Invited Commentary: Intersecting Perinatal Mortality Curves by Gestational AgeAre Appearances Deceiving?
Rolv T. Lie
From the Division for Medical Statistics and Medical Birth Registry of Norway, University of Bergen, Bergen, Norway.
 |
INTRODUCTION
|
---|
In this issue of the Journal, Cheung et al. (1
) present data on the perinatal mortality of twins and singletons from Sweden. A familiar picture of intersecting mortality curves by absolute gestational age emerges. For lower gestational ages, twins have lower mortality than do singletons but for higher gestational ages, twins have higher mortality. The picture persists after adjustment for known risk factors for low gestational age. The authors conclude that twins are initially healthier than singletons, and that they do not benefit as much as singletons do from longer gestational duration. Intersecting mortality curves are often seen when standardizing for gestational age or birth weight. To conclude that twins are initially healthier is to base a longitudinal interpretation on cross-sectional data. Things may not be as they appear.
Nearly 30 years ago, Yerushalmy (2
) reported intersecting mortality curves by birth weight for children of smoking versus nonsmoking mothers. The fact that low birth weight children of smoking mothers were "healthier" was raised as evidence that smoking was not a risk factor. Shortly afterward, Meyer and Comstock (3
) wrote a commentary in the Journal on the smoking issue. They argued that the intersection of mortality curves was difficult to interpret because reduced birth weight is also an effect of smoking. Meyer and Comstock (3
) also demonstrated that the intersection of birth weight-specific mortality curves is a more general phenomenon that emerges when comparing by parity, race, and plurality. Thus, intersecting mortality curves for twins versus singletons were brought into the methodology discussion nearly three decades ago.
Mortality curves have previously been shown to intersect by gestational age when comparing race groups (4
). Cheung et al. (1
) now show the same phenomenon for comparison by plurality. This intersection of gestational age-specific mortality curves for twins and singletons was not altered by adjustment for known risk factors. We used data from the Medical Birth Registry of Norway to confirm the intersection of mortality curves by gestational age for twins versus singletons. All 1,864,820 recorded newborns between 1967 and 1998 were used. The Medical Birth Registry of Norway (5
) has similarities with the birth registry of Sweden (1
). All births with a gestational age of more than 16 weeks are recorded. Follow-up on subsequent mortality is done on the national level through record linkage. A total of 1,712,293 singletons, 39,382 twins, and 996 triplets had a recorded gestational age. Figure 1 shows the distribution of gestational ages for twins and triplets (lower panel). The gestational age distribution for twins is shifted to the left by two weeks as previously reported (6
), and triplets are shifted even more drastically. The mean gestational ages were 229 days for triplets, 258 days for twins, and 281 days for singletons. The gestational age distribution was also wider for triplets and twins with standard deviations of 31 days for triplets, 27 days for twins, and 18 days for singletons. Intersecting perinatal mortality curves are seen in the upper panel of figure 1. Preterm singletons have consistently higher perinatal mortality compared with twins and triplets born with the same gestational age. Before 35 weeks, triplets consistently have the lowest mortality. In both the Swedish data and ours, the mortality curves of singletons and twins tend to cross around 37 weeks of gestational age.

View larger version (32K):
[in this window]
[in a new window]
|
FIGURE 1. Distribution of gestational age and perinatal mortality by gestational age for triplets, twins, and singletons, Norway, 19671998.
|
|
Wilcox and Russell (7
) have proposed an explanation and solution to the intersection of birth weight-specific mortality curves. Adjustment of birth weight to a relative scale (e.g., by expressing birth weight as a z score) removes the effects of smoking or other factors on birth weight and adjusts the weight-specific mortality curves so they no longer intersect (8
, 9
). This method has been generalized to accommodate covariates (10
). In the same spirit, Hertz-Picciotto and Din-Dzietham (4
) have suggested that the intersection of mortality curves by gestational age can be removed by appropriate adjustment to relative gestational age. In this case, the variables under study were racial groups in the United States, and the adjustment was by percentiles of gestational age. As with birth weight, Hertz-Picciotto and Din-Dzietham (4
) found that adjustment removed the intersection of the mortality curves. We find a similar result for the multiple birth versus singleton comparison in our data (figure 2). A consistently increased mortality is seen for twins (and even for triplets) at all percentiles of gestational age. For triplets, there were zero deaths between percentiles 51 and 70 and only one between percentiles 71 and 80.

View larger version (22K):
[in this window]
[in a new window]
|
FIGURE 2. Perinatal mortality by percentiles of gestational age for triplets, twins, and singletons, Norway, 19671998.
|
|
The concept of relative birth weight is not foreign to clinicians. For example, relative birth weight standards by sex, race, parity, and plurality are frequently included in criteria for intrauterine growth retardation (11
, 12
). In contrast, gestational age is a variable that would seem to express more directly the maturity of the fetus (13
). Although adjustments to a relative gestational age may be more radical as a general concept (4
), there may be reasons to consider it for the twin-singleton comparison. A twin pregnancy has limitations that appear to shift the whole distribution of gestational age at delivery to the left, adding the burden of prematurity to whatever other problems the newborn twin may experience. Nearly 10 percent of twins are born at 36 weeks compared with only 1.5 percent of singletons (figure 1). Aside from being twins and slightly preterm, these 10 percent are probably fairly healthy. The 1.5 percent of singletons, however, are among the frailest of the singletons, probably suffering from unknown but specific health problems. This calls into question a direct comparison of twins and singletons at absolute gestational ages, even after adjustment for risk factors for preterm delivery (1
).
The mortality of newborn infants at specific gestational ages does not reflect the frailty among undelivered fetuses at the same gestational ages. It would be precarious to draw conclusions about fetal viability from the mortality curves of (cross-sectional) birth data. This is probably an extreme version of the well-known frailty problems of survival analysis (14
). Preterm babies have more than the prematurity problem of their specific gestational age, for they also suffer from the pathological causes of their preterm delivery, which are usually unknown. When gestational ages are adjusted relative to their separate distributions (figure 2), a comparison is made between children with assumed equal underlying frailty. The remaining difference in mortality would be attributable to the factor that is being studied. The increased mortality observed in figure 2 for twins could be interpreted as the total effect of a twin pregnancy, including the risk added by a delivery at shorter gestation.
The problems of analyzing and interpreting intersecting mortality curves have only begun to be addressed. Different perspectives to the problem, represented by clinical epidemiology on one side and biology on the other, continue to foster different interpretations of the phenomenon. Still, it is likely that singleton infants born before the 37th week of gestation are a highly selected group of critically ill or vulnerable babies compared with twins born at the same gestational age. The limitations of a multiple pregnancy appear to shift and stretch the whole gestational age distribution downward. Cross-sectional data from births cannot be given a longitudinal interpretation. It would be hasty to conclude from the intersecting curves of gestational age-specific mortality that twin fetuses are healthier than singleton fetuses early in pregnancy.
 |
NOTES
|
---|
Reprint requests to Dr. Rolv T. Lie, Section for Medical Statistics, University of Bergen, Armauer Hansens Building, 5021 Bergen, Norway (e-mail: rolv.lie{at}smis.uib.no).
 |
REFERENCES
|
---|
-
Cheung YB, Yip P, Karlberg J. Mortality of twins and singletons by gestational age: a varying-coefficient approach. Am J Epidemiol 2000;152:110716.[Abstract/Free Full Text]
-
Yerushalmy J. The relationship of parents' cigarette smoking to outcome of pregnancyimplications as to the problem of inferring causation from observed associations. Am J Epidemiol 1971;93:44356.[ISI][Medline]
-
Meyer MB, Comstock GW. Maternal cigarette smoking and perinatal mortality. Am J Epidemiol 1972;96:110.[ISI][Medline]
-
Hertz-Picciotto I, Din-Dzietham R. Comparison of infant mortality using a percentile-based method of standardization for birth weight or gestational age. Epidemiology 1998;9:617.[ISI][Medline]
-
Irgens LM. The Medical Birth Registry of Norway. Epidemiological research and surveillance throughout 30 years. Acta Obstet Gynecol Scand 2000;79:4359.[ISI][Medline]
-
Kiely JL. The epidemiology of perinatal mortality in multiple births. Bull N Y Acad Med 1990;66:61837.[ISI][Medline]
-
Wilcox AJ, Russell IT. Birthweight and perinatal mortality: III. Towards a new method of analysis. Int J Epidemiol 1986;15:18896.[Abstract]
-
Wilcox AJ. Birth weight and perinatal mortality: the effect of maternal smoking. Am J Epidemiol 1993;137:1098104.[Abstract]
-
Beukens P, Wilcox AJ. Why do small twins have a lower mortality rate than small singletons? Am J Obstet Gynecol 1993;168:93741.[ISI][Medline]
-
English PB, Eskenazi B. Reinterpreting the effects of maternal smoking on infant birthweight and perinatal mortality: a multivariate approach to birthweight standardization. Int J Epidemiol 1992;21:1097105.[Abstract]
-
Zhang J, Bowes WA Jr. Birth-weight-for-gestational-age patterns by race, sex, and parity in the United States population. Obstet Gynecol 1995;86:2008.[Abstract/Free Full Text]
-
Ananth CV, Vintzileos AM, Shen-Schwarz S, et al. Standards of birth weight in twin gestations stratified by placental chorionicity. Obstet Gynecol 1998;91:91724.[Abstract/Free Full Text]
-
Wilcox AJ, Skjaerven R. Birth weight and perinatal mortality: the effect of gestational age. Am J Public Health 1992;82:37882.[Abstract]
-
Vaupel JW, Yashin AI. Heterogeneity's ruses: some surprising effects of selection on population dynamics. Am Statistician 1985;39:17685.[ISI][Medline]
Received for publication July 7, 2000.
Accepted for publication July 11, 2000.
Related articles in Am. J. Epidemiol.:
- Cheung et al. Respond to "Are Appearances Deceiving?"
- Yin Bun Cheung, Paul Yip, and Johan Karlberg
Am. J. Epidemiol. 2000 152: 1120.
[Extract]
[FREE Full Text]
- Mortality of Twins and Singletons by Gestational Age: A Varying-Coefficient Approach
- Yin Bun Cheung, Paul Yip, and Johan Karlberg
Am. J. Epidemiol. 2000 152: 1107-1116.
[Abstract]
[FREE Full Text]