Comparison of neonatal outcomes between multiples and singletons among very low birth weight infants: The Korean Neonatal Network Cohort Study

Abstract

To compare neonatal outcomes between multiples and singletons among very low birth weight infants (VLBWIs), this was a prospective cohort study that was conducted by collecting data registered in the Korean Neonatal Network (KNN) database from January 2013 to December 2016. There were 8265 infants in the KNN database, and 2958 of them were from a multiple pregnancy (MP VLBWIs). Among them, 2636 infants were twins, 308 infants were triplets, and 14 infants were quadruplets. MP VLBWIs had a higher gestational age, birth weight, Apgar scores at 5 minutes, the rates of caesarean section and artificial reproductive technology (ART) but lower maternal hypertension, oligohydramnios, chorioamnionitis rates and CRIB scores than the singleton VLBWIs (SG VLBWIs). In univariate analysis, the MP VLBWIs had a lower incidence of respiratory distress syndrome, bronchopulmonary dysplasia, and sepsis, but the mortality rate was not significantly different for overall gestational ages except born at ≤ 26 weeks of gestation. In multivariate logistic analysis, the incidences of intraventricular haemorrhage (grade ≥ 3), and retinopathy of prematurity requiring treatment were significantly higher than the SG VLBWIs. A new strategy to improve the mortality of immature MP VLBWIs born at ≤ 26 weeks of gestation should be developed.

Introduction

The number of multiple pregnancies has been increasing mainly in developed countries due to the increase in assisted reproductive technology (ART), including in vitro fertilization, and the increased reproductive age of mothers. In 2018, 33.5 of every 1000 births in the United States were multiple births¹. In Korea, the multiple birth rate also increased from 10.0 to 27.5 per 1000 births between 1991 and 2008², and from 2009 to 2015, the birth rate of twins and triplets increased by 34.5% and 154.3%, respectively³.

Multiple pregnancies are risk factors for pregnancy complications such as preeclampsia, preterm premature rupture of membranes (PPROM), premature birth, intrauterine growth restriction (IUGR) and foetal death^3–5. Preterm infants, particularly those with a very low birth weight (VLBW), are a major risk factor for neonatal outcomes associated with multiple

pregnancies. One-third of the VLBWIs admitted to the neonatal intensive care unit (NICU) were multiples in Spain⁶. In addition, it has been reported that multiple pregnancy has a high incidence of congenital anomalies and lower efficacy of antenatal steroids^7,8. Risk factors for multiple foetuses are the basis for foetal reduction and selective termination during in vitro fertilization^9,10.

Although several studies have reported that these risk factors for multiple pregnancies lead to worse neonatal outcomes in multiples than in singletons^4,11,12, it was recently reported that the neonatal outcomes of multiples are similar to those of singletons¹³.

Therefore, the purpose of this study was to analyse the neonatal mortality and morbidity of multiple VLBWIs compared to those of singleton VLBWIs using a recent large cohort of infants from the Korean Neonatal Network (KNN) database.

Results

A total of 8265 infants were included, of which 2958 (35.8%) were from a multiple pregnancy. Of the 2958 MP VLBWIs, 2636 (89.1%) infants were twins, 308 (10.4%) infants were triplets, and 14 (0.5%) infants were quadruplets.

The mean GA (29^+ 2 weeks vs. 28^+ 4 weeks; P < 0.001) and mean BW (1150 g vs. 1100 g; P < 0.001) were higher in the MP group than in the SG group. The incidences of an Apgar score of ≥ 7 at 5 minutes, caesarean section, and IVF were significantly higher in the MP group than in the SG group. Among the 1564 MP infants (52.9%) conceived by IVF, 1344 (85.9%) were twins, 213 (13.6%) were triplets, and 7 (0.4%) were quadruplets. In contrast, the incidence of male sex, maternal HTN, oligohydramnios, chorioamnionitis, and a CRIB score of ≥ 8 was significantly lower in the MP group than in the SG group. There were no significant differences between groups in the incidence of transfers, maternal DM, PROM, antenatal steroid use, or major congenital defects (Table 1).

When comparing morbidity and mortality, the incidence of RDS was significantly lower in the MP group than in the SG group according to overall GA. The incidence of RDS was not significantly different between the two groups at ≤ 32 weeks of gestation but was significantly decreased in the MP group in the ≥ 33 weeks category. The incidence of PDA requiring surgery was not significantly different between groups at any GA; however, there was a significant increase in the MP group at 29–30 weeks of gestation. BPD and sepsis were significantly decreased in the MP group, but there was no significant difference in the incidence according to the GA category. The incidence of IVH, NEC, and ROP requiring treatment did not differ significantly between these groups across any GA categories. Mortality was not significantly different between these groups according to overall gestational age, except for a significant increase in the MP group at ≤ 26 weeks of gestation (Table 2).

In multivariate logistic regression analysis, the risk of IVH (OR, 1.74; 95% CI, 1.23–2.47; P = 0.002) and ROP requiring treatment (OR, 1.41; 95% CI, 1.01–1.97; P = 0.041) was significantly higher in the MP group than in the SG group (Table 3).

Discussion

Compared to SG infants, MP infants have historically been considered to have increased risk of perinatal mortality and morbidity, primarily because of higher rates of preterm birth and low BW^14–16. Although worse neonatal outcomes for MP infants have been seen at extremely low gestational age in several studies^{4,11,12,17,18}, some recent studies have reported that neonatal outcomes for MP infants are comparable to those for SG infants^13,19. In this study, the mortality rate of extremely premature MP infants born at ≤ 26 weeks of gestation was higher than that of SG infants in univariate analysis. This result is similar to the report of Shinwell²⁰, but MP was not an independent risk factor for mortality in multivariate analysis. However, there was a statistically significant increase in IVH grades ≥ 3 (OR = 1.74, 95% CI 1.23–2.47, p = 0.002) and ROP requiring treatment (OR = 1.41, 95% CI 1.01–1.97, p = 0.041) in MP infants. This is different from some reports that abnormalities shown on brain ultrasound are not high in VLBWIs born through IVF^21,22. Heo²² et al. suggested that pregnant women with VLBWIs who were conceived through IVF had relatively high socioeconomic status, suggesting the possibility that their prenatal management was more thorough. However, as a result of the analysis with multiples and singletons, including those conceived by both IVF and natural pregnancy, epidemiological differences, such as those in GA, BW, and 5-min Apgar scores, were more favourable in the MG group than in the SG group, and these results were inconsistent in these aspects. One of the causes of increased IVH may be differences in blood pressure between singletons and multiples²³ and some qualitative differences in early resuscitation by experienced medical faculty on in neonatal resuscitation program (NRP) teams. It cannot be excluded that the number of NRP team members caring for VLBWIs shortly after birth and the qualitative differences in procedures may differ between MG infants and SG infants. As reported in the paper, the prognosis differs depending on the number and skill level of the medical staff participating in delivery²⁴, and NRP teams may require at least 4 or more neonatal medical personnel per VLBWI to participate in the preparation for one newborn at a time. It is considered that there is a difference in the prognosis between VLBWIs born in hospitals where well-trained faculty members can attend every birth and VLBWIs who do not. However, the difference in these conditions was not included in the national data provided in this paper, so it was difficult to analyse, and more research is needed.

The incidence of ROP is generally known to increase with the use of excess oxygen^25,26. However, according to the results of this study, when the RDS, BPD, and sepsis rates were significantly reduced in the MG group, the increase in ROP requiring treatment was considered meaningful. Considering this, the vascular growth abnormality itself in multiples and the difference in vascular growth factors can be considered²⁷. Kistner et al.²⁷ reported high blood pressure in infants with severe ROP. In addition, as a factor that can vary depending on the individual tendency of an ophthalmologist to screen for and treat ROP, differences between institutions can be considered²⁸.

In the MP VLBWIs, maternal hypertension was low, caesarean section delivery was more frequent, and as expected, there was an increase in the number of pregnancies conceived through IVF. The rates of chorioamnionitis and oligohydramnios at birth were significantly lower, and the number of infants with CRIB scores ≥ 8 were lower in MP VLBWIs than SG VLBWIs. It is possible that the conditions of the foetuses were relatively good in the MP VLBWIs, as much attention and medical care were provided to the mothers²⁹. These cautious antenatal cares may have contributed to the lower rate of RDS, BPD, and sepsis in the MP VLBWIs compared to the SG VLBWIs, and the results were different from other studies³⁰ reporting that the prognosis of multiples and singletons was similar.

In the analysis of all GAs, the frequency of PDA ligation was increased in the MG VLBWIs compared to the SG VLBWIs at 29–32 weeks of gestation and was significantly increased at 29–30 weeks of gestational age. Margaryan et al.³¹ reported that the average age of VLBWIs requiring surgical treatment was 29.1 weeks of gestation, which is consistent with the age of surgery confirmed in this study. More research is needed on the increase in surgical treatment rates in MG VLBWIs.

A limitation of the study was that it was not possible to analyse the differentiation between units such as in medical resources, decision-making processes, and medical faculties including quality and numbers. Therefore, further studies on these issues should be conducted in the future.

Henceforth, new strategies should be developed to improve the mortality rate of premature infants born at ≤ 26 weeks of gestation. Therefore, in women with MP pregnancy, who are expected to give birth extremely prematurely, more intensive prenatal management, such as antenatal steroid administration and planned delivery, should be performed. In addition, to reduce the frequency of IVH and ROP requiring treatment for MP VLBWIs, the cause should be identified, and a strategy should be established.

This study aimed to investigate neonatal mortality and morbidity in MP VLBWIs compared with those of SG VLBWIs in Korea. We found that mortality was not significantly different between MP and SG infants according to overall gestational age, except for a significant increase in MP VLBWIs born at ≤ 26 weeks and a significantly higher risk of IVH and ROP requiring treatment in the MP group. To our knowledge, this study is the first domestic study to evaluate neonatal mortality and morbidity in MP VLBWIs compared with those in SG VLBWIs using a large population-based study in Korea. In addition, close observation and an appropriate response to symptomatic PDA are necessary in MG VLBWIs born between 29–30 weeks of gestation.

Methods

Declarations

Acknowledgements

We thank all patients for their generous contributions. We also thank the members of the Korean Neonatal Network (KNN). 

Author Contributions

J.H.L, J.H.H, H.G.J, and S.C. conceptualized, designed, investigated and conducted research and wrote manuscripts. O.K.N., J.H.L, J.H.H., H.G.J. and S.C. formally analysed the data, and J.H.L, J.H.H. critically reviewed and supervised the manuscript. All authors approved the final version of the manuscript.

Additional information

Competing of interests

The authors declare no competing interests.

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