PEDIATRICS Vol. 120 No. 3 September 2007, pp. 638-639 (doi:10.1542/peds.2007-0950)
COMMENTARY |
Beware of the Weaker Sex: Don't Get Too Close to Your Twin Brother
a Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California
b Department of Pediatrics, University of Texas Medical School, Houston, Texas
In a previous article,1 we added to a chronicle of studies lamenting about the risk of being an infant boy, especially one who is very low in birth weight. We also suggested that "nature's intent" with respect to what we had described as a natural "process biased against boys (an early culling of less adaptable or fit progenitors), or an affirmative action for girls (an early sparing of that segment of the population most important for birthing and nurturing the next generation)" would remain obscure until the biological mechanisms that contribute to the phenomenon are elucidated. To this end, in this month's Pediatrics Electronic Pages Shinwell et al2 have made a provocative contribution to the literature by presenting data derived from the circumstance of twinning. Their results suggest that the male fetus brings it on himself and can, in the situation of twinning, also bring it on his innocent partner in the womb, even if it is a girl. However, in our view, the report is ultimately difficult to interpret, which makes accepting its conclusions less than easy.
Although the study was population based, the sample did not include all pregnancies; in fact, the sample was based on birth weight instead of gestational age (twin pairs were excluded whenever either infant weighed <500 or >1500 g). Using birth weight as the only criterion results in overrepresentation of small-for-age infants and a selection bias that would differ between singletons and twins and also, perhaps, between different twin groups. This problem is not solved by excluding infants born at >34 weeks' gestation, a gestational age at which a small percentage of singleton boys or girls in a healthy population have a birth weight of 
1500 g.3 The use of birth weight inclusion criteria may have unpredictable and not necessarily minor effects on the results.
The adjustment for potential confounding variables, an issue that is often confusing to clinicians and clinical investigators, is also problematic in their study. A confounding variable is associated with both the variable under investigation (in this case, infant sex) and the outcome variable (eg, mortality) as either a cause or a proxy for a cause but not as an effect of the disease. In addition, a confounding variable should not be considered part of the causal pathway by which the variable under investigation is analyzed and influences outcome.4 In evaluating the effect of sex on outcome in analyses of singletons and like-sex twins, the investigators adjusted for a large number of factors that they considered to be potential confounders, including resuscitation at birth, premature rupture of the membranes, chorioamnionitis, antepartum hemorrhage, and cesarean section. However, adjustment for resuscitation at birth is inappropriate if male sex compromises outcome by increasing the need for resuscitation at birth. Likewise, if boys are more likely to develop (1) sepsis if premature rupture of the membranes or maternal chorioamnionitis occurs, (2) hypoxic ischemic injury if antepartum hemorrhage develops, or (3) respiratory distress syndrome or severe transient tachypnea after cesarean section, adjusting for these variables would be inappropriate and would distort (ie, overadjust) the values for the odds ratio or relative risk toward the null. Adjustments were not performed for unlike-sex twins, because these analyses involved male and female infants born to the same mother. As a result, overadjustment in analyses of singletons and like-sex twins would tend to reduce the difference between singletons and unlike-sex twins and between like-sex and unlike-sex twins in their odds ratios for adverse outcomes. This would make the differences observed even more impressive. However, as for a number of the variables in this study, it is often unclear which variables are confounders and whether the adjustment for these variables would artifactually increase or decrease the odds ratio or relative risk for an adverse outcome.
For these and other reasons, the statistical analyses in the Shinwell et al study are complex and difficult to interpret. The need to account for interclass correlation differs for like-sex and unlike-sex twins, and it is unclear how the analyses were performed and how this difference was addressed in calculating the odds ratios, 95% confidence intervals, and P values for the different comparisons. Because the adjustments are critical to the results, it is disappointing that the investigators did not provide more information (either in the text or an appendix) to indicate exactly how the analyses were performed. It is also disappointing that they did not provide the results of simpler analyses adjusted for only those variables that were most likely to be true cofounders.
Nonetheless, the article still provokes some wondering about nature's intent. The point seems to be that the female fetus becomes "disadvantaged" by association with her fetal brother. If the reverse had been the case, then the male fetus would have been advantaged by association with his fetal sister, conferring the female "advantage." Whatever the bad "male humor" might be, it does not seem to be compounding, because like-sex male twins do not seem to be doubly disadvantaged. However, we have no data to assuage the fear that a female triplet with 2 brothers might have much more about which to worry. Shinwell et al2 placed their bet on gender-specific hormonal influences on fetal lung development as the explanation for the differential incidence of respiratory morbidity between the sexes. They further speculated that the hormonal disposition of the male fetus, which creates the disadvantage, can be shared, thus "masculinizing" the pulmonary development of the female fetus. This latter phenomenon suggests a "trumping" effect of testosterone or some other hormone such as Mullerian-inhibiting substance, because there would seem to be no a priori reason why the female fetus might not "feminize" the male one, conferring an accelerated pulmonary development for a given gestational age (one could only have hoped). Nonetheless, the female fetus seems relatively impervious to the maledictory influence of the male fetus, preserving better survivability for a given gestational age and avoiding most injuries (neurologic ones, in particular). One has to conclude that male is the weaker sex, and nature cannot close the distance of inferiority with sheer numbers. Finally, it is important to remember that logistic regression models, however tempting it is to use them, do not provide a prescription for individual decision-making. Moreover, if we accounted for the severity of illness,5 then boys and girls might not be so different in terms of their vulnerabilities, at least as newborns. For the time being, there remains some biological truth to the old nursery rhyme that suggests that boys are made of "snakes, snails, and puppy dog tails," and girls are made of "sugar and spice and everything nice"; and by the way, girls mature earlier and yet live longer. Perhaps nature does know something we do not, and we still have something more to learn about nature's intent.
 |
FOOTNOTES |
|---|
Accepted Apr 3, 2007.
Address correspondence to David K. Stevenson, MD, Division of Neonatal and Developmental Medicine, Department of Pediatrics, Stanford University School of Medicine, 750 Welch Rd, Suite 315, Palo Alto, CA 94306. E-mail: dstevenson{at}stanford.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
|
REFERENCES |
|---|
 TOP REFERENCES |
|---|
- Stevenson DK, Verter J, Fanaroff AA, et al. Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage.
Arch Dis Child Fetal Neonatal Ed. 2000;83
:F182
–F185
[Abstract/Free Full Text] - Shinwell ES, Reichman B, Lerner-Geva L, et al. "Masculinizing" effect on respiratory morbidity in girls from unlike-sex preterm twins: a possible transchorionic paracrine effect. Pediatrics. 2007;120(3) . Available at: www.pediatrics.org/cgi/content/full/120/3/e447
- Kramer MS, Platt RW, Wen SW, et al. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics. 2001;108 (2). Available at: www.pediatrics.org/cgi/content/full/108/2/e35
- Rothman KJ. Epidemiology: An Introduction. New York, NY: Oxford University Press; 2002:108
- Richardson DK, Phibbs CS, Gray JE, McCormick MC, Workman-Daniels K, Goldmann DA. Birth weight and illness severity: independent predictors of neonatal mortality.
Pediatrics. 1993;91
:969
–975
[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
