OBJECTIVE:

To examine whether changes in mortality and morbidities have benefited male more than female infants.

METHODS:

Infants of gestational ages 22 to 29 weeks born between January 2006 and December 2016 at a Vermont Oxford Network center in the United States were studied. We examined mortality and morbidity rate differences and 95% confidence intervals by sex and birth year. We tested temporal differences in mortality and morbidity rates between boys and girls by means of a likelihood ratio test (LRT) on nested binomial regression models with log links.

RESULTS:

A total of 205 750 infants were studied; 97 048 (47.2%) infants were girls. The rate for mortality and chronic lung disease decreased over time faster for boys than for girls (LRT P < .001 for mortality; P = .006 for lung disease). Restricting to centers that remained throughout the entire study period did not change all the above but additionally revealed a significant year-sex interaction for respiratory distress syndrome, with a faster decline among boys (LRT P = .04). Morbidities, including patent ductus arteriosus, necrotizing enterocolitis, early-onset sepsis, late-onset sepsis, severe intraventricular hemorrhage, severe retinopathy of prematurity, and pneumothorax, revealed a constant rate difference between boys and girls over time.

CONCLUSIONS:

Compared with girls, male infants born at <30 weeks’ gestation experienced faster declines in mortality, respiratory distress syndrome, and chronic lung disease over an 11-year period. Future research should investigate which causes of death declined among boys and whether their improved survival has been accompanied by a change in their neurodevelopmental impairment rate.

What’s Known on This Subject:

Mortality and several major in-hospital morbidities have declined among extremely preterm infants over the past 2 decades. However, whether the recent changes in outcomes have benefited both sexes equally has not been examined in studies.

What This Study Adds:

Male infants at <30 weeks’ gestation experienced faster declines in mortality, respiratory distress syndrome, and chronic lung disease than female infants, whereas other in-hospital morbidities revealed a constant rate difference over time.

Preterm birth remains a significant contributor to mortality, in-hospital morbidities, and long-term adverse outcomes. However, recent data indicate that survival among extremely preterm infants has been improving.1,4 More than half of the reduction in overall mortality has been mainly attributed to a decrease in deaths related to respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD).5 Morbidities, including late-onset sepsis (LOS), retinopathy of prematurity (ROP), and severe intracranial hemorrhage, have also declined over the past 2 decades.2 Advances in obstetrical and neonatal care have contributed to the changes in these outcomes.2,6 

In published studies, authors examining mortality and morbidities usually report a sex advantage for female preterm infants, with female infants being at a lower risk for mortality,7,12 sepsis,13 necrotizing enterocolitis (NEC),9 ROP,14 and respiratory outcomes (including RDS11 and BPD9,11,15,16) compared with male infants. Given boys’ higher risk for the above outcomes, we hypothesized that the advances in neonatal care might have influenced sex-specific survival and morbidities differentially, specifically favoring boys compared with girls. Using data from Vermont Oxford Network (VON) on >205 000 male and female infants born at 22 to 29 6/7 weeks’ gestation who received care in the United States between 2006 and 2016, we examined the differences in care practices between male and female infants and whether the change in mortality and morbidities has benefited boys more than girls.

We conducted a retrospective study on infants born between 22 weeks and 0 days and 29 weeks and 6 days’ gestation at 1 of the 766 NICUs located in the United States or Puerto Rico and participating in the VON Very Low Birth Weight Database between January 1, 2006, and December 31, 2016. Our study sample was restricted to inborn, singleton infants without congenital malformations. We excluded infants with unknown sex (n = 36) and missing (n = 107) or implausible (n = 824) birth weight. Implausible birth weights were defined as values below or above gestational-age-specific cutoffs. The latter were determined by using a statistical method based on data sparsity.17,18 Overall, 964 infants were excluded, resulting in 205 750 infants for our main analyses. The University of Vermont Committee on Human Research approved the use of VON’s deidentified research repository for this analysis.

We examined changes over time in maternal morbidities, care practices, and neonatal mortality and morbidity. Maternal morbidities included chorioamnionitis and hypertension (chronic or pregnancy induced). We divided care practices into obstetric practices (antenatal steroids and cesarean delivery), delivery room practices (tracheal intubation, epinephrine, cardiac compressions, face-mask ventilation, and surfactant), and NICU practices (steroids for chronic lung disease [CLD], surfactant therapy at any time [which also includes surfactants if received in the delivery room], conventional ventilation, ventilation after continuous positive airway pressure [CPAP], high-frequency ventilation, nasal ventilation, CPAP before ventilation, nasal CPAP, high-flow nasal cannula, and inhaled nitric oxide). Other variables were the infant’s body temperature measured within the first hour of admission to the NICU and categorized into hypothermia (<36.5°C) and hyperthermia (>37.5°C) and any enteral human milk feeding at discharge for survivors only. All of the above variables were available for the entire study period (2006–2016) except for chorioamnionitis, hypertension, and inhaled nitric oxide, which were added in 2008.

Mortality was defined as death before hospital discharge. RDS was defined as room air Pao2 <50 mm Hg, room air central cyanosis, supplemental oxygen to maintain Pao2 >50 mm Hg, or supplemental oxygen to maintain a pulse oximeter saturation of >85% and a chest radiograph consistent with RDS within the first 24 hours of life.19 Patent ductus arteriosus (PDA) was defined as presenting 1 or more of the following: (1) left-to-right or bidirectional ductal shunt on Doppler echo or (2) systolic or continuous murmur, and 2 or more of the following: (1) hyperdynamic precordium, (2) bounding pulses, (3) wide pulse pressure, or (4) pulmonary vascular congestion, cardiomegaly, or both.19 NEC was diagnosed at surgery or postmortem or required at least 1 clinical sign (eg, bilious gastric aspirate, abdominal distension, or occult blood in stool) and at least 1 radiographic finding (eg, pneumatosis intestinalis, hepatobiliary gas, or pneumoperitoneum).19 Focal intestinal perforation, separate from NEC, was defined as a single focal perforation with the remainder of the bowel appearing normal diagnosed at the time of surgery or postmortem examination.19 NEC and focal intestinal perforation were combined into 1 outcome labeled NEC. Early-onset sepsis (EOS) (less than or equal to day 3 of life) was defined as recovery of a bacterial pathogen from blood or cerebrospinal fluid.19 LOS (greater than day 3 of life) was defined as recovery of a bacterial pathogen or coagulase-negative Staphylococcus from blood or cerebrospinal fluid or recovery of a fungus from blood culture.19 Coagulase-negative Staphylococcus infection also required at least 1 sign of generalized infection and treatment with at least 5 days of intravenous antibiotics.19 Severe intraventricular hemorrhage (IVH) was defined as grades 3 or 4 by using Papile’s classification within 28 days of birth.20 Severe ROP was defined as stages 3 to 5 on the basis of a retinal examination before hospital discharge.21 CLD was defined as any use of supplemental oxygen at 36 weeks’ postmenstrual age or on oxygen at discharge at 34 to 35 weeks if transferred or discharged before 36 weeks.19 We also examined survival to discharge without a major neonatal morbidity, which was defined as having at least 1 of the following: early bacterial infection, late bacterial or fungal infection, NEC, CLD, severe IVH, periventricular leukomalacia, or severe ROP. Reporting hospitals tracked mortality before hospital discharge and after transfer until ultimate disposition or the infant’s first birthday, whichever came first. Morbidity outcomes were assessed until hospital discharge and were tracked if transferred infants were admitted to VON hospitals within 28 days of birth or if infants were readmitted to the original reporting hospital.

We computed summary statistics of maternal and neonatal characteristics and care practices for female and male infants. We subsequently calculated the following:

  1. incidence rates of maternal morbidities, obstetric practices, delivery room practices, NICU practices, and other practices by sex and year of birth along with 95% confidence intervals (CIs);

  2. mortality and morbidity relative risks (RRs) for boys versus girls, adjusted for gestational age in days, along with 95% CIs;

  3. incidence rates of infant mortality and morbidity by sex and year of birth along with 95% CIs and differences between rates for boys versus girls by year of birth along with 95% CIs; and

  4. differences between rates for boys versus girls of infant mortality and morbidity by year of birth and gestational age group (22–23, 24–25, 26–27, and 28–29 weeks) along with 95% CIs.

Adjusted RRs (2) were estimated by using standard Poisson regression. We tested differences in mortality and morbidity rates between boys and girls by means of a likelihood ratio test (LRT) on nested binomial regression models with log links. The null model included main effects for sex and a third-degree polynomial on year of birth. The alternative model included main effects as well as an interaction between sex and a third-degree polynomial on year of birth. No additional adjustments were made for other variables related to medical care to prevent masking of temporal effects. Statistical significance was set at the 5% level. Analyses were performed by using R22 and SAS software (version 9.4; SAS Institute, Inc, Cary, NC).

We assessed the sensitivity of the results when restricting the study sample to centers that participated in VON throughout the whole 11-year study period. In the restricted sample, there were 426 centers accounting for 77% of the infants.

Of 205 750 infants born at VON participating centers, 97 048 (47.2%) infants were girls whereas 108 702 (52.8%) infants were boys. Maternal and newborn characteristics and care practices of our study sample by sex are shown in Table 1. Girls were more likely than boys to be born to mothers with hypertension (31.2% vs 25.9%) and mothers who delivered by cesarean delivery (64.4% vs 62.1%). Boys were less likely than girls to have hypothermia at NICU admission (43.3% vs 45.1%) and more likely to receive surfactants at any time (76.3% vs 74.2%) and postnatal steroids (14.0% vs 11.6%).

TABLE 1

Number and Percentage of Female and Male Infants by Maternal and Newborn Characteristics and Care Practices

Characteristics and Care Practices22 wk23 wk24 wk25 wk22–29 wk
Female Infants, N = 3317Male Infants, N = 3948Female Infants, N = 7105Male Infants, N = 7720Female Infants, N = 10 769Male Infants, N = 11 968Female Infants, N = 11 958Male Infants, N = 13 342Female Infants, N = 97 048Male Infants, N = 108 702
Maternal, n (%)           
 Race           
  African American 1311 of 3267 (40.1) 1543 of 3890 (39.7) 2797 of 7057 (39.6) 3015 of 7679 (39.3) 4186 of 10 735 (39.0) 4359 of 11 929 (36.5) 4509 of 11 926 (37.8) 4672 of 13 301 (35.1) 34 045 of 96 666 (35.2) 35 541 of 108 302 (32.8) 
  Hispanic 748 of 3267 (22.9) 871 of 3890 (22.4) 1493 of 7057 (21.2) 1664 of 7679 (21.7) 2190 of 10 735 (20.4) 2445 of 11 929 (20.5) 2276 of 11 926 (19.1) 2629 of 13 301 (19.8) 18 825 of 96 666 (19.5) 21 970 of 108 302 (20.3) 
  White 996 of 3267 (30.5) 1238 of 3890 (31.8) 2374 of 7057 (33.6) 2558 of 7679 (33.3) 3772 of 10 735 (35.1) 4436 of 11 929 (37.2) 4446 of 11 926 (37.3) 5142 of 13 301 (38.7) 37 886 of 96 666 (39.2) 43 769 of 108 302 (40.4) 
  Asian American 138 of 3267 (4.2) 160 of 3890 (4.1) 238 of 7057 (3.4) 301 of 7679 (3.9) 372 of 10 735 (3.5) 463 of 11 929 (3.9) 417 of 11 926 (3.5) 544 of 13 301 (4.1) 3742 of 96 666 (3.9) 4545 of 108 302 (4.2) 
  Other 74 of 3267 (2.3) 78 of 3890 (2.0) 155 of 7057 (2.2) 141 of 7679 (1.8) 215 of 10 735 (2.0) 226 of 11 929 (1.9) 278 of 11 926 (2.3) 314 of 13 301 (2.4) 2168 of 96 666 (2.2) 2477 of 108 302 (2.3) 
 Prenatal care 3023 of 3277 (92.3) 3575 of 3902 (91.6) 6611 of 7061 (93.6) 7126 of 7665 (93.0) 10 138 of 10 735 (94.4) 11 270 of 11 933 (94.4) 11 349 of 11 918 (95.2) 12 627 of 13 304 (94.9) 92 230 of 96 745 (95.3) 103 187 of 108 364 (95.2) 
 Hypertensiona 202 of 2701 (7.5) 225 of 3185 (7.1) 747 of 5898 (12.7) 725 of 6324 (11.5) 1874 of 8919 (21.0) 1713 of 9917 (17.3) 2734 of 9889 (27.7) 2427 of 11 008 (22.0) 25 080 of 80 359 (31.2) 23 260 of 89 957 (25.9) 
 Chorioamnionitis 891 of 2695 (33.1) 906 of 3184 (28.5) 1716 of 5875 (29.2) 1658 of 6319 (26.2) 2293 of 8911 (25.7) 2478 of 9899 (25.0) 2215 of 9872 (22.4) 2320 of 10 977 (21.1) 15 220 of 80 229 (19.0) 16 642 of 89 811 (18.5) 
 Antenatal corticosteroidsb 521 of 3287 (15.9) 639 of 3893 (16.4) 4564 of 7071 (64.6) 4764 of 7668 (62.1) 8945 of 10 743 (83.3) 9966 of 11 934 (83.5) 10 293 of 11 937 (86.2) 11 377 of 13 314 (85.4) 79 926 of 96 836 (82.5) 88 580 of 108 407 (81.7) 
 Cesarean delivery 306 of 3316 (9.2) 368 of 3946 (9.3) 2842 of 7103 (40.0) 3008 of 7719 (39.0) 6872 of 10 768 (63.8) 7510 of 11 966 (62.8) 8119 of 11 957 (67.9) 8906 of 13 341 (66.8) 62 488 of 97 040 (64.4) 67 518 of 108 691 (62.1) 
Newborn           
 Birth wt, g, mean (SD) 479 (73) 507 (78) 557 (87) 590 (93) 631 (112) 675 (115) 716 (140) 768 (141) 887 (286) 947 (300) 
 Apgar score at 5 min of ≤3, n (%) 2428 of 2981 (81.4) 2958 of 3554 (83.2) 2607 of 6830 (38.2) 3040 of 7355 (41.3) 1809 of 10 574 (17.1) 2368 of 11 795 (20.1) 1247 of 11 862 (10.5) 1644 of 13 207 (12.4) 10 790 of 95 796 (11.3) 13 568 of 107 257 (12.7) 
 Delivery room intubation, n (%) 821 of 3307 (24.8) 1003 of 3936 (25.5) 5558 of 7099 (78.3) 6069 of 7708 (78.7) 9758 of 10 765 (90.7) 10 903 of 11 960 (91.2) 10 258 of 11 956 (85.8) 11 657 of 13 337 (87.4) 61 980 of 97 009 (63.9) 70 495 of 108 649 (64.9) 
 Postnatal life support, n (%)c 955 of 3317 (28.8) 1177 of 3948 (29.8) 5935 of 7105 (83.5) 6420 of 7720 (83.2) 10 561 of 10 769 (98.1) 11 703 of 11 968 (97.8) 11 891 of 11 958 (99.4) 13 274 of 13 342 (99.5) 92 204 of 97 048 (95.0) 103 377 of 108 702 (95.1) 
 Surfactants at any time, n (%)d 717 of 3314 (21.6) 846 of 3943 (21.5) 5350 of 7102 (75.3) 5763 of 7708 (74.8) 9895 of 10 767 (91.9) 11 038 of 11 962 (92.3) 10 928 of 11 957 (91.4) 12 315 of 13 338 (92.3) 71 953 of 97 022 (74.2) 82 939 of 108 664 (76.3) 
 Postnatal steroids, n (%) 158 of 814 (19.4) 173 of 986 (17.6) 1595 of 5490 (29.1) 1676 of 5883 (28.5) 2867 of 10 262 (27.9) 3596 of 11 397 (31.6) 2539 of 11 758 (21.6) 3306 of 13 080 (25.3) 10 699 of 91 904 (11.6) 14 388 of 102 690 (14.0) 
 Admission temperature, n (%)e           
  36.5°C–37.5°C 169 of 681 (24.8) 202 of 819 (24.7) 1666 of 5125 (32.5) 1799 of 5489 (32.8) 3853 of 9885 (39.0) 4347 of 10 950 (39.7) 5165 of 11 435 (45.2) 5911 of 12 713 (46.5) 43 474 of 89 444 (48.6) 50 104 of 99 932 (50.1) 
  <36.5°C 482 of 681 (70.8) 589 of 819 (71.9) 3239 of 5125 (63.2) 3443 of 5489 (62.7) 5482 of 9885 (55.5) 5959 of 10 950 (54.4) 5453 of 11 435 (47.7) 5957 of 12 713 (46.9) 40 304 of 89 444 (45.1) 43 269 of 99 932 (43.3) 
  >37.5°C 30 of 681 (4.4) 28 of 819 (3.4) 220 of 5125 (4.3) 247 of 5489 (4.5) 550 of 9885 (5.6) 644 of 10 950 (5.9) 817 of 11 435 (7.1) 845 of 12 713 (6.7) 5666 of 89 444 (6.3) 6559 of 99 932 (6.6) 
 Enteral feeding at discharge among survivors           
  None, n (%) 33 of 294 (11.2) 38 of 256 (14.8) 358 of 3045 (11.8) 373 of 2873 (13.0) 750 of 7402 (10.1) 898 of 7636 (11.8) 769 of 9804 (7.8) 932 of 10 403 (9.0) 4124 of 80 727 (5.1) 5297 of 87 675 (6.0) 
  Any human milk, n (%) 61 of 294 (20.8) 63 of 256 (24.6) 817 of 3045 (26.8) 838 of 2873 (29.2) 2295 of 7402 (31.0) 2456 of 7636 (32.2) 3391 of 9804 (34.6) 3555 of 10 403 (34.2) 33 572 of 80 727 (41.6) 37 061 of 87 675 (42.3) 
  Formula only, n (%) 200 of 294 (68.0) 155 of 256 (60.6) 1870 of 3045 (61.4) 1662 of 2873 (57.9) 4357 of 7402 (58.9) 4282 of 7636 (56.1) 5644 of 9804 (57.6) 5916 of 10 403 (56.9) 43 031 of 80 727 (53.3) 45 317 of 87 675 (51.7) 
 Total length of stay, d, median (IQR) 1 (1–1) 1 (1–1) 23 (1–122) 14 (1–121) 102 (33–126) 102 (17–128) 95 (76–116) 96 (76–118) 69 (48–95) 69 (47–97) 
Characteristics and Care Practices22 wk23 wk24 wk25 wk22–29 wk
Female Infants, N = 3317Male Infants, N = 3948Female Infants, N = 7105Male Infants, N = 7720Female Infants, N = 10 769Male Infants, N = 11 968Female Infants, N = 11 958Male Infants, N = 13 342Female Infants, N = 97 048Male Infants, N = 108 702
Maternal, n (%)           
 Race           
  African American 1311 of 3267 (40.1) 1543 of 3890 (39.7) 2797 of 7057 (39.6) 3015 of 7679 (39.3) 4186 of 10 735 (39.0) 4359 of 11 929 (36.5) 4509 of 11 926 (37.8) 4672 of 13 301 (35.1) 34 045 of 96 666 (35.2) 35 541 of 108 302 (32.8) 
  Hispanic 748 of 3267 (22.9) 871 of 3890 (22.4) 1493 of 7057 (21.2) 1664 of 7679 (21.7) 2190 of 10 735 (20.4) 2445 of 11 929 (20.5) 2276 of 11 926 (19.1) 2629 of 13 301 (19.8) 18 825 of 96 666 (19.5) 21 970 of 108 302 (20.3) 
  White 996 of 3267 (30.5) 1238 of 3890 (31.8) 2374 of 7057 (33.6) 2558 of 7679 (33.3) 3772 of 10 735 (35.1) 4436 of 11 929 (37.2) 4446 of 11 926 (37.3) 5142 of 13 301 (38.7) 37 886 of 96 666 (39.2) 43 769 of 108 302 (40.4) 
  Asian American 138 of 3267 (4.2) 160 of 3890 (4.1) 238 of 7057 (3.4) 301 of 7679 (3.9) 372 of 10 735 (3.5) 463 of 11 929 (3.9) 417 of 11 926 (3.5) 544 of 13 301 (4.1) 3742 of 96 666 (3.9) 4545 of 108 302 (4.2) 
  Other 74 of 3267 (2.3) 78 of 3890 (2.0) 155 of 7057 (2.2) 141 of 7679 (1.8) 215 of 10 735 (2.0) 226 of 11 929 (1.9) 278 of 11 926 (2.3) 314 of 13 301 (2.4) 2168 of 96 666 (2.2) 2477 of 108 302 (2.3) 
 Prenatal care 3023 of 3277 (92.3) 3575 of 3902 (91.6) 6611 of 7061 (93.6) 7126 of 7665 (93.0) 10 138 of 10 735 (94.4) 11 270 of 11 933 (94.4) 11 349 of 11 918 (95.2) 12 627 of 13 304 (94.9) 92 230 of 96 745 (95.3) 103 187 of 108 364 (95.2) 
 Hypertensiona 202 of 2701 (7.5) 225 of 3185 (7.1) 747 of 5898 (12.7) 725 of 6324 (11.5) 1874 of 8919 (21.0) 1713 of 9917 (17.3) 2734 of 9889 (27.7) 2427 of 11 008 (22.0) 25 080 of 80 359 (31.2) 23 260 of 89 957 (25.9) 
 Chorioamnionitis 891 of 2695 (33.1) 906 of 3184 (28.5) 1716 of 5875 (29.2) 1658 of 6319 (26.2) 2293 of 8911 (25.7) 2478 of 9899 (25.0) 2215 of 9872 (22.4) 2320 of 10 977 (21.1) 15 220 of 80 229 (19.0) 16 642 of 89 811 (18.5) 
 Antenatal corticosteroidsb 521 of 3287 (15.9) 639 of 3893 (16.4) 4564 of 7071 (64.6) 4764 of 7668 (62.1) 8945 of 10 743 (83.3) 9966 of 11 934 (83.5) 10 293 of 11 937 (86.2) 11 377 of 13 314 (85.4) 79 926 of 96 836 (82.5) 88 580 of 108 407 (81.7) 
 Cesarean delivery 306 of 3316 (9.2) 368 of 3946 (9.3) 2842 of 7103 (40.0) 3008 of 7719 (39.0) 6872 of 10 768 (63.8) 7510 of 11 966 (62.8) 8119 of 11 957 (67.9) 8906 of 13 341 (66.8) 62 488 of 97 040 (64.4) 67 518 of 108 691 (62.1) 
Newborn           
 Birth wt, g, mean (SD) 479 (73) 507 (78) 557 (87) 590 (93) 631 (112) 675 (115) 716 (140) 768 (141) 887 (286) 947 (300) 
 Apgar score at 5 min of ≤3, n (%) 2428 of 2981 (81.4) 2958 of 3554 (83.2) 2607 of 6830 (38.2) 3040 of 7355 (41.3) 1809 of 10 574 (17.1) 2368 of 11 795 (20.1) 1247 of 11 862 (10.5) 1644 of 13 207 (12.4) 10 790 of 95 796 (11.3) 13 568 of 107 257 (12.7) 
 Delivery room intubation, n (%) 821 of 3307 (24.8) 1003 of 3936 (25.5) 5558 of 7099 (78.3) 6069 of 7708 (78.7) 9758 of 10 765 (90.7) 10 903 of 11 960 (91.2) 10 258 of 11 956 (85.8) 11 657 of 13 337 (87.4) 61 980 of 97 009 (63.9) 70 495 of 108 649 (64.9) 
 Postnatal life support, n (%)c 955 of 3317 (28.8) 1177 of 3948 (29.8) 5935 of 7105 (83.5) 6420 of 7720 (83.2) 10 561 of 10 769 (98.1) 11 703 of 11 968 (97.8) 11 891 of 11 958 (99.4) 13 274 of 13 342 (99.5) 92 204 of 97 048 (95.0) 103 377 of 108 702 (95.1) 
 Surfactants at any time, n (%)d 717 of 3314 (21.6) 846 of 3943 (21.5) 5350 of 7102 (75.3) 5763 of 7708 (74.8) 9895 of 10 767 (91.9) 11 038 of 11 962 (92.3) 10 928 of 11 957 (91.4) 12 315 of 13 338 (92.3) 71 953 of 97 022 (74.2) 82 939 of 108 664 (76.3) 
 Postnatal steroids, n (%) 158 of 814 (19.4) 173 of 986 (17.6) 1595 of 5490 (29.1) 1676 of 5883 (28.5) 2867 of 10 262 (27.9) 3596 of 11 397 (31.6) 2539 of 11 758 (21.6) 3306 of 13 080 (25.3) 10 699 of 91 904 (11.6) 14 388 of 102 690 (14.0) 
 Admission temperature, n (%)e           
  36.5°C–37.5°C 169 of 681 (24.8) 202 of 819 (24.7) 1666 of 5125 (32.5) 1799 of 5489 (32.8) 3853 of 9885 (39.0) 4347 of 10 950 (39.7) 5165 of 11 435 (45.2) 5911 of 12 713 (46.5) 43 474 of 89 444 (48.6) 50 104 of 99 932 (50.1) 
  <36.5°C 482 of 681 (70.8) 589 of 819 (71.9) 3239 of 5125 (63.2) 3443 of 5489 (62.7) 5482 of 9885 (55.5) 5959 of 10 950 (54.4) 5453 of 11 435 (47.7) 5957 of 12 713 (46.9) 40 304 of 89 444 (45.1) 43 269 of 99 932 (43.3) 
  >37.5°C 30 of 681 (4.4) 28 of 819 (3.4) 220 of 5125 (4.3) 247 of 5489 (4.5) 550 of 9885 (5.6) 644 of 10 950 (5.9) 817 of 11 435 (7.1) 845 of 12 713 (6.7) 5666 of 89 444 (6.3) 6559 of 99 932 (6.6) 
 Enteral feeding at discharge among survivors           
  None, n (%) 33 of 294 (11.2) 38 of 256 (14.8) 358 of 3045 (11.8) 373 of 2873 (13.0) 750 of 7402 (10.1) 898 of 7636 (11.8) 769 of 9804 (7.8) 932 of 10 403 (9.0) 4124 of 80 727 (5.1) 5297 of 87 675 (6.0) 
  Any human milk, n (%) 61 of 294 (20.8) 63 of 256 (24.6) 817 of 3045 (26.8) 838 of 2873 (29.2) 2295 of 7402 (31.0) 2456 of 7636 (32.2) 3391 of 9804 (34.6) 3555 of 10 403 (34.2) 33 572 of 80 727 (41.6) 37 061 of 87 675 (42.3) 
  Formula only, n (%) 200 of 294 (68.0) 155 of 256 (60.6) 1870 of 3045 (61.4) 1662 of 2873 (57.9) 4357 of 7402 (58.9) 4282 of 7636 (56.1) 5644 of 9804 (57.6) 5916 of 10 403 (56.9) 43 031 of 80 727 (53.3) 45 317 of 87 675 (51.7) 
 Total length of stay, d, median (IQR) 1 (1–1) 1 (1–1) 23 (1–122) 14 (1–121) 102 (33–126) 102 (17–128) 95 (76–116) 96 (76–118) 69 (48–95) 69 (47–97) 

Reported wk are rounded down to the largest previous wk. Hypertension and chorioamnionitis variables were added in 2008; postnatal steroids and admission temperature variables were only recorded for infants admitted to the NICU. Data missing on race for 0.39% girls and 0.37% boys; prenatal care for 0.31% girls and 0.31% boys; hypertension for 17.2% girls and 17.2% boys; chorioamnionitis for 17.3% girls and 17.4% boys; antenatal corticosteroids for 0.22% girls and 0.27% boys; cesarean delivery for 0.01% girls and 0.01% boys; the Apgar score at 5 min for 1.3% girls and 1.3% boys; delivery room intubation for 0.04% girls and 0.05% boys; surfactants at any time for 0.03% girls and 0.03% boys; postnatal steroids for 0.17% girls and 0.18% boys; admission temperature for 2.8% girls and 2.9% boys; enteral feeding at discharge among survivors for 0.07% girls and 0.08% boys; and length of stay for 0.62% girls and 0.71% boys. IQR, interquartile range.

a

Maternal hypertension is defined as chronic or pregnancy-induced, as with or without edema and proteinuria, or as a maternal blood pressure of >140 systolic or 90 diastolic before or during the present pregnancy.

b

Exposure to antenatal corticosteroids is defined as steroids administered intramuscularly or intravenously to the mother during pregnancy at any time before delivery.

c

Postnatal life support includes any of the following: surfactant therapy at any time, endotracheal tube ventilation, ventilator support at any time (including nasal CPAP, nasal ventilation, face mask ventilation, or mechanical ventilation), epinephrine, or cardiac compressions.

d

Surfactants at any time also include surfactants if received in the delivery room.

e

An infant’s body temperature was measured by taking a rectal, esophageal, tympanic, or axillary temperature and was recorded within the first hour after admission to the NICU.

The chorioamnionitis rate was relatively stable over time with no differences in the rate noted between boys and girls (Supplemental Fig 4). The rate of maternal hypertension revealed an increasing trend over time for both sexes but was higher for female than for male infants.

The use of antenatal corticosteroids increased over time similarly for both sexes (Supplemental Fig 5). The cesarean delivery rate increased over time for mothers of either male or female infants, but the rate was higher for mothers of female infants.

Delivery room tracheal intubation, epinephrine, cardiac compression, and surfactant therapy rates decreased over time whereas the rate of face-mask ventilation increased over time for both boys and girls (Fig 1). Rates of epinephrine and cardiac compression were slightly higher for male than for female infants. Supplemental oxygen use remained relatively constant over time, with similar rates in boys and girls.

FIGURE 1

Rates of delivery room practices among female and male infants by birth year. The pink line represents female infants, the blue line represents male infants, and the borders represent 95% CIs.

FIGURE 1

Rates of delivery room practices among female and male infants by birth year. The pink line represents female infants, the blue line represents male infants, and the borders represent 95% CIs.

Rates of NICU practices were, in general, similar in male and female infants, but when different, they were higher for male infants. The use of nasal CPAP, nasal ventilation, high-flow nasal cannula, and nasal CPAP before assisted ventilation revealed positive trends over time, but rates were similar in boys and girls (Fig 2). Conventional ventilation decreased over time for all infants, but rates were higher in boys. The rate of high-frequency ventilation was relatively constant over time but remained higher in boys compared with girls. Ventilation after CPAP revealed a negative trend followed by a positive trend, with higher rates for boys. The use of inhaled nitric oxide was relatively constant over time but remained slightly higher for boys.

FIGURE 2

Rates of NICU practices among female and male infants by birth year. The pink line represents female infants, the blue line represents male infants, and the borders represent 95% CIs.

FIGURE 2

Rates of NICU practices among female and male infants by birth year. The pink line represents female infants, the blue line represents male infants, and the borders represent 95% CIs.

Although the rate of steroids for CLD increased over time for all infants, the rate was higher for male than for female infants. Surfactants at any time decreased over time for all infants, with higher rates observed in boys (Fig 2).

The hypothermia rate revealed a negative trend over time but remained slightly higher for female than for male infants. Hyperthermia rates increased over time similarly for both sexes. The rate of any enteral human milk feeding at discharge, restricted to survivors, increased over time and was similar in both sexes (Supplemental Fig 6).

Overall mortality and morbidity rates as well as adjusted RRs with 95% CIs are reported in Table 2. Compared with girls, boys had significantly higher risks of mortality before hospital discharge, RDS, NEC, LOS, severe IVH, severe ROP, CLD, pneumothorax, and survival with morbidities. Mortality and morbidity rates during the study period are shown separately for girls and boys in Supplemental Fig 7. Rate differences between boys and girls during the study period are shown in Fig 3. PDA, EOS, LOS, and severe ROP revealed a constant rate difference over time. PDA and EOS rates did not differ between boys and girls during the study period. LOS and severe ROP rates revealed occasionally higher rates for boys than for girls. The rate differences of RDS, NEC, severe IVH, pneumothorax, and survival with morbidities were also constant over time. However, rates of NEC, severe IVH, and survival with morbidities were higher in boys than in girls throughout the study period. On the other hand, rates of RDS and pneumothorax were higher in boys for most but not all of the years. The rate difference for mortality and CLD decreased faster over time for male than for female infants, with a significant year-sex interaction (LRT P value <.001 for mortality; P value = .006 for CLD).

TABLE 2

Number and Percentage of Female and Male Infants by In-Hospital Mortality and Morbidities

Female Infants, N = 97 048Male Infants, N = 108 702Adjusted RR (95% CI)
Died within 12 h of birth, n (%) 4992 of 97 048 (5.1) 5831 of 108 702 (5.4) 1.02 (0.98–1.06) 
Died before hospital discharge, n (%) 15 769 of 96 553 (16.3) 20 298 of 108 046 (18.8) 1.15 (1.12–1.17) 
Postnatal age at death, d, median (IQR) 3 (1–17) 3 (1–18) — 
Time of death, n (%)    
 0–12 h 4992 (31.7) 5831 (28.8) — 
 >12 h–28 d 8230 (52.3) 11 027 (54.4) — 
 >28 d 2525 (16.0) 3419 (16.9) — 
Infants who survived beyond delivery room, N 92 056 102 871  
 RDS, n (%) 78 605 of 92 039 (85.4) 89 375 of 102 853 (86.9) 1.02 (1.01–1.03) 
 PDA, n (%) 37 201 of 91 842 (40.5) 41 784 of 102 630 (40.7) 1.01 (0.99–1.02) 
 NEC or focal intestinal perforation, n (%) 7761 of 91 970 (8.4) 10 368 of 102 766 (10.1) 1.20 (1.17–1.24) 
 EOS, n (%) 2357 of 91 940 (2.6) 2565 of 102 740 (2.5) 0.98 (0.92–1.03) 
 LOS, n (%) 15 397 of 86 978 (17.7) 18 146 of 96 097 (18.9) 1.08 (1.06–1.10) 
Infants with cranial sonogram within 28 d, N 86 043 95 555  
 Severe IVH, n (%) 7118 of 86 012 (8.3) 10 365 of 95 530 (10.9) 1.33 (1.29–1.37) 
Retinal exam, N 74 334 80 666  
 Severe ROP, n (%) 6484 of 74 272 (8.7) 7338 of 80 600 (9.1) 1.10 (1.06–1.14) 
CLD, n (%) 25 440 of 77 661 (32.8) 32 640 of 83 940 (38.9) 1.22 (1.20–1.24) 
Pneumothorax, n (%) 4147 of 92 028 (4.5) 5481 of 102 838 (5.3) 1.19 (1.14–1.24) 
Survived to discharge, N 80 784 87 748  
 Survival without morbidities, n (%) 38 254 of 73 647 (51.9) 36 868 of 80 043 (46.1) 0.87 (0.86–0.88) 
Female Infants, N = 97 048Male Infants, N = 108 702Adjusted RR (95% CI)
Died within 12 h of birth, n (%) 4992 of 97 048 (5.1) 5831 of 108 702 (5.4) 1.02 (0.98–1.06) 
Died before hospital discharge, n (%) 15 769 of 96 553 (16.3) 20 298 of 108 046 (18.8) 1.15 (1.12–1.17) 
Postnatal age at death, d, median (IQR) 3 (1–17) 3 (1–18) — 
Time of death, n (%)    
 0–12 h 4992 (31.7) 5831 (28.8) — 
 >12 h–28 d 8230 (52.3) 11 027 (54.4) — 
 >28 d 2525 (16.0) 3419 (16.9) — 
Infants who survived beyond delivery room, N 92 056 102 871  
 RDS, n (%) 78 605 of 92 039 (85.4) 89 375 of 102 853 (86.9) 1.02 (1.01–1.03) 
 PDA, n (%) 37 201 of 91 842 (40.5) 41 784 of 102 630 (40.7) 1.01 (0.99–1.02) 
 NEC or focal intestinal perforation, n (%) 7761 of 91 970 (8.4) 10 368 of 102 766 (10.1) 1.20 (1.17–1.24) 
 EOS, n (%) 2357 of 91 940 (2.6) 2565 of 102 740 (2.5) 0.98 (0.92–1.03) 
 LOS, n (%) 15 397 of 86 978 (17.7) 18 146 of 96 097 (18.9) 1.08 (1.06–1.10) 
Infants with cranial sonogram within 28 d, N 86 043 95 555  
 Severe IVH, n (%) 7118 of 86 012 (8.3) 10 365 of 95 530 (10.9) 1.33 (1.29–1.37) 
Retinal exam, N 74 334 80 666  
 Severe ROP, n (%) 6484 of 74 272 (8.7) 7338 of 80 600 (9.1) 1.10 (1.06–1.14) 
CLD, n (%) 25 440 of 77 661 (32.8) 32 640 of 83 940 (38.9) 1.22 (1.20–1.24) 
Pneumothorax, n (%) 4147 of 92 028 (4.5) 5481 of 102 838 (5.3) 1.19 (1.14–1.24) 
Survived to discharge, N 80 784 87 748  
 Survival without morbidities, n (%) 38 254 of 73 647 (51.9) 36 868 of 80 043 (46.1) 0.87 (0.86–0.88) 

Model adjusted for gestational age in d (continuous). IQR-interquartile range. —, not applicable.

FIGURE 3

Rate differences in mortality and morbidity outcomes among male versus female infants by birth year. The solid black line represents the rate difference and the borders represent 95% CIs.

FIGURE 3

Rate differences in mortality and morbidity outcomes among male versus female infants by birth year. The solid black line represents the rate difference and the borders represent 95% CIs.

Similar results were obtained after the analysis was restricted to VON centers that were in the study throughout the entire period, except that now the year-sex interaction for RDS was significant (P value = .04), with boys having a faster decline in RDS (Supplemental Fig 8).

In the analyses by gestational age groups (Supplemental Figs 9–12), we observed that mortality decreased in boys at a faster rate than in girls specifically for infants at 24 to 25 (P value = .021), 26 to 27 (P value = .019), and 28 to 29 (P value = .0072) weeks’ gestation but not for infants at 22 to 23 week’s gestation (P value = .27). A statistically significant faster decline in CLD rates for boys compared with girls was observed only at 24 to 25 (P value = .032) weeks’ gestation. A significant sex-year interaction term was also observed for pneumothorax for infants born at 22 to 23 weeks’ gestation (LRT P value = .0062).

In a study of >205 000 infants born in the United States over a period of 11 years, we examined changes in the rates of care practices in male and female infants and whether changes4 in mortality and morbidities benefited 1 sex over the other. We report that boys had higher rates than girls for conventional ventilation, high frequency ventilation, ventilation after CPAP, inhaled nitric oxide, steroids for CLD, and surfactants at any time; on the other hand, girls had higher rates than boys for maternal hypertension and cesarean delivery. We also show that although boys still had higher rates for mortality, RDS, and CLD, the rates of decline over the study period for these outcomes were faster for boys than for girls (ie, the gap narrowed between 2006 and 2016).

Preterm male infants are known to be at a higher mortality risk than preterm female infants.23,24 Sex is 1 of the predictors in the Eunice Kennedy Shriver National Institute of Child Health and Human Development calculator, which was developed to predict mortality for infants born at the edge of viability between 22 and 25 weeks’ gestation; being born of female sex was associated with reductions in the risk of death equivalent to those associated with an extra gestational week.12 To our knowledge, the authors of only 1 study have examined whether boys and girls have benefited equally from the improved infant survival. Using linked birth and death certificates for live-born infants in Massachusetts between 1989 and 1995, the authors of that study showed a more rapid decline in neonatal mortality among male (1.5 of 1000 live births) than among female (0.9 of 1000 live births) infants.25 The largest decline in male excess mortality was observed among very premature infants with a gestational age of ≤30 weeks and resulted primarily from a more rapid decline in male deaths from RDS.25 The authors of that study suggested that the changes in neonatal care (including increased use of antenatal corticosteroids and the availability of surfactant therapy) during 1989–1995 contributed to the decrease in RDS and ultimately to the subsequent improvement in survival among male infants.25 In our study, we examined a larger sample size of preterm infants in a different time period (2006–2016). Because a statistically significant faster rate of decline in mortality for boys versus girls was observed only for those born between 24 and 29 weeks’ gestation, we speculate that the benefits of improved neonatal care practices do not extend to male infants born at earlier gestational ages or that extreme immaturity takes precedence over the benefits of improved care practices. We also speculate that the observed decline might reflect increasingly aggressive respiratory care practices for those infants who need it the most (ie, male infants). Given the importance of sex in mortality prognostic models, the equivalent benefit of added gestational days for being born of female sex will have to be reassessed in the future.

Compared with female infants, preterm male infants are reported to be at a higher risk for severe IVH,23 sepsis,13,23 NEC,9 ROP,14 and respiratory outcomes (including RDS11,26 and BPD9,11,15,16), similar to what we observed in our study. Increased rates of respiratory disorders among boys are partly due to their delayed lung maturation.27 Sex hormones have been shown to impact fetal lung development with androgens negatively and estrogens positively, influencing surfactant production.27,29 However, to our knowledge, there have been no studies in which the authors examined whether changes in morbidities, as reported in recent studies,1,2,4 have affected male and female infants differently. Interestingly, we observed that the rate of decline for RDS and CLD was faster in boys than in girls. However, it is difficult to assess the direct effect of practice changes on this improvement in the rate of RDS and CLD among boys.

Compared with female preterm infants, male preterm infants achieve targeted arterial oxygen saturation levels at a later time,30 and they tend to have a higher need for mechanical ventilation31 and postnatal steroids.10 Because boys are more vulnerable to respiratory conditions, the changes in neonatal care might have influenced sex-specific survival, RDS, and CLD differently. Treatments and care practices that have benefited male more than female infants reflect in utero differences in terms of biological factors. Such differences can potentially provide insight into causal pathways that impact male vulnerability and can guide future research in which sex-specific interventions are explored. Unfortunately, we did not have information on the causes of death to be able to further explore the faster decline in male mortality. However, in a study by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in which the authors examined the causes of death among extremely preterm infants, results revealed that fewer deaths attributed to RDS and BPD have occurred in 2008–2011 compared with 2000–2003 and 2004–20075; these are morbidities that, in our study, revealed a decline among male infants faster than that among female infants.

Strengths of our study include a large sample size with >205 000 infants examined over a period of 11 years. Data collected by VON on these infants represent 88% of all US births at 22 to 29 weeks’ gestation. Our findings were confirmed when we restricted our study sample to hospitals that participated in VON throughout the entire study period. However, our study has limitations. We were unable to determine which changes in care practices are responsible for the narrowing gap between male and female infants. Also, we did not have information on the causes of death. It is worth noting that postnatal life support, as defined elsewhere,32 was similar in boys and girls throughout the study period (results not shown).

We show that between 2006 and 2016, male infants at <30 weeks’ gestation were still at a higher risk for mortality and several morbidities than female infants. However, male infants had a faster decline in mortality, RDS, and CLD than female infants, whereas other in-hospital morbidities revealed a constant rate difference over time. Authors of future studies should examine which causes of death among boys declined over time and whether boys’ improved survival has been accompanied by a change in their neurodevelopmental impairment rate.

     
  • BPD

    bronchopulmonary dysplasia

  •  
  • CI

    confidence interval

  •  
  • CLD

    chronic lung disease

  •  
  • CPAP

    continuous positive airway pressure

  •  
  • EOS

    early-onset sepsis

  •  
  • IVH

    intraventricular hemorrhage

  •  
  • LOS

    late-onset sepsis

  •  
  • LRT

    likelihood ratio test

  •  
  • NEC

    necrotizing enterocolitis

  •  
  • PDA

    patent ductus arteriosus

  •  
  • RDS

    respiratory distress syndrome

  •  
  • ROP

    retinopathy of prematurity

  •  
  • RR

    relative risk

  •  
  • VON

    Vermont Oxford Network

Dr Boghossian participated in the conception and design of the study (including the analysis plan and the interpretation of the data), wrote all drafts of the manuscript, and helped to revise the manuscript critically for important intellectual content; Dr Geraci participated in designing the analysis plan, was responsible for the data management and data analysis, participated in the interpretation of the data, contributed to writing sections of the manuscript, and helped to revise the manuscript critically for important intellectual content; Dr Edwards participated in the conception of the study and the interpretation of the data and revised the manuscript critically for important intellectual content; Dr Horbar participated in the conception of the study, is the Chief Executive and Scientific Officer of the Vermont Oxford Network (from which the data were drawn), participated in the interpretation of the data, and helped to revise the manuscript critically for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

We thank our medical and nursing colleagues and the infants and their parents who agreed to take part in this study. Participating centers are listed in Supplemental Table 3.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Horbar is an employee of the Vermont Oxford Network; Dr Edwards receives salary support from the Vermont Oxford Network; and Drs Boghossian and Geraci have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data