Published online August 31, 2007
PEDIATRICS Vol. 120 No. 3 September 2007, pp. e447-e453 (doi:10.1542/peds.2006-3574)
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ARTICLE

"Masculinizing" Effect on Respiratory Morbidity in Girls From Unlike-Sex Preterm Twins: A Possible Transchorionic Paracrine Effect

Eric S. Shinwell, MDa, Brian Reichman, MB ChBb,c, Liat Lerner-Geva, MDb,c, Valentina Boyko, MScb, Isaac Blickstein, MDd in collaboration with the Israel Neonatal Network

a Departments of Neonatology
d Obstetrics and Gynecology, Kaplan Medical Center, Rehovot, Hebrew University, Jerusalem, Israel
b Women and Children's Health Research Unit, Gertner Institute, Tel Hashomer, Israel
c Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVES. Preterm male infants are at a disadvantage when compared with female infants regarding the incidence of respiratory and neurologic morbidity and mortality. At term, female infants from unlike-sex twin pairs have birth weights that are closer to their male co-twins than to girls from like-sex twin pairs. We hypothesized that if the male disadvantage is mediated via factors that affect fetal lung development, there may be a potential effect on the incidence of respiratory distress syndrome and its complications in female infants from unlike-sex pairs.

PATIENTS AND METHODS. In this population-based study we used data from the Israel Neonatal Network, which included data from 8858 very low birth weight (500–1500 g) infants of 24 to 34 weeks' gestation. The incidence of morbidity and mortality was compared in male and female infants from singletons and like-sex and unlike-sex twin pairs. Multivariable analyses were used, accounting for relevant confounding variables.

RESULTS. Male singletons and like-sex twins were at increased risk for mortality, respiratory distress syndrome, pneumothorax, bronchopulmonary dysplasia, periventricular-intraventricular hemorrhage, and periventricular leukomalacia. However, in unlike-sex twin pairs, no difference was seen in the incidence of respiratory morbidity between male and female twins. The male disadvantage was maintained for mortality and periventricular-intraventricular hemorrhage.

CONCLUSIONS. These findings suggest that the difference in morbidity and mortality between male and female premature infants represents a male disadvantage as opposed to a female advantage and that this disadvantage may be transferred from boys to girls in unlike-sex twin pairs, perhaps via an intrauterine paracrine effect.

Key Words: gender differences • preterm infants • very low birth weight • twins • multiple pregnancy

Abbreviations: RDS—respiratory distress syndrome • BPD—bronchopulmonary dysplasia • PIVH—periventricular-intraventricular hemorrhage • VLBW—very low birth weight • ROP—retinopathy of prematurity • PVL—periventricular leukomalacia • OR—odds ratio • CI—confidence interval

Preterm male infants are at a significant disadvantage when compared with female infants of comparable gestation in terms of morbidity and mortality.1 Specifically, boys have a higher incidence of respiratory distress syndrome (RDS) and its associated morbidity, such as pulmonary air leak, bronchopulmonary dysplasia (BPD) and periventricular-intraventricular hemorrhage (PIVH).1,2

The mechanisms underlying gender-specific patterns of morbidity and mortality are only partly understood, both in neonates and in other age groups. The major factor in the pathogenesis of RDS in preterm infants is immature surfactant synthesis in alveolar type 2 epithelial cells. Gender-specific hormonal influences on fetal lung development include estrogens, which accelerate, and androgens and mullerian inhibiting substance, which cause inhibition.3–7

Studies in twins offer a unique potential to understand gender-related differences. It has been shown recently that girls in unlike-sex twin pairs are significantly heavier than girls from like-sex pairs or female singletons.8 This finding suggests the possibility of an intertwin mediator, produced by the male, that somehow affects the female co-twin despite the presence of a dichorionic placenta.

We, therefore, hypothesized that if the male disadvantage is mediated via factors that may inhibit fetal lung development, there may be a potential effect on the incidence of RDS and its complications in girls from unlike-sex pairs. Such an effect could be termed either the "transfer of the male disadvantage" or "masking of the female advantage." To test this hypothesis, we compared morbidity and mortality in male and female infants in very low birth weight (VLBW) preterm singletons, as well as in like- and unlike-sex pairs of twins from a large, population-based database.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Israel National VLBW Infant Database
The study was based on the Israel National VLBW infant database, which has been described in detail elsewhere.2 Briefly, infants with birth weight of ≤1500 g (VLBW) who are born alive in all of the country's 28 neonatal units (see "Acknowledgments") have been included in the database since 1995. Data are prospectively collected on a prestructured form and include parental demographic information, maternal pregnancy history and antenatal care, mode of delivery, infant's status at birth, procedures and morbidity during hospitalization, and outcome at discharge. Data are collected on all of the infants until discharge or death. Definitions used were concomitant with those of the Vermont-Oxford Trials Network, were defined by the scientific committee before data collection, and have remained unaltered since. Once collected by the local investigators, the data are sent to the database coordinating center, checked for missing items and logic errors, corrected, completed, and then entered into a computerized database. Patient information is cross-checked with the national birth registry, and data from any missing infant are requested from the birth hospital. The hospital of birth and patient identification subsequently remain confidential. This study was approved by the human research committee of the Sheba Medical Center. The database contains the data from >99% of all VLBW infants in Israel.

Study Sample
The study sample included singletons and twins who were born alive between 1995 and 2003 at 24 to 34 weeks' gestation with a birth weight of 500 to 1500 g. Exclusion criteria included major congenital malformations and infants born alive after late abortions.

The total number of VLBW infants born during the study period was 13430. For the purpose of comparisons between singletons and twins, only complete sets of twins (ie, sets of twins in which both infants met the study criteria) were included. The final sample was composed of 6410 singletons and 2448 twins.

To test the hypothesis as described above, comparisons of the outcome variables were made between boys and girls in 3 groups of infants: singletons (n = 3324 boys and 3086 girls), like-sex twins (n = 796 male-male twins and 696 female-female twins), and unlike-sex twins (n = 478 boys and 478 girls).

In the subsequent analysis of neonatal morbidities, further exclusions were because of neonatal deaths or missing data. The analysis of RDS and pneumothorax included 8776 infants after excluding 82 delivery room deaths. BPD was evaluated in 7411 infants after excluding 1447 deaths before 36 weeks' postconceptional age. PIVH was evaluated in 8070 infants, excluding 397 deaths before 3 days of age and 391 infants without an appropriate ultrasound examination. Retinopathy of prematurity (ROP) and periventricular leukomalacia (PVL) were assessed in 6898 and 6238 infants, respectively. Excluded were 1302 deaths before 28 days of age, 658 infants without ophthalmologic examination, and 1318 infants without ultrasound examination after 28 days of age for diagnosis of PVL.

Outcome Variables
The outcome variables included respiratory and neurologic morbidity and mortality. The diagnosis of BPD is problematic, because there is much variation between units, and the newly developed "physiologic definition" is not as yet widely applied.9 Thus, BPD was defined as oxygen dependency at 36 weeks' postmenstrual age. Postmenstrual age was calculated as gestational age at birth plus chronologic age in completed weeks. The correlation between oxygen dependency and an assigned clinical diagnosis of BPD was >95%. RDS was defined by the presence of both characteristic clinical and radiographic findings, together with the need for supplementary oxygen or mechanical ventilation. PIVH was defined by cerebral ultrasound findings,10 and the outcome variable for this analysis included grades 3 to 4 (ie, severe PIVH). PVL was defined by the presence of characteristic cystic lesions on cerebral ultrasound.11 ROP was defined according to the international classification, and the outcome variable for this analysis included grades 3 and above.12 Death was defined as occurring before discharge from the hospital.

Possible obstetric and perinatal confounding variables were considered. Gestational age (in completed weeks) was determined by the best obstetric estimate of gestational age based on last menstrual period, obstetric history and examination, first trimester ultrasound, and postnatal physical examination. Birth weight for gestational age was expressed as z scores determined from gender-specific charts.13 Antenatal steroid therapy was defined as "partial" if delivery occurred at <24 hours after the first dose or >1 week after the last dose, and "complete" if delivery occurred >24 hours and <7 days after a complete course of therapy. Premature rupture of membranes was defined as membrane rupture >6 hours before the onset of regular spontaneous uterine contractions. Diagnosis of chorioamnionitis was based on maternal fever (>37.8°C orally or 38°C rectally), associated with suggestive clinical signs. Preterm labor was considered in the presence of uterine contractions occurring before 35 weeks' gestation together with cervical effacement and dilatation. Maternal hypertensive disorder was defined as either chronic hypertension (persistent elevation of blood pressure before 20 weeks of gestation or before pregnancy) or preeclampsia/pregnancy-induced hypertension if blood pressure >145/95 mmHg was first recorded after 20 weeks of gestation.

Statistical Analysis
In singletons, multivariable logistic regression analyses were conducted to account for potential confounding variables that included infertility treatment, gestational age at start of prenatal care, antenatal steroid therapy, premature labor, premature rupture of membranes, chorioamnionitis, tocolytic therapy, antepartum hemorrhage, delivery by cesarean section, gestational age, ethnic origin, and resuscitation in the delivery room. Generalized logistic regression models were used to account for interclass correlation in sets of twins. The variable birth order was included in these analyses. Results of the models are presented as odds ratios (ORs) and 95% confidence intervals (CIs). Statistical analyses were performed by using SAS 9 (SAS Institute, Inc, Cary, NC).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Population Characteristics
Table 1 shows baseline demographic and perinatal data for each of the study groups. As expected, a higher incidence of infertility therapy, earlier prenatal care, preterm labor, and antenatal steroid therapy were seen in twin pregnancies. Among the unlike-sex twins, 50.4% of firstborn infants were boys.


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  		TABLE 1 Demographic and Perinatal Characteristics of Mothers According to Singleton and Twin Gender Groups

 
Table 2 shows birth weight, gestational age, and birth weight z scores for boys and girls in each of the study groups. All of the groups showed moderately negative mean z scores in the range of –0.484 to –0.652, which reflect the fact that this population is defined by a birth weight upper limit and, therefore, has relative overrepresentation of infants born after intrauterine growth retardation. No significant differences were found between boys and girls from each of the respective study groups.


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  		TABLE 2 Birth Weight, Gestational Age, and Birth Weight z-Score Data According to Gender Groups

 
Outcomes
Mortality rates were higher for male compared with female infants in all of the study groups (Table 3). Multivariable logistic regression analysis showed that, after adjustment for confounding variables, male gender was associated with increased odds for mortality in singletons (OR: 1.29; 95% CI: 1.1–1.51; P = .002) and unlike-sex twins (OR: 1.36; 95% CI: 1.05–1.77; P = .02). A similar result that did not attain statistical significance was noted for like-sex twins (OR: 1.29; 95% CI: 0.91–1.83; P = .15; Table 4).


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  		TABLE 3 Mortality and Major Morbidities According to Singleton and Twin Gender Groups

 

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  		TABLE 4 Adjusted ORs and 95% CIs Comparing Mortality and Morbidity Between Boys and Girls in Singletons and Like-Sex and Unlike-Sex Twin Pairs

 
Male singletons and boys from like-sex twin pairs were at significantly increased adjusted risk for RDS (singletons: OR: 1.30; 95% CI: 1.15–1.46; P = .001; like-sex twins: OR: 1.60; 95% CI: 1.14–2.26; P = .007) and BPD (singletons: OR: 1.66; 95% CI: 1.38–1.99; P = .001; like-sex twins: OR: 1.59; 95% CI: 1.01–2.51; P = .04). A similar trend that did not attain statistical significance was seen for pneumothorax in singletons. In contrast, and in keeping with the hypothesis of this study, no difference was found in the adjusted risk for RDS (OR: 0.99; 95% CI: 0.77–1.26; P = .92), BPD (OR: 1.06; 95% CI: 0.72–1.55; P = .76), and pneumothorax (OR: 1.03; 95% CI: 0.68–1.56; P = .90) between boys and girls from unlike-sex twin pairs.

Singleton boys were at significantly higher adjusted risk for severe PIVH (OR: 1.35; 95% CI: 1.13–1.62; P = .001) and cystic PVL (OR: 1.38; 95% CI: 1.10–1.74; P = .006). No significant differences were found in the adjusted risk for these morbidities in like- or unlike-sex twins, although a nonsignificant trend of similar magnitude toward increased PIVH was seen in male infants from both like- and unlike-sex twin pairs. No differences were found in the adjusted risk for ROP between male and female infants in any of the groups.

We further analyzed all of our data by using generalized logistic regression, looking for an interaction effect between gender and twin/singleton type for the outcomes evaluated. For RDS and BPD, the interaction terms were significant (P = .01 and .02, respectively) suggesting that the effects observed were unlikely to have happened by chance. The interaction effect was not significant in the models for mortality, PIVH, PVL, and ROP. For pneumothorax, the interaction term was not significant in the total population; however, the analysis limited to the twin populations showed a significant interaction between gender and type of twin pairs (P = .01).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
With this study we demonstrate a definite "masculinization" effect on respiratory morbidity in female siblings from unlike-sex VLBW twin pairs. The worsening of the female in the direction of the male suggests that increased respiratory morbidity in male preterm infants reflects a male disadvantage rather than an inherent female advantage. This male disadvantage seems to be transferred from the male to the female fetus perhaps via an intrauterine paracrine effect, in a manner similar to that described in rodents and other animals.

Studies in animals have suggested that variation in gender-specific physical and behavioral traits may be related to differences in exposure to hormones during fetal development. In rodents, the effects of intrauterine position of fetuses between 2 males as compared with between 2 females have been studied as surrogate measures of possible transfer of hormones between adjacent fetuses.14 Levels of testosterone in the blood and amniotic fluid were significantly higher in both male and female fetuses that were positioned between 2 males than in those positioned between 2 females.15 Hormones such as testosterone have been shown to be transferred between fetuses in different species either by diffusion between amniotic sacs or indirectly via the uteroplacental blood flow.16,17 Physiologic, morphologic, and behavioral effects of masculinization have been shown in fetuses that were positioned between 2 males. Physiologic effects include inhibition of pulmonary surfactant production,18 later vaginal opening,19 later mating and impregnation, more male offspring in the next generation,20 increased sensitivity to testosterone,21 and changes in neurotransmitters, such as {gamma}-amino butyric acid, and metabolic activity (cytochrome oxidase) in the hypothalamus and limbic system.22,23 Morphologic effects include increased anogenital distance,20 larger testes and seminal vesicles and smaller prostate glands,24,25 and a larger sexually dimorphic nucleus in the adult rat brain.26 Behavioral effects include increased likelihood to mount females,27 more parental behavior,28 and more aggression.29 In summary, animal studies suggest that interfetal hormone transfer has significant effects, some of which are involved in fetal programming and persist until adulthood.

In humans, possible paracrine effects between fetuses in multiple pregnancies have been studied in various gender-related physical and behavioral characteristics in girls from unlike-sex twin pairs. Physical findings that may characterize masculinization in girls from unlike-sex twin pairs include decreased spontaneous and click-induced otoacoustic emissions,30 increased myopia,31 reduced finger length (2-digit/4-digit) ratios,32 increased tooth size,33 and increased functional cerebral lateralization.34 Behavioral effects have also been described,35,36 although the confounding effect of environmental influences, such as growing up with a co-twin brother, must be assessed in the quantification of the relative contributions of genetic, hormonal, and environmental effects.

Moreover, alterations in intrauterine hormone levels may influence the risk for cancer in adults.37 Specifically, high estrogen levels in preterm birth before 33 weeks and dizygotic twinning were associated with an increased risk for breast cancer, whereas low levels in preeclampsia were associated with a decreased risk.38–40 Similarly, testicular cancer was more common in male twins from unlike-sex than from like-sex twin pairs.41 Although the changes in risk in these studies were modest in degree, these findings support the concept of some long-term effects of intrauterine exposure to the presence of a co-twin with a different gender.

In our study, the absence of any significant difference in birth weight between the different groups of preterm infants likely reflects the pattern of intrauterine growth that is slowed in multiples after ~28 weeks. Hence, the masculinization effect in birth weight of a boy on its female co-twin, repeatedly shown in previous studies,8,37 cannot be shown in this cohort of preterm infants with a mean gestational age of 28 to 29 weeks.

The nature of this masculinization effect remains speculative. What is known at present is that the effect seems to begin as early as midgestation, influencing respiratory morbidity. In this study, neurologic morbidity and mortality were not influenced, and this needs to be confirmed in further large studies. Second, the effect is strong enough to be detectable despite numerous other confounding influences on respiratory morbidity. Finally, the effect continues until term, influencing birth weight.

In contrast, the mediator of the masculinization is entirely unknown, although hormones seem to be logical candidates. Likewise, the route of mediation is obscure. Studies in animal models make plausible a transchorionic paracrine mechanism, because the placenta of unlike-sex twins is always dichorionic and devoid of intertwin vascular anastomoses.

Large database studies with important findings generate hypotheses that may be confirmed in clinical studies. The challenge ahead is to evaluate the nature of this interfetal paracrine transfer in multiple pregnancies.


   ACKNOWLEDGMENTS
 
The Israel National VLBW Infant database is partially funded by the Israel Center for Disease Control and the Ministry of Health.

The Israel Neonatal Network participating centers (in alphabetical order) are Assaf Harofeh Medical Center, Rishon Le Zion; Barzilay Medical Center, Ashkelon; Bikur Holim Hospital, Jerusalem; Bnei Zion Medical Center, Haifa; Carmel Medical Center, Haifa; English (Scottish) Hospital, Nazareth; French Hospital, Nazareth; Hadassah University Hospital, Ein-Kerem, Jerusalem; Hadassah University Hospital, Har Hatzofim, Jerusalem; Haemek Medical Center, Afula; Hillel Yaffe Medical Center, Hadera; Italian Hospital, Nazareth; Kaplan Medical Center, Rehovot; Laniado Hospital, Netanya; Mayanei Hayeshua Hospital, Bnei Brak; Meir Medical Center, Kfar Saba; Misgav Ladach Hospital, Jerusalem; Nahariya Hospital, Nahariya; Poria Hospital, Tiberias; Rambam Medical Center, Haifa; Rivka Ziv Hospital, Tsfat; Schneider Children's Medical Center of Israel and Rabin Medical Center (Beilinson Campus), Petach Tikva; Shaarei Zedek Hospital, Jerusalem; Soroka Medical Center, Beersheva; Sourasky Medical Center, Tel Aviv; Wolfson Medical Center, Holon; and Yoseftal Hospital, Eilat. The coordinating center is the Women's and Children's Health Research Unit, Gertner Institute for Epidemiology and Health Policy Research, Tel Hashomer.


   FOOTNOTES
 
Accepted Feb 28, 2007.

Address correspondence to Eric S. Shinwell, MD, Department of Neonatology, Kaplan Medical Center, PO Box 1, Rehovot 76100, Israel. E-mail: eric_s{at}clalit.org.il

The authors have indicated they have no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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