas cluster B showed comparable risk with the referent category (0.8, 0.5–1.4; P for trend > .05).
CONCLUSION: The presence of anomalous fetuses compromises the survival of normal cotriplets. These findings could prove useful for counseling affected parents and highlight the need for follow-up of normal coinfants of anomalous fetuses.
LEVEL OF EVIDENCE: II-2
Data also tend to suggest that congenital anomalies among multiples, specifically twins, may affect the survival of not only the affected fetus but also that of the normal cotwin, although results on the issue have remained inconclusive.6,7 Knowing the risk for stillbirth or infant death of a normal comultiple in an anomalous pregnancy is important for parents trying to make an informed decision about continuation of the pregnancy, selective termination, or complete termination. Because of dearth of information on the topic, we undertook this study among triplet pregnancies guided by the following hypotheses:
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MATERIALS AND METHODS |
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Because correct analysis of multiple and correlated data such as that of triplets is not possible without prior matching, the National Center for Health Statistics undertook the matching of records for deliveries involving multiple gestations for the years 1995–1998. The first stage of the matching involved the building of an algorithm consisting of variables from live birth and fetal death records that were considered the most uniquely identifying. Live birth and fetal death records that had identical values for these variables were then identified. If the number of records with identical information equalled the reported plurality (eg, 3 records reported as triplets), these records were considered members of the same multiple gestation and assigned a unique set identification number. In those instances where the number of records with identical data exceeded the reported plurality of the records, visual review was conducted and matching done as appropriate. Approximately 93% of all records were matched in this first stage. All other records were considered unmatched and included in subsequent matching procedures that involved use of additional variables and a composite of algorithmic combinations in addition to manual identification methods. Perfect matching was finally achieved for 98.8% of the records. This process has been validated as very accurate.8
The exposure of interest was the presence or absence of congenital anomalies in individual triplets. Data for this item relate to 21 specific anomalies or anomaly groups, including chromosomal aberrations. The format also allows for the identification of more than one anomaly in an individual triplet. We then classified triplet sets into cluster A (all triplet members anomaly-free), cluster B (only 1 triplet member anomalous), cluster C (2 triplet members anomalous), and cluster D (all 3 triplets in a cluster anomalous).
The main outcomes of the study were stillbirth (intrauterine fetal demise at 
20 weeks of gestation) and infant mortality (death of the baby within the first year after birth). Crude stillbirth rate was defined as counts of stillbirth divided by total births (live births + stillbirths) multiplied by 1,000, whereas infant mortality rate was measured as the total number of infant deaths divided by the total number of live births multiplied by 1,000.
We estimated regression parameters by taking into account the presence of intracluster correlation using the methodology of generalized estimating equations.9 We constructed the regression models and assessed goodness-of-fit of the regression models using the –2 log likelihood ratio test. We assessed goodness-of-fit of models by introducing each of the sociodemographic covariates, including fetal sex, into the model sequentially. The model that contained the following variables—maternal age, parity, adequacy of prenatal care, and fetal sex—gave the best fit and was subsequently retained.
We estimated the significance of main effects by means of the Wald test and assessed dose-response using the 
2 test for linear trend.10 The GENMOD procedure in SAS 9 (SAS Institute Inc, Cary, NC) was used to conduct the analysis. All tests of hypothesis were 2-tailed, with a type 1 error rate fixed at 5%. This study was approved by the Institutional Review Board at the University of Alabama at Birmingham.
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RESULTS |
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Because the aim of the study was to investigate the impact of the occurrence of malformation in 1 individual on birth outcomes in the nonanomalous cluster members, we proceeded with our analysis by excluding cluster D (the set with all members affected). Tables 2 and 3 display the maternal sociodemographic characteristics and pregnancy complications across the 3 cluster phenotypes. Differences across groups were observed for maternal age, prenatal smoking, and the following complications of pregnancy: anemia, chronic hypertension, and pregnancy-associated hypertension.
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The 3 groups differed significantly in terms of gestational age at birth. The mean gestational age was longest (mean ± standard deviation, 32.1 ± 4.0 weeks) among triplets in group A (all members anomaly-free) and shortest (29.2 ± 4.6 weeks) among members of group C (2 anomalous members), while that of group B (only 1 anomalous member) was in between (31.2 ± 3.5 weeks) in a dose-response pattern (P for linear trend < .001).
Table 5 displays the frequency of stillbirth and infant death within the 3 cluster subtypes. The clusters with no anomaly had the lowest crude rate for stillbirth and infant death, whereas those with anomalous members had higher rates proportional to the number of individuals affected with anomalies in a dose-effect pattern (P for trend < .001).
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We then restricted our analysis to the healthy members of the clusters (Table 6). The results for stillbirth were somewhat different from those for infant mortality. The crude stillbirth rate for unaffected triplets rose slightly in clusters with a single anomalous member and then increased substantially when 2 members had malformations. When these rates were arranged in an array fashion, we observed a positive trend, namely, the occurrence of stillbirth among healthy members increased significantly with increment in the number of fetuses affected with birth defects (P for trend = .02). On the other hand, the crude infant mortality rate among clusters with a single affected member declined slightly in comparison with that of anomaly-free clusters. Subsequently, we observed a rise in infant mortality rate among anomaly-free members in those clusters with up to 2 affected members, so that, instead of a linear trend (as in stillbirth), the pattern for infant mortality was a "J" shape.
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The adjusted risk estimates for the association between the presence of a congenital anomaly in a clustermate and survival of the unaffected cotriplets are displayed in Table 7. Compared with cluster A, nonanomalous fetuses in cluster B had a 50% higher likelihood for stillbirth, although the difference was statistically not significant. Infant mortality was comparable in the 2 groups. Among nonanomalous fetuses in cluster C, the likelihood for in utero demise was more than 5 times as great when compared with clustermates in cluster A, whereas the likelihood of infant mortality was more than tripled. Despite the lack of statistical significance of the result for stillbirth risk in cluster B, the likelihood for in utero demise increases with increment in the number of anomaly-affected cotriplets in a dose-effect fashion (P for trend = .03).
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DISCUSSION |
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Previous studies of the effect of congenital anomalies on the survival of unaffected comultiples have focused on twins. Based on an analysis conducted on 970 twin pregnancies delivered at a tertiary health care facility,6 the authors observed that perinatal mortality and neonatal outcomes of the normal cotwin were similar to that in other nonanomalous twin gestations. Although the study was carefully carried out, it was no doubt severely under-powered (18 pregnancies with major malformations and 18 with minor, totaling 36 twin pregnancies with anomalous fetuses), a limitation that explains the results. Our findings are, however, in closer agreement with another study in which the authors reported a 5-fold increase in risk for perinatal death among normal cotwins of anomalous twin sets as compared with healthy controls,7 although despite the appreciable relative risk, their estimates failed to reach statistical significance as a result of insufficient sample size.
The results of our study suggest that both in utero and ex utero survival of normal cotriplets of anomalous sets are compromised, particularly where up to 2 members are congenitally malformed. This information could prove useful in counseling affected parents antenatally so that they can make an informed decision regarding continuation of the pregnancy or selective termination. Further, the higher-than-expected infant mortality rate observed among anomaly-free triplets belonging to sets in which 2 clustermates are anomalous may be a result of the shortened gestation period experienced by members of these clusters because mean gestational age at birth was lowest among members of this group.
Several limitations of this analysis require mention. It is known that the presence of birth defects as documented on birth certificates is not complete, and the diagnosis may not be as accurate or as detailed as one will desire.11 One effect that this lowered sensitivity will have on our results is a bias toward the null, and this could probably have partly explained why the adjusted odds ratio (especially for stillbirth for which the odds ratio was 1.5) between normal controls and normal triplets within clusters with a single anomalous member did not attain statistical significance.
Another shortcoming in this work is our inability to determine whether a diagnosed malformation is major or minor because the anomaly as recorded on the birth certificate is not accompanied with detailed information to permit such a classification. As a result, fetuses with diagnosed major or minor anomalies may be assigned to the same group. Consequently, the estimated relative risks we report in this study could have been diluted, and as a result, we probably underestimate the true association between the presence of an anomalous triplet and the in utero or ex utero demise of unaffected clustermates.
Our analysis does not take into account the effect of ART on the outcome being measured. This is an important omission because a substantial fraction of triplets born in the United States resulted from ART procedure, and it is documented that ART-related infants generally have a greater number of adverse birth outcomes, including congenital anomalies and imprinting disorders, than their spontaneous counterparts. Because information on ART is not available in the data set, the extent to which our result is impacted by this source of confounding is difficult to assess. Other limitations of the data set include lack of information on chorionicity and time of diagnosis of the anomaly (antenatal versus postnatal).
Despite these limitations this study has some merits. Previous studies of the topic were restricted to twins, so that the findings in this study will potentially expand our knowledge base as well as enhance our understanding of the interaction between normal and anomalous clustermates within the context of multiple gestations.
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Footnotes |
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Address reprint requests to: Hamisu Salihu, MD, PhD. Department of Maternal and Child Health, University of Alabama at Birmingham, 1665 University Boulevard, Room 320, Birmingham, AL 35294; e-mail: hsalihu{at}uab.edu.
Received December 30, 2005. Received in revised form February 8, 2005. Accepted February 16, 2005.
doi:10.1097/01.AOG.0000161374.70882.22
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REFERENCES |
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This article has been cited by other articles:
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  A. T. N. Tita, H. M. Salihu, and P. S. Ramsey Impact of Anomalous Triplets on Morbidity Outcomes of Normal In Utero Siblings. Obstet. Gynecol., June 1, 2006; 107(6): 1352 - 1356. [Abstract] [Full Text] [PDF]
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