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 BW14–16. Although worse neonatal outcomes for MP infants have been seen at extremely low gestational age in several studies4,11,12,17,18, some recent studies have reported that neonatal outcomes for MP infants are comparable to those for SG infants13,19. 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 IVF21,22. 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 oxygen25,26. 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.