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Obstetrics & Gynecology 2004;103:327-332
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

The Association Between Fetal Sex and Preterm Birth in Twin Pregnancies

Hongzhuan Tan, MB, MSc, Shi Wu Wen, MB, PhD, Walker Mark, MD, Karen Fung Kee Fung, MD, Kitaw Demissie, MD, PhD and George G. Rhoads, MD, MPH

From the OMNI Research Group and Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Ottawa, Faculty of Medicine, Ottawa, Canada; School of Public Health, Central South University, Changsha, Hunan, P. R. China; and Division of Epidemiology, School of Public Health, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey.

Address reprint requests to: Dr. Shi Wu Wen, OMNI Research Group, Department of Obstetrics & Gynecology, University of Ottawa, Faculty of Medicine, 501 Smyth Road, Ottawa, Canada, K1H 8L6; e-mail: swwen{at}ohri.ca.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To assess the association between the fetal sex and preterm birth.

METHODS: We performed a retrospective population-based cohort study using the 1995–1997 registration twin data in the United States (148,234 live-birth twin pairs). The twin pairs were divided into 3 groups: male-male (male-male), female-female, and opposite sex. We used 3 different cutoff values of preterm birth: less than 28, 32, and 36 gestational weeks. The preterm birth rates among the 3 study groups were compared, and the adjusted risk ratios (relative risk) were estimated by multiple logistic regression.

RESULTS: The male-male twin pairs had the highest pre-term birth rate (less than 28 weeks: 4.9%; less than 32 weeks: 12.4%; less than 36 weeks: 40.2%), the female-female twin pairs were intermediate (less than 28 weeks: 4.1%; less than 32 weeks: 10.6%; less than 36 weeks: 37.8%), and the opposite-sex twin pairs had the lowest rate (less than 28 weeks: 4.1%; less than 32 weeks: 10.1%; less than 36 weeks: 36.8%). Adjustment for important confounding factors or excluding twin pairs born to mothers who had an induction of labor or a cesarean delivery with medical complications did not change the results. The adjusted relative risks (95% confidence intervals) were 1.19 (1.11, 1.27), 1.21 (1.16, 1.26), and 1.09 (1.07, 1.11), respectively, for male-male twins compared with the opposite-sex twins under the 3 different cutoff values of preterm births.

CONCLUSION: Male sex is associated with increased risk of preterm births in twin pregnancy.

LEVEL OF EVIDENCE: II-2

Preterm birth is the single most important cause of perinatal mortality and morbidity in industrialized countries; 60–80% of deaths of infants without congenital anomalies are related to preterm birth.1,2 Furthermore, preterm birth is also associated with cerebral palsy and other long-term health sequelae.3 Although only 1–2% of all infants are delivered before 32 weeks of gestation, they account for nearly 50% of all long-term neurological morbidity and approximately 60% of perinatal mortality.1 For unknown reasons, preterm birth rate has been increasing in many industrialized countries.1,4,5

The etiology of preterm births remains largely unknown. Animal experiments suggest that fetal factors may play a more important role than maternal factors in the etiology of preterm births.6 Epidemiological studies have found an increased rate of preterm birth among male fetuses,7–10 but the results are inconsistent, especially for multiple pregnancies.9,11 We hypothesized that the risk of preterm birth is increased in male-male twin pairs more than in either female-female or opposite-sex twin pairs. The objective of this study is to test this hypothesis with a large twin registry data.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We conducted a population-based retrospective cohort study of twin births in the United States for the period from 1995 to 1997 using the matched multiple-birth file created by the Centers for Disease Control and Prevention.12 The multiple-birth file contains all twin births in the United States, with data extracted from birth certificates and discharge abstracts.12 Sets of multiples in the 1995–1997 birth file were matched by plurality, state and county of occurrence of delivery, mother’s date of birth, date of last menstrual period, number of prenatal visits, level of education, weight gain during pregnancy, and date of delivery. The matching was successful for 98% of the multiple sets.12 Available study variables in the database include sociodemographic information of the parents; maternal lifestyle factors, such as smoking and alcohol consumption during pregnancy; obstetric history; complications of the pregnancy, labor, and delivery; and birth weight, gestational age, and other infant outcome variables. Twin pairs with an incomplete match, with one or both twins dying in uterus, or with no available sex information were excluded.

The outcome variable of the study was preterm birth. To assess the association between fetal sex and different degrees of preterm, we used 3 thresholds to define pre-term birth: less than 28, less than 32, and less than 36 completed weeks of gestation. Gestational age in the database was estimated by the interval between the first day of last normal menstrual period and the date of delivery. If the date of last normal menstrual period was not recorded, or if the calculated gestation weeks fell beyond duration considered biologically plausible, the gestation weeks estimated by physician was used. The main determinant of the study was the fetal sex of twin pairs. We divided the twin pairs into 3 groups: male-male twin pairs, female-female twin pairs, and opposite-sex twin pairs. The twin pair was used as the unit of analysis in the current study.

We first described the distribution of maternal characteristics and the mean sum of birth weight of the twin pairs among the 3 study groups. We then compared the preterm birth rates among the 3 study groups. Finally, adjusted risk ratios (RRs) were estimated by using multiple logistic regression models. Confounding factors that were included in the multiple logistic regression model were maternal age (less than 20, 20–24, 25–29, 30–34, 35 or more years, with 25–29 years as reference), maternal race (white, black, and other, with white as the reference), maternal education (less than 12, 12, 13–15, 16, more than 16 years, with more than 16 years as the reference), marital status (married, unmarried, unknown, with married as the reference), maternal smoking (yes, no, not available, with no as the reference), live-birth parity (1, 2, and >=3, with >=3 as the reference), and prenatal care visits initiation time (first, second, third trimester, and no prenatal care, with first trimester as the reference).

To assess the impact of medical intervention on the observed association, we repeated the analysis after excluding twins born to mothers who had an induction of labor or who had a cesarean delivery with a diagnosis of cardiac disease, lung disease, diabetes, hydramnios, hemoglobinopathy, chronic hypertension, pregnancy-induced hypertension, eclampsia, renal disease, Rh sensitization, placenta previa, or abruption placenta.

Because preterm births are not rare in twins, we converted the adjusted odds ratio generated from multiple logistic regression to RR using the method of Zhang and Yu.13 This method derives RR from odds ratio and the incidence of the outcome of interest in the nonexposed group.


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
There were 152,233 completely matched twin pairs in the database. Of these, 11 twin pairs were excluded because of missing information on fetal sex, and 3,988 twin pairs were excluded because of stillbirths in one or both twins. The remaining 148,234 (97.37%) twin pairs were included in the final analysis. Of these, 49,838 (33.62%) were male-male twin pairs, 49,443 (33.35%) were female-female twin pairs, and 48,953 (33.02%) were opposite-sex twin pairs.

Table 1Go compares the distribution of maternal characteristics and the mean sum of birth weight of the twin pairs among the 3 study groups. Maternal age, education levels, proportion of black race, proportion of maternal smoking, and the mean sum of birth weight of the twin pairs were slightly higher in the opposite-sex twins (Table 1Go). The distribution of other maternal characteristics was similar among the 3 study groups (Table 1Go).


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  		Table 1. Distribution of Maternal and Infant Characteristics Among the Three Study Groups
 
The preterm birth rate was the highest in the male-male group (4.9%, 12.4%, and 40.2% for less than 28, less than 32, and less than 36 complete weeks of gestation, respectively), intermediate in the female-female group (4.1%, 10.6%, and 37.8%, respectively), and the lowest in the opposite-sex group (4.1%, 10.1%, 36.8%, respectively) (Table 2Go and Figure 1Go). The RR of preterm birth in male-male group was 1.20, 1.23, and 1.09 for less than 28, less than 32, and less than 36 complete weeks of gestation, respectively, and 1.00, 1.05, and 1.03 for less than 28, less than 32, and less than 36 complete weeks of gestation, respectively, in female-female group compared with the opposite-sex group. Adjustment for important confounding factors did not change the results (Table 2Go). Additional analysis after excluding indicated preterm births yielded similar results, although the magnitude of the association between the fetal sex and pre-term birth was slightly reduced (Table 3Go).


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  		Table 2. Comparison of Preterm Birth Rate Among Twin Pairs With Different Sex Concordance
 


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  		Figure 1. Preterm birth rate in the 3 study groups. M-M = male-male; F-F = female-female; OS = opposite sex.

Tan. Fetal Sex and Preterm Birth. Obstet Gynecol 2004.

 

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  		Table 3. Comparison of Preterm Birth Rate Among Twin Pairs With Different Sex Concordance (Excluding Indicated Preterm Birth*)
 

   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our large population-based study found that the fetal sex and sex concordance were associated with preterm births, with the highest preterm birth rate observed in the male-male twin pairs, intermediate rate in the female-female twin pairs, and the lowest rate in the opposite-sex twin pairs. Using the opposite-sex twin pairs as the reference, the RRs for male-male group ranged from 1.09 to 1.23, and the RRs for female-female group ranged from 1.00 to 1.06. Adjustment for important potential confounding factors or excluding indicated pre-term births did not change the pattern of the association of fetal sex and sex concordance with preterm births, although the association between fetal sex and sex concordance and preterm birth was slightly reduced when indicated preterm births were excluded. If we assume the differences in adjusted RRs between male-male twins and female-female twins after excluding indicated pre-term births represent the male fetal effects, a 19%, 21%, and 6% male fetal factor-related increased risk of preterm births, respectively, for less than 28 weeks, less than 32 weeks, and less than 36 weeks could be expected (Table 3Go).

Our study was based on a large twin registry data set (148,234 twin pairs); the largest of the issue to date. With the large sample size and rich demographic and clinical information contained in the data, we have managed to make adjustment for important confounding factors. We have also been able to assess the impact of medical intervention on the observed association by excluding the indicated births.

Our study used birth certificate data, which lack details and are prone to certain degree of coding errors. As a result, residual confounding is possible. However, the differences in baseline characteristics among the 3 study groups, especially between the male-male and female-female groups, were small, and there is no biological reason to expect large differences among them. Coding errors, if any, were likely to be random, which tend to attenuate the observed effects.14

A few previous studies have assessed the association between fetal sex and preterm births. A study by Cooperstock and Campbell9 found a 7.2% excess preterm births in male fetuses among white singletons and 2.8% excess among black singletons. In another study of twins, Cooperstock et al11 found that the male-male twins had the highest preterm rate, opposite-sex twins had the intermediate rate, and the female-female twins had the lowest rate. The sample size of the twin study by Cooperstock et al11 was much smaller (a total of 9,993 twin pairs). As a result, unstable estimation is expected. Our study adds to the literature by providing a stable estimation of the association between the fetal sex and preterm births.

There are 3 hypothesized explanations for the increased risk of preterm births of male-male and female-female twins. The first hypothesis speculates that male fetuses grow faster than female fetuses, induce greater uterine stretch, and therefore result in preterm births more frequently.11 However, the fetal growth hypothesis cannot explain the findings from our study because the opposite-sex twin pairs, although having the lowest preterm birth rate, also had the highest mean sum of birth weight. The results of Loos et al15 suggest that the girl in the opposite-sex twin pairs prolongs gestation for her twin brother, resulting in a higher birth weight than that of boys male-male births. The second hypothesis suggests that the higher preterm birth rate in the same-sex twins is the results of monozygosity and/or monochorionicity. About 60% of the same-sex twin pairs are monozygotic,16 and half of the monozygotic twin pairs are monochorionic.17 Two fetuses sharing one chorion may result in nutrition shortage, growth restriction, and preterm birth.18–20 However, the monozygosity and/or monochorionicity theory cannot explain the difference in preterm births between male-male twin pairs and female-female twin pairs because pathological data did not show any difference in the frequency of monozygosity and monochorionicity between the 2 groups,21 and there is no biological reason to believe so. The third hypothesis is related to fetal hormones. The exact mechanism of labor and preterm birth is complex and cannot be illustrated simply by hormone composition and/or concentration. However, both animal experiments and human pregnancy studies have indicated that sex hormones play a central role in the initiation of labor and therefore possibly preterm birth.6,22 It is reasonable to assume that the sex hormone composition/concentration/metabolism in male-male twins is different from female-female twins and opposite-sex twins, which in its turn may result in more frequent preterm births.

Our study can only assess the association between fetal sex and preterm birth in twins, with no detailed information to examine the mechanisms. Regardless of the mechanism, however, our findings could be helpful for clinicians caring for twin pregnancies. For example, if a prenatal ultrasound detected male-male twin pairs, physicians should be alert about the higher probability of pre-term labor. Basic scientists may also find our study results helpful in designing their animal experiments investigating the mechanisms of labor and preterm labor.


   Footnotes
 
The authors thank Joyce Martin for assistance in record linkage and Yan Chen for assistance in data analysis.

doi: 10.1097/01.AOG.0000109427.85586.71

Received July 23, 2003. Received in revised form September 23, 2003. Accepted November 3, 2003.


   REFERENCES
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Goldenberg RL. The management of preterm labor [review]. Obstet Gynecol 2002;100:1020–37.[Abstract/Free Full Text]

2. Mesleh RA, Kurdi AM, Sabagh TO, Algwiser AA. Changing trends in perinatal deaths at the Armed Forces hospital, Riyadh, Saudi Arabia. J Obstet Gynecol 2001; 21:49–55.

3. Hack M, Fanaroff AA. Outcomes of children of extremely low birthweight and gestational age in the 1990s [review]. Early Hum Dev 1999;53:193–218.[Medline]

4. Alexander GR, Slay M. Prematurity at birth: Trends, racial disparities, and epidemiology. Ment Retard Dev Disabil Res Rev 2002;8:215–20.[Medline]

5. Roberts CL, Algert CS, Morris JM, Henderson-Smart DJ. Trends in twin births in New South Wales, Australia, 1990–1999. Int J Gynaecol Obstet 2002;78:213–9.[Medline]

6. Challis JRG, Matthews SG, Gibb W, Lye SJ. Endocrine and paracrine regulation of birth at term and preterm [review]. Endocr Rev 2000;21:514–50.[Abstract/Free Full Text]

7. Mcgregor JA, Leff M, Orleans M, Baron A. Fetal gender differences in preterm birth: findings in a North American cohort. Am J Perinatol 1992;9:43–8.[Medline]

8. Astolfi P, Zonta LA. Risks of preterm delivery and association with maternal age, birth order, and fetal gender. Hum Reprod 1999;14:2891–4.[Abstract/Free Full Text]

9. Cooperstock M, Campbell J. Excess males in preterm birth: interaction with gestational age, race, and multiple birth. Obstet Gynecol 1996;88:189–93.[Abstract]

10. Zeitlin J, Saurel-Cubizolles MJ, De Mouzon J, Rivera L, Ancel PY, Blondel B, et al. Fetal sex and preterm birth: are males at greater risk? Hum Reprod 2002;17:2762–8.[Abstract/Free Full Text]

11. Cooperstock MS, Bakewell J, Herman A, Schramm WF. Effects of fetal sex and race on risk of very preterm birth in twins. Am J Obstet Gynecol 1998;179:762–5.[Medline]

12. National Center for Health Statistics. 1995–1997 matched multiple birth data set. NCHS CD-ROM Series 21, No. 12. Hyattsville (MD): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2000.

13. Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998;280:1690–1.[Abstract/Free Full Text]

14. Rothman KJ, Greenland S. Modern epidemiology. 2nd ed. Philadelphia (PA): Lippincott Raven Publishers; 1998.

15. Loos RJ, Derom C, Eeckels R, Deron R, Vlietinck R. Length of gestation and birthweight in dizygotic twins. Lancet 2001;358:560–1.[Medline]

16. Hopper JL, Hannah MC, Macaskill GT, Mathews JD. Twin concordance for a binary trait. III. A bivariate analysis of hay fever and asthma. Genet Epidemiol 1990;7: 277–89.[Medline]

17. Dube J, Dodds L, Armson BA. Does chorionicity or zygosity predict adverse perinatal outcomes in twins? Am J Obstet Gynecol 2002;186:579–83.[Medline]

18. Weekes AR, Menzies DN, West CR. Spontaneous premature birth in twin pregnancy. Br Med J 1977;2:16–8.

19. Machin G, Bamforth F, Innes M, McNichol K. Some perinatal characteristics of monozygotic twins who are dichorionic. Am J Med Genet 1995;55:71–6.[Medline]

20. Sebire NJ, Snijders RJ, Hughes K, Sepulveda W, Nicolaides KH. The hidden mortality of monochorionic twin pregnancies. Br J Obstet Gynaecol 1997;104:1203–7.[Medline]

21. Wade TD, Bulik CM, Heath AC, Martin NG, Eaves LJ. The influence of genetic and environmental factors in estimations of current body size, desired body size, and body dissatisfaction. Twin Res 2001;4:260–5[Medline]

22. Challis JRG. Mechanism of parturition and preterm labor [review]. Obstet Gynecol Surv 2000;55:650–60.[Medline]




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