Short-term prognosis of very-preterm infants of ethnic minorities and Han nationality at high altitude: a single-center, retrospective study

Abstract Objective We aimed to analyze the perinatal care of very-preterm infants (VPIs) in plateau areas of China and to explore any differences in short-term outcomes between ethnic minorities and Han nationality. Methods VPIs with gestational age (GA) <32 weeks admitted to Qinghai Red Cross Hospital from 1 January 2018 to 31 December 2020 were enrolled. Maternal information, neonatal information, perinatal care and discharge outcomes were retrospectively collected and analyzed. Results A total of 302 VPIs were examined, including 143 (47.4%) ethnic minority infants and 159 (52.6%) Han infants. Mothers of ethnic minority infants were significantly younger than those of Han infants (27 y vs. 30 y, p < .001). There were no differences in the incidence of assisted reproduction, multiple pregnancies, maternal hypertension, clinical chorioamnionitis or premature rupture of membranes >18 h between ethnic minority mothers and Han mothers. Lower proportions of cesarean section and incidence of maternal diabetes were observed in ethnic minority mothers than in Han mothers [(9.1 vs.17.6%, p < .05) and (42.7 vs. 57.9%, p < .05, respectively)]. Meanwhile, fewer antenatal steroids were used in minority group than Han group (65.7 vs. 81.1%, p < .05). No significant differences in rates of death, active treatment, necrotizing enterocolitis stage ≥2, moderate-to-severe BPD, and incidence of severe retinopathy of prematurity in VPIs were found between the two groups and in all GA subgroups. Severe neurological injury was significantly less common in the minority newborns than in the Han infants (1.2 vs. 6.1%, p < .05). Compared with Han group, no excess risk of death, death or major morbidity, death despite active treatment, death or major morbidity despite active treatment was observed in ethnic minorities, with or without adjusting for gestational age and prenatal steroids. Conclusions Short-term prognosis of VPIs of ethnic minorities were similar to those of Han nationality.


Background
Very-preterm infants (VPIs) are premature infants with a gestational age (GA) <32 weeks who have higher incidence of death and morbidities than mature infants.On accounting for differences in perinatal care, therapeutic method and medical conditions, the survival rate and incidence of major morbidities of VPIs vary greatly in different regions [1,2].A variety of factors, including race/ethnicity, affect the outcomes of VPIs.A population-based study in New York demonstrated that African American, Hispanic, and Asian premature babies have increased risks of morbidities than Caucasian babies [3].A systematic review showed that differences in breastfeeding rates, mortality or serious complications, and follow-up rates after discharge existed among premature infants of different races or nationalities [4].China is a multi-ethnic country, with ethnic minorities accounting for 8.89% of the country's total population [5].Most ethnic minorities live in remote and economically disadvantaged areas of the country.Owing to the relatively poor maternal and infant healthcare conditions in these areas, the infant mortality is higher than the national average [6].Qinghai Province, on the Qinghai-Tibet Plateau, houses approximately 5.92 million people from ethnic minorities, accounting for 49.49% of the province's total population.Approximately 80,000 ethnic minority infants are born annually.However, there are no reports on the outcomes of VPIs of ethnic minorities in China and whether there are any differences in the mortality and incidence of morbidities between ethnic minorities and Han populations.To investigate the short-term prognosis of VPIs from ethnic minorities in the plateau areas of China, we conducted a single-center, retrospective study.By collecting clinical data, we compared and analyzed the short-term outcomes of VPIs of ethnic minorities and Han populations.The aim of our study was to examine whether perinatal care and short-term outcomes of VPIs vary between ethnic minorities and Han populations at high altitudes populations.

Research participants
VPIs with a GA <32 weeks admitted to the neonatal intensive care unit (NICU) of Qinghai Red Cross Hospital from 1 January 2018 to 31 December 2020 were enrolled.The inclusion criteria were as follows: (1) GA <32 weeks, (2) delivered at the hospital, (3) admitted to the NICU within 24 h after birth, and (4) complete clinical information.Infants who were born with severe congenital malformations and those who had genetic or metabolic diseases were excluded.This study was approved by the Ethics Committee of the Qinghai Red Cross Hospital (approval no: KY-2021-29).

Data collection
This was a retrospective study.By searching the medical record system of Qinghai Red Cross Hospital, VPIs who met the inclusion criteria were identified and the following information was collected: (1) maternal information, including ethnicity, age, parity, assisted reproduction status, multiple pregnancy status, hypertension, diabetes, chorioamnionitis, duration of premature rupture of membranes, mode of delivery, and use of prenatal glucocorticoids; (2) neonatal information, including GA at birth, birth weight, small for gestational age (SGA), sex, 5-min Apgar score, and delivery room resuscitation; and (3) short-term outcomes of premature infants, including discharge outcomes, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP).

Definitions
The ethnic minorities in China included 55 ethnic groups, excluding Han nationality.Maternal hypertension included chronic hypertension, gestational hypertension, pre-eclampsia, and eclampsia [7].Maternal diabetes mellitus included maternal diabetes of any type or severity [8].Prenatal glucocorticoid use meant that the mother received at least one dose of glucocorticoid intravenously or intramuscularly at any time prior to delivery.Assisted reproduction meant that the mother conceived using any means of assisted reproduction.Clinical chorioamnionitis referred to an elevated maternal temperature (!38 C) accompanied by two or more of the following symptoms or signs: increased pulse (>100 beats/min), increased fetal heart rate (>160 beats/min), tenderness of the uterine floor, foul smelling amniotic fluid, and elevated white blood cell levels (>15 Â 10 9 /L or nuclear shift to the left) [9].SGA was defined as a birth weight below the 10th percentile, based on the Fenton Growth Chart [10].BPD was defined as oxygen dependency at 28 days after birth, and moderate-to-severe BPD referred to ventilation or oxygen dependency at 36 weeks' corrected age or at discharge, transfer, or death before 36 weeks [11].Severe neurological injury included IVH grade 3 or 4 based on Papile's criteria [12], or any grade of PVL.NEC was defined as stage 2 or higher based on Bell's criteria [13].Severe ROP was defined as ROP stage III or above or the need for treatment according to the International Classification of Retinopathy of Prematurity [14].Study main outcomes were mortality (death despite active treatment or death occurred after withholding or withdrawing from care) and major morbidity, which was defined as the presence of moderate-to-severe BPD, severe neurological injury, NEC stage !2, or severe ROP [8].

Patient grouping
According to the mother's ethnicity, VPIs were divided into two groups: ethnic minorities and Han.The ethnic minorities included Tibetan, Hui, Salar, Mongolian, and Tu ethnic groups.

Statistical methods
Categorical variables were expressed as number (percentage), and the v 2 test was used for intergroup comparisons.Continuous variables were expressed as (mean ± SD) or median and interquartile range (P25, P75) and compared using Student's t-test or a nonparametric test, as appropriate.According to the GA, VPIs were divided into 26-27-week, 28-29-week, and 30-31week groups for subgroup analysis.Outcomes of ethnic minorities and Han were compared after controlling for GA and prenatal glucocorticoid use using logistic regression analysis.Two-tailed p-values <.05 were considered statistically significant.Statistical analyses were performed using IBM SPSS Statistics, version 20.

Patient characteristics
The median maternal age of ethnic minority infants was significantly lower than that of Han infants (27 y vs. 30 y, respectively) (p < .001).No significant differences in the incidence of assisted reproduction, multiple pregnancies, maternal hypertension, clinical chorioamnionitis, or premature rupture of membranes >18 h between the two groups were found (p > .05).The rates of cesarean section, maternal diabetes and prenatal glucocorticoid use were lower in ethnic minority mothers than those in the Han population (p < .05).There were no significant differences in GA, birth weight, SGA ratio, male ratio, 5-min Apgar score 7, or delivery room tracheal intubation rate between the two groups (Table 1).

Short-term outcomes
The proportion of VPIs receiving active treatment for minority infants and Han populations were 66.4 and 74.8%, respectively, without significant differences.Meanwhile, the similar rates of death and death or major morbidity were observed in minority infants and Han populations [(35.7 vs. 26.4%,p > .05)and (53.1 vs. 46.5%,p > .05),respectively].In addition there were no significantly differences in death despite active treatment and death or major morbidity despite active treatment between the VPIs of two group [(9.5 vs.6.7%, p > .05)and (35.8 vs. 33.6%,p > .05),respectively].Furthermore, no significantly differences of rates of necrotizing enterocolitis stage !2, moderate-to-severe BPD and incidences of severe retinopathy of prematurity in VPIs were found between the two groups and in all GA subgroups.However, less common severe neurological injury in the minority infants was observed than the Han infants (1.4% vs. 6.3%, p < .05)(Table 2).

Multivariate analysis of death or serious complications in VPIs of ethnic minorities
No excess risk of adverse outcomes (death, death or major morbidity, death despite active treatment, death or major morbidity despite active treatment) was observed in minority group compared with Han group, with or without controlling for gestational age and prenatal glucocorticoid use (Table 3).

Discussion
We conducted a single-center, retrospective study to compare the short-term prognosis of VPIs of ethnic minorities with those of Han nationality on the Qinghai-Tibet Plateau in China.The results showed that the mothers of ethnic minorities were younger and had lower rates of cesarean section and prenatal glucocorticoid use.The risk of severe neurological injury was significantly lower in the ethnic minorities than that in the Han population, but no significant difference in incidence of death, death or major morbidity, active treatment, or any major morbidity (NEC stage !2, moderate-to-severe BPD, and severe ROP) was observed.Perinatal care, especially prenatal care, is closely related to neonatal prognosis [15].According to a study conducted in New York, 80.3, 72.8, 66.1, and 61.7% of Caucasian, Asian, Hispanic, and African-American mothers, respectively, received prenatal care 3 months before childbirth.Of the African American mothers, 10.7% did not receive prenatal counseling before giving birth [3].A multicenter study conducted in 8 provinces of China showed that only 78.79% pregnant women received five times antenatal care throughout pregnancy [16].Another study showed that the proportion of prenatal care is different in different cities across China [17].According to the joint survey data of the United Nations and the Chinese government in 2010, the main ethnic groups in Qinghai and Tibet are ethnic minorities.The coverage rate of antenatal examinations (completed at least once) in Qinghai and Tibet is <80%, and only 6-7% of the participants completed four antenatal examinations [18].The reasons for these results are varied, possible reasons include scarcity of health care resources caused by regional margins and lack of awareness regarding prenatal care owing to the relatively low educational level of the ethnic minority population.A study on the health status of infants and mothers of different ethnicity in Vietnam reported similar results [19].Our study showed that the rates of cesarean section and prenatal glucocorticoid use were lower in ethnic minorities, which might be related to poor availability of medical resources of ethnic minorities.
Increasing the availability of perinatal care for ethnic minority mothers might help improve the prognosis of preterm infants.Differences have been found in the incidences of NEC and BPD in different races in previous studies [3,4].Study in the United States have shown that African Americans have higher risk of developing NEC and BPD than Caucasians, while Hispanics and Asians have no increased risk [3].Differences in morbidities for different races and genetic susceptibility are correlated, but the specific mechanism remains unknown [20,21].In our study, no difference was observed in the incidence of NEC or BPD between ethnic minorities and Han populations.This could have been related to the fact that ethnic minorities and Han nationalities living in plateau areas are all Asian, the genetic background differences could be relatively small.
IVH and PVL are the main neurological complications of preterm infants.Preterm infants with IVH or PVL have increased risk of developing poor neurological outcomes, such as cerebral palsy, intellectual disability, blindness, deafness, and language disorders [22].A multicenter study in the United States showed that the incidence of IVH in premature infants with a GA 30 weeks was 25%, and the incidence of severe (grades III-IV) IVH was 10% [23].In our study, the proportion of VPIs with severe neurological injury was 1.4% in ethnic minorities and 6.3% in Han populations, which is quite surprising.A study conducted in China showed that the incidence of severe IVH was 6.9% in 1079 infants whose GA was less than 30 weeks [24].A large study conducted by the Canadian Neonatal Network, including eight international collaborative units, showed that the incidence of severe IVH in VPIs (GA 24-32 weeks) was 7% [25].In our study, the incidence of severe IVH in VPIs of ethnic minorities and Han population was lower than those in previous studies.This result could have been attributed to the fact that the infants enrolled in this study were more mature than those in other studies.As for the reasons for lower incidence of neurological injury of ethnic minority VPIs, no reasonable explanation can be found currently.
Our study showed that more than one third of the ethnic minority VPIs and over a quarter of Han VPIs died after active treatment or after withdrawing from treatment.The unacceptable high rate of withdrawing from treatment could have been the primary reason of the high incidence of death of the VPIs.The reasons for withdrawing from treatment are varied, the main reasons included parental concerns about the prognosis and high hospital costs.To lower the rate of withdrawing from treatment, measures to improve the parents' understanding of the prognosis of preterm infants and to reduce their financial burden should be taken.
To the best of our knowledge, this is the first study to compare short-term outcomes of VPIs of ethnic minorities and Han in Qinghai-Tibet Plateau.This study found differences in prenatal care for VPIs between ethnic minorities and Han, while no significant differences was found in short-term outcomes except for the incidence of severe neurological injury.Our study has several limitations.First, it was a retrospective, single center, small sample size study, and some data were missing.Second, preterm infants born outside the hospital were excluded due to lack of maternal information.Finally, only short-term outcomes of VPIs were investigated, long-term outcomes of these infants were not available.

Conclusions
In summary, prenatal care of VPIs from ethnic minorities was poorer than those of Han, however, no difference was found in the incidence of death or major morbidities except for severe neurological injury.More investigations of larger sample size are needed, as well as studies investigating long-term outcomes of VPIs at plateau area.

Ethical approval
The study was approved by the Qinghai Red Cross Hospital Ethics Committee (KY-2021-29).Informed consent was waived by ethics committee because this study was a retrospective analysis of clinical data.Anonymity was maintained by using the identified number instead of the patient's names.All methods were performed in accordance with the ethical guidelines.

Table 1 .
Maternal and neonatal characteristics.

Table 2 .
Short-term outcomes of the infants.

Table 3 .
Multivariate analysis of outcomes between the two groups.