Objective: To determine whether male gender has an effect on survival, early neonatal morbidity, and long-term outcome in neonates born extremely prematurely.
Methods: Retrospective review of the New South Wales and Australian Capital Territory Neonatal Intensive Care Unit Data Collection of all infants admitted to New South Wales and Australian Capital Territory neonatal intensive care units between January 1998 and December 2004. The primary outcome was hospital mortality and functional impairment at 2 to 3 years follow-up.
Results: Included in the study were 2549 neonates; 54.7% were male. Risks of grade III/IV intraventricular hemorrhage, sepsis, and major surgery were found to be increased in male neonates. Hospital mortality (odds ratio 1.285, 95% confidence interval 1.035–1.595) and moderate to severe functional disability at 2 to 3 years of age (odds ratio 1.877, 95% confidence interval 1.398–2.521) were more likely in male infants. Gender differences for mortality and long-term neurologic outcome loses significance at 27 weeks gestation.
Conclusions: In the modern era of neonatal management, male infants still have higher mortality and poorer long-term neurologic outcome. Gender differences for mortality and long-term neurologic outcome appear to lose significance at 27 weeks gestation.
- ACT —
- Australian Capital Territory
- CI —
- confidence interval
- CLD —
- chronic lung disease
- GQ —
- general quotient
- IUGR —
- intrauterine growth restriction
- IVH —
- intraventricular hemorrhage
- MDI —
- mental developmental index
- NSW —
- New South Wales
- OR —
- odds ratio
- PDA —
- patent ductus arteriosus
- ROP —
- retinopathy of prematurity
What’s Known On This Subject:
Very low birth weight (VLBW) male neonates appear to have increased mortality. VLBW female neonates appear to have better long-term outcomes.
What This Study Adds:
VLBW male neonates have increased mortality and poorer neurological outcome. This gender difference appears to disappear at weeks' gestation.
Identifying risk factors associated with increased mortality and morbidity in infants born extremely prematurely (<29 weeks' gestation) has become the foundation for counseling of parents regarding outcomes and is often the basis for instituting intensive care. A number of consensus guidelines to advise clinicians and parents on outcomes at various gestations have been developed.1–7 However, these guidelines have limitations, one of which is whether gender has an effect on morbidity and mortality.
A number of studies have shown that male gender is associated with an increased risk of neonatal mortality in preterm infants.8–13 However, 2 recent studies have not found any difference in gender and neonatal mortality.14,15 Nwosu et al found an increased risk of neonatal mortality in boys associated with placental abruption.16 The evidence for risk of intrauterine growth restriction (IUGR) and male gender is also unclear. Quinones et al17 found no gender difference, whereas Spinillo et al found there was an increased risk of IUGR in female infants of mothers with pregnancy-induced hypertension, whereas male infants were at increased risk of IUGR in mothers with a low prepregnancy weight or BMI.18 This gender difference has also been described in the infants of mothers with asthma in pregnancy. Female infants were more likely to respond to this in utero stressor with reduced growth, whereas male infants were at higher risk of mortality.19
There are a number of studies that have shown increased morbidity, including hyaline membrane disease, chronic lung disease (CLD), retinopathy of prematurity (ROP), and length of stay in male infants born with an extremely low birth weight or born extremely preterm.20–25 Herbst et al26 has shown that male infants are at an increased risk of acidemia at birth, and Bracero et al reported that male infants of diabetic mothers had a greater risk of hypoglycemia and increased length of stay.27 Sheep and piglet animal studies have demonstrated gender differences in asphyxial models that may demonstrate some of the underlying physiologic dimorphism to cardiovascular stressors.28,29
The evidence for gender differences in long-term outcomes in extremely low birth weight/preterm neonates is unclear. Some authors have found poorer outcomes in male infants,30–32 whereas Valcamonico found no gender difference.33 Jennische et al found that female neonates had poorer long-term neurodevelopmental outcome.34
The aim of this current study was to determine whether male gender has an effect on survival, early neonatal morbidity, and developmental outcome in extremely premature neonates born in a geographically discrete population.
This is a population-based longitudinal cohort study of very premature babies (<29 weeks' gestation) admitted to any of the 10 NICUs in New South Wales (NSW) and the Australian Capital Territory (ACT) in Australia between January 1998 and December 2004. Neonates with major malformations or known syndromes with developmental implications were excluded.
The primary outcome was gender differences in survival at hospital discharge and moderate/severe functional disability at 2 to 3 years of age, corrected for prematurity.
NICU Data Collection
NICU Data Collection is an ongoing prospective statewide audit of infants admitted to the 10 NICUs in NSW and the ACT during the neonatal period for one of the following reasons: (1) gestation age <32 weeks, (2) birth weight ≤1500 g, (3) assisted ventilation (mechanical ventilation or continuous positive airways pressure) for 4 hours or more commenced during the first 28 days of life, or (4) major surgery (opening of a body cavity first performed in the first 28 days of life). Definitions and accuracy of the database have been documented elsewhere.35
NICU Follow-up Data Collection
NICU Follow-up Data Collection is an ongoing prospective statewide audit at 2 to 3 years of age, corrected for prematurity, of infants born at <29 weeks' gestation and admitted to a NSW or ACT NICU.
Follow-up Assessment and Tools
All surviving children were offered an assessment at 2 to 3 years of age, corrected for prematurity. These children were assessed by the developmental assessment team at the tertiary hospitals (90%). If the parents were unable to travel to a tertiary hospital, the local pediatrician or general practitioner examined the child (10%) and the child was then referred for a detailed developmental assessment if indicated. The assessment involved examining 4 domains: (1) developmental, (2) neurologic, (3) vision, and (4) hearing. The developmental assessment used the Griffiths Mental Developmental Scales (85%)36 or Bayley Scales of Infant Development-II (15%).37
Neurologic assessment included an evaluation of muscle tone, primitive reflexes, automatic reactions, and volitional movement.38 Cerebral palsy was diagnosed if the child had nonprogressive motor impairment characterized by abnormal muscle tone and a decreased range or decreased control of movements, accompanied by neurologic signs.39
Moderate/severe functional disability was defined as one or more of the following: developmental delay (<2 SD below the mean for adjusted age determined by the Griffiths Mental Developmental Scales or Bayley Scales of Infant Development-II), cerebral palsy (unable to walk without aids), bilateral blindness (visual acuity <6/60 in better eye), or bilateral deafness (requiring bilateral hearing aids or cochlear implants.40–42 CLD was defined as an oxygen requirement or ventilatory support at 36 weeks postconceptional age. ROP was defined according to the International Classification of ROP with a stage of I to IV assigned to positive cases.43
Statistical analyses were performed using the Predictive Analytics SoftWare (PASW) (PASW for windows. Release 18.0.2. SPSS: Chicago, IL,). Data are presented as number (%) with odds ratio (OR) and 95% confidence interval (CI) or mean ± SD. The clinical and demographic characteristics were compared by χ2 test with continuity correction and the t test where appropriate. Adjusted differences between male and female genders in survival and neurodevelopmental outcome were estimated by using multiple logistic regression.44 Criteria for entry and removal were a P < .05 and P > .10, respectively. The level of statistical significance for all analyses was set at P < .05 by using 2-tailed comparisons. The significance level was not changed when multiple comparisons were performed.45
The study was approved by the NICUS data management committee and the ACT Human Research Ethics Committee.
There was a total of 2701 admissions of neonates of <29 weeks' gestation during the study period. A major congenital anomaly was noted in 152 neonates, which left 2549 for assessment, 1394 (51.6%) boys and 1155 girls (48.4%). Follow-up data at 2 to 3 years of age was available for 1473 (75%) neonates, 787 (53.4%) boys and 686 girls (47.6%) (Fig 1).
Male infants were more likely to be delivered because of an antepartum hemorrhage (P = .005) and to be delivered by emergency caesarean section (P = .014). Female infants were more likely to have mothers with pregnancy-induced hypertension (P = .002), in utero growth restriction (P = .002), and fetal distress before delivery (P = .002) (Table 1).
Male infants were more likely to have lower Apgar scores at birth (P = .013). Female infants were more likely to have a lower birth weight (P < .001) and head circumference (P < .001) (Table 1).
Mortality and Major Neonatal Morbidities
Mortality was more likely in male infants (P = .009). The following conditions and treatments were more common in male infants than in female infants: grade III or IV intraventricular hemorrhage (P = .018); infection (P = .008); postnatal steroids (P = .037); and major surgery (P < .001) (Table 1). A multiple logistic regression analysis examining perinatal characteristics for risk of mortality still found male gender to be significant (P = .023) along with gestation 22 to 26 weeks (P < .001), small for gestational age (P < .001), antepartum hemorrhage (P = .036), pregnancy-induced hypertension (P = .009), and Apgar score <7 at 5 minutes (P < .001) (see Table 2).
Long-term follow-up at 2 to 3 years of age was available for 1473 neonates. Lower maternal age (P < .001), aboriginal ethnicity (P < .001), multiparity (P = .003), and being born in a nontertiary center (P < .001) were associated with a higher risk of being lost to follow-up.
Male infants were more likely to have functional disability noted at 2 to 3 years of age (P < .001). Male infants were also more likely to have a general quotient or mental developmental index <2 SDs from normal (P < .001). Female infants were more likely to have a head circumference less than the 10th percentile (P = .009), and overall were lighter and shorter than their male counterparts (P < .001;Table 3). There was no difference in rate of cerebral palsy requiring walking aids, blindness, and deafness between genders. A multiple logistic regression model looking at perinatal characteristics and risk for poor neurologic outcome still found male gender to be a significant risk (P < .001). Gestation of 22 to 26 weeks and small for gestational age were also found to be significant in the regression model (P < .001 and P < .001, respectively; Table 4).
Gestational age-specific mortality and moderate to severe functional disability related to gender was assessed loses significance at 27 weeks gestation (Fig 2).
This large regional study indicates that extremely premature male infants are more likely to have a higher mortality rate before discharge from hospital, significant major neonatal morbidities, and poorer long-term neurologic outcome. This mortality and long-term neurologic deficit risk loses significance at 27 weeks gestation. This result should be interpreted with caution because the subgroup relationships between gender and gestation are uncorrected for confounding factors (Fig 2). If the gender of an extremely premature neonate is known before delivery, this may be extra information presented to parents regarding the risks of mortality and long-term neurologic deficits as part of antenatal counseling. Whether knowing the gender and these increased risks would alter a parent’s or clinician’s decisions regarding commencement of resuscitation at 23 to 25 weeks is questionable.
Although this is a retrospective study, the data collected for the NICU database is done on a prospective basis. The 75% rate of follow-up, although reasonable in comparison with some studies, may affect the validity of the results. However, those lost to follow-up had lower rates of many of the factors that would be considered high risk for developing long-term sequelae. It is recognized that some parents do not return to follow-up because they do not wish to hear further “bad news” about their child’s outcome, but conversely many with poor outcomes attend follow-up to avail themselves of community and hospital supports.
Our study is consistent with the findings of other studies showing male gender associated with increased mortality.8–13 Similar to Spinillo our study showed that female infants were more likely to have mothers with pregnancy-induced hypertension and to have in utero growth restriction.18 However, unlike other studies, we did not find a gender difference for the requirement of surfactant (treatment of hyaline membrane disease), CLD, or ROP.20–25 These may be related to differences in overall intensive care practice, for example, protocol-driven administration of surfactant. The major significant neonatal morbidities noted in our study were grade III or IV intraventricular hemorrhages, sepsis, and the need for major surgery.
The mechanisms underlying the male disadvantage are unclear. It commences from early in gestation with a higher ratio of male to female fetal loss the earlier in pregnancy one looks.46 Although the chromosomal difference undoubtedly allows the differentiation of this dimorphic risk, the subsequent events appear to be independent of known X or Y chromosome-related products. Differences in the placenta and induced responses in the hypothalamic-pituitary-adrenal axis and cardiovascular stress responses may well also be important in the neonate.28,29,47,48 In addition, dimorphism has been demonstrated in some pathways associated with neural protection, and therefore the potential for long-term developmental differences.49
Although our study did not show more male infants with cerebral palsy requiring walking aids, there was a significant increase in boys having moderate to severe functional disability at 2 to 3 years of age. Our findings are similar to other studies showing male infants having poorer neurologic outcome at 2 to 3 years of age.30–32 Unfortunately, the NICU database only monitors children to the age of 3 years, and thus more detailed long-term neurologic sequelae relating to speech, language, mathematical, and reasoning skills are not available for assessment.
Male infants born extremely prematurely have increased risk of mortality before discharge from the hospital, major neonatal morbidities, and poorer long-term neurologic outcome. This information should be included for parents in pre- and postnatal counseling.
We thank the Directors, the NICUS members, and the audit officers of all tertiary units in supporting this collaborative study: NICUS, Dr Jennifer Bowen (Chairperson), Barbara Bajuk (Coordinator), Trina Vincent (Research Officer); Canberra Hospital, A/Prof Zsuzsoka Kecskés (Director), Dr Hazel Carlisle, John Edwards; John Hunter Children’s Hospital, Dr Chris Wake (Director), Dr Anne Vimpani, Lynne Cruden; Royal Prince Alfred Hospital, A/Prof Nick Evans (Director), Dr Phil Beeby, A/Prof David Osborn, Dr Ingrid Rieger, Shelley Reid; Liverpool Hospital, Dr Robert Guaran (Director), Dr Ian Callander, Dr Jacqueline Stack, Kathryn Medlin, Sara Wilson; Nepean Hospital, Dr Lyn Downe (Director), Dr Basiliki Lampropoulos, Mee Fong Chin; The Children’s Hospital at Westmead, Prof Nadia Badawi (Director), Dr Alison Loughran-Fowlds, Caroline Karskens; Royal North Shore Hospital, Dr Mary Paradisis (Acting Director), A/Prof Martin Kluckow, Sara Sedgley; Sydney Children’s Hospital, Dr Andrew Numa (Director), Dr Gary Williams, Janelle Young; Westmead Hospital, Dr Mark Tracy (Acting Director), Dr Melissa Luig, Jane Baird; and Royal Hospital for Women, A/Prof Kei Lui (Director), Dr Julee Oei, Dr Lee Sutton, Diane Cameron. We also thank the babies and their families, the nursing and midwifery, obstetric and medical records staff of the obstetric and children’s hospitals in NSW and the ACT.
- Accepted September 14, 2011.
- Address correspondence to Alison Kent, Department of Neonatology, Canberra Hospital, PO Box 11, Woden, 2606, ACT, Australia.E-mail:
FINANCIAL DISCLOSURE: The authors have no financial relationships relevant to this article to disclose.
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WATER-LESS JEANS: One of my boys came home the other day with a new pair of jeans. I was not so much interested in the cut or even the wash but a tag dangling from a belt loop with “Water-less” written in large type. Did the tag mean water less or waterless? According to an article in The New York Times (Science: November 1, 2011), some international jean makers are trying to reduce the amount of water used to make and maintain a pair of jeans. By one estimate, approximately 919 gallons of water are used during the life span of each pair of jeans. This includes the water necessary to irrigate the crops, sew the jeans together, and wash the jeans at home. Several manufactures underwrite international nonprofit programs, such as the Better Cotton Initiative, that teaches farmers in the developing world sophisticated irrigation and rainwater-capture techniques. Others have introduced stone-washed jeans smoothed with rocks without the addition of water. Customers are urged to wash jeans infrequently, if at all. The interest by denim manufacturers in water conservation highlights a growing problem around the world: water scarcity. Beverage companies have responded by experimenting with bottle cleaning systems that use hot air rather than water. Still, the denim industry is particularly sensitive. Approximately two pounds of cotton goes into the manufacturing of a pair of jeans. With much of the cotton produced on small farms without water holding systems, the water hungry plants are susceptible to drought conditions. According to the article, cotton, the world's biggest nonfood crop, already accounts for more than 3 percent of the world's agricultural water use. So far, the efforts seem to be working. Farmers in India following advice from the Better Cotton Initiative to install drip irrigation systems report up to a 70% reduction in water use, fewer weeds, less pesticide use, lusher crops, and an increase in profits. One denim manufacturer now buys approximately 5% of its cotton from farmers using such techniques and plans to increase that number to 20%. I am happy that our kids are interested in “Water-less” labeled jeans. The next task will be to convince them that jeans don't need to be washed after each wearing.
Noted by WVR, MD
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