Outcomes After Co-Twin Intrauterine Fetal Death in Extremely Preterm Infants From Multiple Pregnancies

Outcomes After Co-Twin Intrauterine Fetal Death in Extremely Preterm Infants From Multiple Pregnancies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Outcomes After Co-Twin Intrauterine Fetal Death in Extremely Preterm Infants From Multiple Pregnancies Sumin Kim, So Yoon Ahn, Danbee Kang, Misun Yang, Sein Sung, Juhee Cho, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9281364/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives This study examines the effects of exposure to second-trimester intrauterine fetal death (IUFD) on extremely preterm infants (EPIs) from twin or triplet pregnancies, specifically comparing the outcomes of surviving co-twin or co-triplet based on IUFD status. Methods Twins or triplets of EPIs within the Korean Neonatal Network (KNN) from 2013 to 2021 were analyzed, focusing on the morbidities and mortality of surviving infants after IUFD. Long-term growth and neurodevelopmental impairment (NDI) were evaluated using composite scores from the Bayley Scales of Infant Development II & III, the Korean Developmental Screening Test. Results Among 2 018 EPIs, IUFD multiple (surviving EPIs with fetal death) had no significant differences in comparison to normal multiple (surviving EPIs without fetal death). However, the mortality rate at NICU discharge was higher in IUFD multiple than in normal multiples. Long-term growth and NDI revealed no significant differences among groups, but IUFD multiple had higher postnatal growth failure (PGF) than normal multiple. Conclusion EPIs following intrauterine co-twin or co-triplet fetal death exhibited a significantly higher mortality rate than EPIs from twin or triplet pregnancies where all survived. Biological sciences/Developmental biology Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Infant Extremely Premature Pregnancy Fetal Death Figures Figure 1 Figure 2 Figure 3 Article Summary In a large national cohort, co-twin intrauterine fetal death was associated with increased in-hospital mortality, NEC, blindness, and restricted head growth in extremely preterm infants. What’s Known on This Subject Extremely preterm infants exposed to co-twin intrauterine fetal death have higher mortality but evidence on long-term outcomes remains limited. What This Study Adds Preterm infants from multiple pregnancies exposed to co-twin intrauterine fetal death may be at risk for adverse short- and long-term outcomes, underscoring the importance of careful monitoring and follow-up. INTRODUCTION Recent global trends indicate a notable increase in multiple pregnancies, including twins and higher-order multiples, driven largely by advanced maternal age 1 and the widespread application of assisted reproductive technologies (ART), particularly in vitro fertilization (IVF) 2 . Multiple pregnancies inherently carry elevated risks of adverse perinatal outcomes, such as preterm birth, stillbirth, and associated neonatal complications, in comparison to singleton pregnancies 3 . Consequently, this phenomenon has contributed significantly to the rising prevalence of preterm deliveries and the corresponding increase in extremely preterm infants (EPIs) 4 . Intrauterine fetal death (IUFD) occurred with an incidence of approximately 3.7% to 6.8% in multiple pregnancies 5 . Notably, the rate of stillbirth in multiple pregnancies exceeded that of singletons by approximately fourfold 6 – 8 . When IUFD occurs in the second and third trimesters, it markedly influences the survival and clinical outcomes of the surviving co-twin, with the impact varying according to chorionicity 9 , 10 . In particular, IUFD occurring before 28 weeks of gestation in monochorionic twins was strongly associated with increased mortality among surviving co-twins compared with cases where IUFD occurred later in gestation 11 . A prospective cohort study also demonstrated higher mortality and morbidity rates among multiples than singletons in EPIs, especially among those born below 26 weeks’ gestation 12 . Despite significant advances in neonatal intensive care and perinatal management, EPIs with IUFD-affected co-twins represent a particularly vulnerable population, facing considerable risks for mortality, severe short-term morbidities, and long-term neurodevelopmental impairment (NDI) 13 . However, previous studies have predominantly relied on small case series, limiting the reliability of their findings. To address this gap and expand on previous studies, we conducted a systematic evaluation of the impact of IUFD on mortality, short-term morbidities, and long-term growth and neurodevelopment in EPIs. By stratifying our large cohort into meaningful subgroups based on perinatal and maternal factors, we aimed to identify potential heterogeneity in treatment effects and uncover differential impacts of IUFD on specific patient populations, ultimately informing more personalized care strategies. METHODS Study Design and Data Source We conducted this cohort study using a deidentified data set from the Korea Neonatal Network (KNN). The KNN registry was approved by the Samsung Medical Center Institutional Review Board (2013-03-002) and informed consent was obtained from the parents when their infants were enrolled in the registry. All methods were performed in accordance with the relevant guidelines and regulations of the this study 14 . This included data on growth and neurodevelopment at discharge, during NICU hospitalization, and at 18–24 months’ corrected age (CA) and 3 years old. The data collection followed the pre-set KNN Manual of Operation (MOP) 14 . After ensuring data quality through inquiries and site visit monitoring, the KNN registry data are saved annually on the Korea National Institute of Health server. Study Population We identified all twins or triplets with gestational age (GA) of 21 to 27 weeks, born as EPIs [22] between January 2013 to December 2021 and registered in the KNN. Among the 2,060 EPIs from KNN data, we excluded 42 EPIs with severe congenital anomalies, then the eligible participants were 2,018 (Figure 1). IUFD The criteria for defining IUFD in multiple pregnancies differed between two periods according to the KNN MOP 15 . During phase 1 (2013–2018), IUFD was recorded based on obstetric clinicians’ documentation. Typically, fetal demise occurring before 12 weeks of gestation was not considered as IUFD in multiple pregnancies, whereas demise at or beyond 20 weeks was consistently classified as IUFD in multiple pregnancies. For fetal demise between 12 and 20 weeks of gestation, classification depended on clinical judgment. During phase 2 (2019–2021), following the revised KNN MOP guidelines, only fetal demise occurring at or beyond 16^+0 weeks of gestation was classified as IUFD in twin or triplet pregnancies. In both periods, pregnancies were consistently categorized into two groups: IUFD multiple, defined as twin or triplet pregnancies in which the number of live-born infants was fewer than the original number of fetuses identified during pregnancy, and normal multiple, defined as pregnancies in which all fetuses survived. This definition was uniformly applied to twins and triplets throughout the study. Outcomes The primary outcome was in-hospital mortality, defined as death at NICU discharge. Secondary outcomes were short-term morbidities, long-term growth and NDI at a CA of 18-24 months (follow-up 1) and 3 years old (follow-up 2). Short-term morbidities included periventricular leukomalacia (PVL) 16 , bronchopulmonary dysplasia (BPD) of moderate or greater severity 17 , retinopathy of prematurity (ROP) over stage3 or requiring laser treatment 18 , necrotizing enterocolitis (NEC) at Bell's stage 2 or higher 19 , culture-proven sepsis, intraventricular hemorrhage (IVH) of grade 3 or higher, length of hospitalization, and mortality at NICU discharge were obtained from KNN database (Supplementary Table 1). The long-term NDI assessed at a CA of 18-24 months and 3 years old using Bayley Scales of Infant Development (BSID) II & III, and Korean Developmental Screening Test for infants and children (K-DST) 20 . Cerebral palsy (Gross Motor Function Classification System ≥2) 21 , blindness, wearing glasses, hearing aid. Postnatal growth failure (PGF) 22 were defined as below z-score of –2 (2.3rd percentile) in weight, height, or head circumference for gestational ages between 22 and 50 weeks were calculated using the Fenton Lambda-Mu-Sigma (LMS) tables with 2013 Fenton growth chart 23 and according to the 2006 World Health Organization (WHO) child growth standards for children aged 0 to 5 years 22,24 . Based on the findings of each assessment that was available, we classified NDI into three unique domains: the mental, motor, and social domains. The determination of NDI in the Mental domain was based on the following criteria: 1) a mental developmental index of less than 70 on the BSID II; 2) a cognitive or language score of less than 70 on the BSID III; or 3) a cognition, language, or self-help score that falls below the threshold on the K-DST for those who were assessed only with the K-DST but not with the BSID. For the Motor domain, NDI was identified by: 1) a psychomotor developmental index of less than 70 on the BSID II; 2) a motor score of less than 70 on the BSID III; or 3) a gross motor or fine motor score that is below the threshold on the K-DST for those who were assessed only with the K-DST but not with the BSID. In the Social domain, NDI was determined by a social interaction score that falls below the cut-off value on the K-DST. Therefore, regardless of screening results from K-DST, NDI in each domain was defined mainly when the BSID scores was <70, and secondly when at least one of the scores in a particular domain from K-DST was <-2 standard deviations (SD) if BSID data were missing 20 . The total domain was labeled as NDI if any of the three domains showed abnormalities 20,25,26 . Confounding factors Infant characteristic including gestational age (GA), birth weight, small for gestational age (SGA) (<10 th percentile of the Fenton growth chart) 23 , sex, Apgar scores at 1 and 5 minutes was obtained from KNN database. Maternal characteristics included maternal age, oligohydramnios, polyhydramnios, use of antenatal steroid, cesarean section (C/S), pathologic chorioamnionitis, diabetes mellitus (DM), maternal hypertension, preterm rupture of membranes (PROM) within a 24-hour timeframe, and IVF were also obtained from KNN database. All the variables were measured by standard manual of operation (Supplementary Table 1). Statistical analysis Data were presented as a mean ± standard deviation for continuous variables and as a number or percentage for categorical variables. The chi-squared or Fisher’s exact test was performed for categorical variables, and the t-test or Mann–Whitney U test was used for continuous variables accordingly. To compare mortality, short-term and long-term outcomes by IUFD and normal multiple, a generalized linear model with a modified Poisson regression and robust error variance was used. Then we estimated relative risk (RR) for common binary outcomes. Adjusted RRs with 95% confidence intervals (CIs) were calculated to account for potential confounders including IVF, Oligohydramnios, use of antenatal steroids, and pathological chorioamnionitis of mother as Model 1; sex, gestational age, Apgar score at 1 minute of infant as Model 2; Model 1+ Model 2 as Model 3. We evaluated the impact of one triplet’s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal. A subgroup analysis to analyze the heterogeneity of rates, presenting the results in a forest plot with the p-value for interaction. We conducted survival and cumulative incidence analyses to compare the outcomes between the two groups. To compare cumulative incidence of long-term mortality, Kaplan-Meier analysis was used. The log-rank test was used to compare cumulative survival and incidence differences between the groups. Hazard ratios (HRs) and adjusted HRs with 95% CIs were estimated using the Cox proportional hazards model to assess the relative risk between the two groups. Statistical analysis was performed using STATA 17.0 version [StataCorp., College Station, TX, USA], and R version 4.1.3. P-values <0.05 were considered statistically significant. RESULTS Clinical characteristics Among 2,018 participants, 274 (13.6%) were live-born EPIs from IUFD-complicated multiple pregnancies (IUFD multiple group), and 1,744 (86.4%) were infants from uncomplicated multiple pregnancies (Normal multiple group). Compared to the normal multiple group, the IUFD multiple group demonstrated a significantly lower gestational age and birth weight. Mothers of IUFD multiple group were less likely to have maternal diabetes, cesarean sections, and use of antenatal steroids compared to those of normal multiple group (Table 1). In contrast, the incidence of oligohydramnios and pathological chorioamnionitis occurred significantly more frequently in the IUFD multiple group than in the normal multiple group. Short-term outcomes In-hospital mortality rate was 43.1% and 29.2%, in IUFD multiple group and normal multiple group, respectively with RR 1.47 (95% CI, 1.25–1. 73). Even after adjustment for confounders of lower gestational age, sex, lower Apgar score at 1min, IVF, oligohydramnios, antenatal steroid, and pathological chorioamnionitis, fully adjusted RR of IUFD was 1.17 (95% CI, 1.01–1.37). The incidence of NEC ≥ stage II was also significantly higher in the IUFD multiple (65.8% vs. 57.1%, adjusted RR = 1.37, 95% CI, 1.01–1.87) when compared to normal multiple (Table 2). The association between co-twin IUFD and increased in-hospital mortality among live born infants was consistent in all subgroups of sex, gestational age, Apgar score at 1 minute, IVF, use of antenatal steroid, and pathological chorioamnionitis (p for interaction > 0.05) (Figure 2). In contrast, in the olilgohydramnios subgroups, the association between co-twin IUFD and higher in-hospital mortality after live-born seems to be inconstant (Figure 2). From a clinical perspective, oligohydramnios appears to have a substantial impact on mortality, and this strong influence might affect this association between co-twin IUFD and mortality of live-born EPI. Long-term outcomes IUFD multiple group infants were associated with significantly lower cumulative 1-year survival than normal multiple group infants (log-rank test, p < 0.001). The adjusted HR for in-hospital mortality was 1.56 (95% CI, 1.3–1.9) (Figure 3). For the long-term growth and neurodevelopmental outcomes, among 1,391 NICU survivors, 740 infants (53.1%) were followed up at a corrected age of 18 to 24 months and 414 infants (29.8%) were followed up at corrected age of 3 years (Figure 1). Although gestational age and birth weight were lower in infants lost in normal multiple, there was no difference between infants who had follow-up or loss (Supplementary Table 3). At corrected ages of 18–24 months (follow-up 1), although blindness was more frequent in the IUFD multiple group compared to the normal multiple group (3.4% vs. 0.6%; RR, 4.56; 95% CI, 1.35 – 15.34), other outcomes were not differences between the IUFD multiple and normal multiple (Table 3). At corrected ages of 3 years (follow-up 2), neurodevelopmental impairment or growth outcomes were similar between IUFD multiple and normal multiple except head circumference growth restriction (32.1% vs. 18.5%; RR, 1.58; 95% CI, 1.01 – 2.48) (Table 3). DISCUSSION This study examined the impact of second-trimester IUFD on live-born premature infants from multiple pregnancies, focusing on short-term morbidities and long-term growth and neurodevelopmental outcomes. In the extremely premature infants, IUFD was strongly associated with increased in-hospital NICU mortality among live-born infants. Regarding short-term morbidities, EPIs with IUFD-affected co-twins were associated with a higher incidence of NEC ≥ stage II. For long-term outcomes, growth and neurodevelopmental parameters did not differ significantly, apart from an elevated risk of blindness at 18–24 months follow-up and restricted head growth at 3 years follow-up in live-born EPIs with IUFD-affected co-twins. A systematic review and meta-analysis by Hillman et al. reported that the rate of co-twin perinatal death after single fetal demise was 15% in monochorionic twins versus 3% in dichorionic twins and thus monochorionic twins are at substantially increased risk of co-twin demise following single fetal death compared to dichorionic twins due to shared placental circulation 11 . However, the meta-analysis was limited by the inclusion of very small-scale studies, such as case series reports. In other population-based study using the data obtained from Vital Statistics Branch at the US National Center for Health Statistics, demonstrated that fetal death at 20 weeks’ gestation or later is uncommon, occurring in 2.6% of twin and 4.3% of triplet gestations and the probability of survival for the remaining fetuses improved dramatically with increasing gestational age at the time of the fetal death 27 . However, in this population-based data, there was several limitations of excluding fetal death occurred before 20 weeks’ gestation and thus it is unlikely that majority of fetal losses occurring in the 2nd trimester were included. In addition, the Matched Multiple Birth File did not contain information regarding chorionicity and infertility treatment. The results data of our present study based on nine years of prospective national VLBWI registry data and thus the finding that higher mortality rate and increased NEC incidence in live-born EPIs with IUFD-affected co-twins than normal unaffected multiples can be considered highly reliable. Moreover, this is the first study to demonstrate outcomes of live-born premature infants following IUFD exposure in a cohort composed of extremely preterm infants, a population at high risk for adverse clinical outcomes. In addition, this national registry data set includes the majority of 2nd trimester fetal loss because the information of fetal demise was defined as the fetal death after 14 weeks’ gestation and the analyzed EPI population was limited to the live-born premature infants lower than 28 gestational weeks. However, the absence of chorionicity data in multiple pregnancies induced an inevitable limitation, limiting the evaluation of the association between chorionicity and mortality in live-born EPIs with IUFD-affected co-twins. Accordingly, there is a need for further meticulously designed study to analyze whether IVF-related procedures such as selective abortion and chorionicity influence the outcomes of live-born EPIs with IUFD-affected co-twins Also, the prevalence of NEC ≥ stage II was significantly higher among live-born EPIs with IUFD-affected co-twins (17.1%) compared to normal unaffected multiples (11.3%). Previous studies on IUFD have not reported an association between IUFD and an increased risk of NEC in live-born EPIs with IUFD-affected co-twins and our present study provides the first evidence suggesting this relationship. In the recent national cohort study about maternal chorioamnionitis and NEC, maternal chorioamnionitis is associated with increased incidence of NEC in the infants of birth weight 2500-4499g 28 . Another multicenter cohort study in very preterm infants and VLBWI also presented positive association between maternal chorioamnionitis and NEC or death 29 . Given these reports above, antenatal inflammation may be associated with the development of NEC and thus further studies are warranted to elucidate the association between IUFD-related antenatal inflammation and the development of NEC. Long-term follow-up at 18–24 months corrected age showed no significant differences in neurodevelopmental outcomes between groups, apart from a higher incidence of blindness among live-born EPIs with IUFD-affected co-twins. This increased risk of blindness may not solely result from sensory pathway disruptions but could also reflect the compounding effects of neurological injuries, such as IVH ≥ grade III 30 or PVL those were more prevalent in IUFD multiple compared to normal multiples, though there was not any statistical significance. A study based on national registrations by Pharoan et al. showed that surviving co-twins of fetuses who experienced intrauterine death have an elevated risk of cerebral impairment, with an overall risk estimated at 20%. The prevalence of cerebral palsy, adjusted for gestational age, was found to be significantly higher in these cases compared to the general twin population 8 . However, in the Swedish national registry, with a 50% loss to follow-up, the disability rate at 8 years of age was recorded as 46 per 1000, which was lower than that reported in other studies. The differences in disability rates might be attributed to variations in definitions, methodologies, including the use of questionnaires sent to rehabilitation centers, and population bases 31 . Though these above reports with national registry thoroughly performed survey about long-term developmental delays in survived co-twins of fetuses who experienced intrauterine death, there was no comparison with twins or triplets all survived as a control group. Our current study targeted only premature infants born at < 29 weeks’ gestation, the cerebral palsy rates at 2 years were 9.6% and 9.5% in IUFD multiples and all live-born multiples, respectively and the motor development delay at 3 years old also showed 35.2% and 28.5% in IUFD multiples and all live-born normal multiples, respectively. Though there was no statistically significant difference between groups, it is hard to say that IUFD co-twin exposure did not seem to induce developmental delay, because of substantial amount of follow-up loss in this cohort. Future studies should link this cohort with national health insurance data to minimize loss to follow-up and to accurately assess the developmental outcomes between IUFD multiples and normal multiples. Recent societal shifts, including delayed marriage and the increased use of assisted ART, have led to a significant rise in multiple pregnancies, particularly among older mothers 32 – 34 . ART procedures, including IVF and intracytoplasmic sperm injection (ICSI), have become more accessible and successful, contributing further to the rise 35 – 38 . However, these pregnancies are inherently associated with increased risks, such as preterm birth, low birth weight, and congenital anomalies 39 , leading to a 2- to 4-fold higher risk of maternal or neonatal death. In response to declining fertility rates and delayed marriage, South Korea has implemented policies such as ART insurance coverage since October 2017 to reverse population decline 40 . In addition, in South Korea, where a policy mandating single embryo transfer is not in place, the incidence of IVF-induced multiple pregnancies is increasing annually [51]. These policies, while beneficial in promoting ART, have inadvertently increased the rate of multiple pregnancies and, consequently, the risks associated with in-utero fetal demise 35 . Our study demonstrated that the proportion of infants conceived via IVF (59.6%) was higher compared to those conceived spontaneously (40.4%). A retrospective cohort study indicated that the survival rate of MCDA twins conceived via IVF/ICSI is lower (79%) compared to those conceived spontaneously (90%). Additionally, the risk of losing one or both twins is twice as high in IVF/ICSI pregnancies (29% vs. 14%) compared to spontaneous pregnancies 41 . Notably, the increased risk of adverse outcomes in IVF pregnancies appears to be mediated by the higher prevalence of monochorionic rather than by IVF itself 42 . Thus, the increased incidence of adverse outcomes in IVF twins may be mediated by chorionicity, underscoring the importance of placental type in predicting fetal loss and neonatal outcomes 43 . The sub-group analysis data of our present study, co-twin IUFD exposure seems to increase mortality rate of live-born EPI among infants from multiple pregnancies conceived by IVF; adjusted RR (95% CI), 1.36 (1.12–1.66), but not in the infants from multiple pregnancies conceived spontaneously; adjusted RR (95% CI), 1.06 (0.83–1.35). In the present study has several limitations. First, we could not the identify between fetal death in the delivery room, type of placenta and membranes including chorionicity with dichorionic diamniotic, monochorionic diamniotic and fetal death time due to lack of information in KNN registry. Second, the study population enrolled a loss of follow-up rate of neurodevelopmental assessment which might decrease the strength of adverse impact of EPIs on long-terms results. Although, a significant number of EPIs were included in our study after IUFD. This was accomplished at the national level by examining the real long-term clinical course under well-supervised quality 14 , including neurodevelopmental features, using data obtained from a large prospective cohort. Finally, due to the nature of the multi-center registry, this study utilized various neurodevelopmental assessment tools. To include all available data and reduce selection bias, we created a composite score by integrating BSID-II and III as confirmatory tests, along with K-DST 20 . Despite K-DST is reported to be valid and show strong correlation with BSID 44 , 45 , it is important to recognize the potential for bias due to the variability between tests. Although questionnaires like we used a consistent cut-off value (< 70 for NDI) for both BSID-II and III, as done in previous studies 46 – 48 , but debates continue regarding the use of different cut-off values for these tests 25 , 45 , 49 . Conclusion This large-scale national study demonstrated that second-trimester IUFD was strongly associated with higher in-hospital mortality, increased risks of NEC ≥ stage II, and blindness among EPIs. In contrast, other short-term morbidities and long-term growth and neurodevelopmental outcomes were not significantly affected. Therefore, we suggest that second-trimester IUFD is a crucial risk factor affecting the surviving EPI. Consequently, this study provides evidence to support comprehensive counseling for patients, after a fetal demise in a multifetal gestation and the need for meticulous clinical management of the surviving live-born EPI after co-twin IUFD exposure. Abbreviations EPIs, extremely preterm infants; BPD, bronchopulmonary dysplasia; NICU, neonatal intensive care unit; CA, corrected age; NDI, neurodevelopmental impairment; KNN, Korean Neonatal Network; MOP, manual of operation; GA, gestational age; BW, birth weight; C/S, cesarean section; SGA, small for gestational age; PDA, patent ductus arteriosus; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; BSID, Bayley Scales of Infant Development; K-DST, Korean Developmental Screening Test for infants and children; aOR, adjusted odds ratio; RR, relative risk; CI, confidence intervals; Declarations Conflict of Interest Disclosures: The authors have indicated no conflicts of interest relevant to this article to be disclosed. Funding/Support: This research was supported by a fund by Research of the Korea National Institute of Health (2022-ER0603-02#), Future Medicine 2030 project of the Samsung Medical Center (#SMX1220081) and grant from SMC-Ottogi Research Fund (SMX1210881). Data availability The data that support the findings of this study are available from the corresponding author ( [email protected] ) upon reasonable request. Contributors Statement Page Sumin Kim, So Yoon Ahn, Juhee Cho, Danbee Kang and Yun Sil Chang conceptualized and designed the study, drafted the initial manuscript, coordinated and supervised data collection, and critically reviewed and revised the manuscript. Sumin Kim and So Yoon Ahn designed the data collection instruments, collected data, carried out the initial analyses, and critically reviewed the manuscript. Misun Yang, Se In Sung, Danbee Kang, Juhee Cho and Yun Sil Chang critically reviewed and revised the manuscript, and supervised data collection. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. References Pettersson ML, Bladh M, Nedstrand E, Svanberg AS, Lampic C, Sydsjö G. 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Front Pediatr . 2025;13:1620101 O'Keefe M, Kafil-Hussain N, Flitcroft I, Lanigan B. Ocular significance of intraventricular haemorrhage in premature infants. British Journal of Ophthalmology . 2001;85(3):357-359 Rydhström H, Ingemarsson I. Prognosis and long-term follow-up of a twin after antenatal death of the co-twin. J Reprod Med . 1993;38(2):142-146 Santana DS, Silveira C, Costa ML, et al. Perinatal outcomes in twin pregnancies complicated by maternal morbidity: evidence from the WHO Multicountry Survey on Maternal and Newborn Health. BMC Pregnancy and Childbirth . 2018;18(1):449 Wang Y, Shi H, Chen L, et al. Absolute Risk of Adverse Obstetric Outcomes Among Twin Pregnancies After In Vitro Fertilization by Maternal Age. JAMA Netw Open . 2021;4(9):e2123634 Cheong-See F, Schuit E, Arroyo-Manzano D, et al. Prospective risk of stillbirth and neonatal complications in twin pregnancies: systematic review and meta-analysis. BMJ . 2016;354:i4353 Carson SA, Kallen AN. Diagnosis and Management of Infertility: A Review. Jama . 2021;326(1):65-76 Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med . 2012;9(12):e1001356 Sunderam S, Kissin DM, Zhang Y, et al. Assisted Reproductive Technology Surveillance - United States, 2018. MMWR Surveill Summ . 2022;71(4):1-19 Nik Hazlina NH, Norhayati MN, Shaiful Bahari I, Nik Muhammad Arif NA. Worldwide prevalence, risk factors and psychological impact of infertility among women: a systematic review and meta-analysis. BMJ Open . 2022;12(3):e057132 Bakkensen JB, Smith KS, Cheung EO, et al. Childbearing, Infertility, and Career Trajectories Among Women in Medicine. JAMA Network Open . 2023;6(7):e2326192-e2326192 Cha W, Yun I, Nam CM, Nam JY, Park EC. Evaluation of Assisted Reproductive Technology Health Insurance Coverage for Multiple Pregnancies and Births in Korea. JAMA Netw Open . 2023;6(6):e2316696 Couck I, Van Nylen L, Deprest J, Lewi L. Monochorionic twins after in-vitro fertilization: do they have poorer outcomes? Ultrasound Obstet Gynecol . 2020;56(6):831-836 Wang M, Chai J. Comparison of outcomes of monochorionic twin pregnancies conceived by assisted reproductive technology vs. spontaneous conceptions: A systematic review and meta-analysis. Frontiers in Pediatrics . 2022;10:962190 Sperling L, Kiil C, Larsen LU, et al. Naturally conceived twins with monochorionic placentation have the highest risk of fetal loss. Ultrasound in Obstetrics and Gynecology: the Official Journal of the International Society of Ultrasound in Obstetrics and Gynecology . 2006;28(5):644-652 Yim C-H, Kim G-H, Eun B-L. Usefulness of the Korean Developmental Screening Test for infants and children for the evaluation of developmental delay in Korean infants and children: a single-center study. Korean journal of pediatrics . 2017;60(10):312 Jang CH, Kim SW, Jeon HR, et al. Clinical Usefulness of the Korean Developmental Screening Test (K-DST) for Developmental Delays. Ann Rehabil Med . 2019;43(4):490-496 Moore T, Johnson S, Haider S, Hennessy E, Marlow N. Relationship between test scores using the second and third editions of the Bayley Scales in extremely preterm children. J Pediatr . 2012;160(4):553-558 Yi YG, Sung IY, Yuk JS. Comparison of Second and Third Editions of the Bayley Scales in Children With Suspected Developmental Delay. Ann Rehabil Med . 2018;42(2):313-320 Johnson S, Moore T, Marlow N. Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used? Pediatr Res . 2014;75(5):670-674 Squires J, Bricker D, Potter L. Revision of a parent-completed development screening tool: Ages and Stages Questionnaires. J Pediatr Psychol . 1997;22(3):313-328 Tables Table 1. Characteristics of infants and their mothers C haracteristic s Total (n=2 , 018) IUFD multiple (n=274) Normal multiple (n=1 , 744) p -value Infant Male (%) 1074 (53.2) 143 (52.1) 931 (53.3) 0.713 Gestational age 25.2±1.5 24.6±1.6 25.3±1.4 <0.001 SGA (%) 149 (7.3) 28 (10.2) 121 (6.9) 0.054 Birth weight (g) 800.1±197.9 740.4±207.9 809.4±194.7 <0.001 Apgar scores 1 minute 3.6±1.8 3.5±1.7 3.7±1.8 0.294 5 minutes 5.9±2.0 5.7±1.9 5.9±1.9 0.065 Z-score at birth Weight -0.01±0.7 -0.04± 0.8 -0.01±0.7 0.733 Height -0.3±1.0 -0.4±1.0 -0.3±1.0 0.527 Head circumference 0.1±1.1 0.03±1.2 0.09±1.1 0.200 M other Maternal age 33.2±3.9 33.2±3.6 33.2± 3.9 0.891 IVF (%) 1 , 203 (59.6) 155 (56.5) 1 , 048 (60.1) 0.269 Diabetes (%) 181 (8.9) 15 (5.4) 166 (9.5) 0.029 Hypertension (%) 133 (6.5) 15 (5.4) 118 (6.7) 0.423 Cesarean section (%) 1 , 612 (79.8) 170 (62.0) 1 , 442 (82.6) <0.001 PROM, cut off 24h (%) 367/622 (59.0) 75/112 (66.9) 292/510 (57.2) 0.059 Oligohydramnios (%) 215/1 , 819 (11.8) 42/241 (17.4) 173/1 , 578 (10.9) 0.004 Polyhydramnios (%) 54/1 , 819 (2.9) 11/241 (4.5) 43/1 , 578 (2.7) 0.117 Antenatal steroid (%) 1 , 700/1 , 984 (85.6) 215/269 (79.9) 1 , 485/1 , 715 (86.5) 0.004 Pathological chorioamnionitis (%) 713/1 , 721 (41.4) 129/233 (55.3) 584/1 , 488 (39.2) <0.001 Continuous variables are presented as means (standard deviation). Categorical variables are presented as N (%). IUFD: intrauterine fetal death; SGA: small for gestational age; PROM: premature rupture of membrane; IVF: in vitro fertilization. We evaluated the impact of one triplet’s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal. Table 2. Short-term morbidities by IUFD multiple and normal multiple Outcome s IUFD multiple (n=274) Normal multiple (n=1 , 744) IUFD multiple vs. Normal multiple (reference) Crude RR (95% CI) Model 1 Adjusted RR a (95% CI) Model 2 Adjusted RR a (95% CI) Model 3 Adjusted RR a (95% CI) In-hospital mortality 118 (43.1) 509 (29.2) 1.47 (1.25 - 1.73)* 1.42 (1.21 - 1.67)* 1.17 (1.01 - 1.36)* 1.17 (1.01 - 1.37)* BPD ≥ moderate 108/164 (65.8) 708/1,238 (57.1) 1.15 (1.01 - 1.30)* 0.98 (0.83 - 1.15) 1.01 (0.86 - 1.19) 1.02 (0.87 - 1.20) IVH ≥ grade III 67/239 (28.0) 359/1,597 (22.4) 1.24 (0.99 - 1.56) 1.15 (0.91 - 1.44) 1.03 (0.81 - 1.31) 1.03 (0.81 - 1.31) Sepsis 97/272 (35.6) 561/1,734 (32.3) 1.10 (0.92 - 1.31) 1.09 (0.91 - 1.30) 1.04 (0.87 - 1.25) 1.04 (0.86 - 1.25) PVL 33/237 (13.9) 184/1,589 (11.5) 1.20 (0.84 - 1.70) 1.15 (0.80 - 1.63) 1.11 (0.77 - 1.60) 1.12 (0.78 - 1.60) NEC ≥ stage Ⅱ 46/268 (17.1) 194/1,711 (11.3) 1.51 (1.12 - 2.04) * 1.52 (1.12 - 2.07)* 1.33 (0.98 - 1.82) 1.37 (1.01 - 1.87)* ROP ≥ stage III 58/165 (21.1) 424 (24.3) 1.06 (0.84 - 1.32) 0.88 (0.69 - 1.13) 0.83 (0.64 - 1.07) 0.84 (0.65 - 1.09) ROP OP. 51/168 (30.3) 326/1,074 (30.4) 1.00 (0.77 - 1.28) 0.97 (0.74 - 1.27) 0.92 (0.70 - 1.21) 0.92 (0.70 - 1.21) Postnatal growth failure at NICU discharge (Z-score< -2.0) Weight 52 (18.9) 333 (19.1) 0.99 (0.76 - 1.29) 1.03 (0.78 - 1.35) 0.98 (0.75 - 1.29) 1.02 (0.77 - 1.34) Height 102 (37.2) 678 (38.8) 0.65 (0.81 - 1.13) 0.97 (0.82 - 1.14) 0.95 (0.80 - 1.12) 0.95 (0.81 - 1.13) Head circumference 62 (22.6) 348 (19.9) 1.13 (0.88 - 1.44) 1.11 (0.87 - 1.42) 1.08 (0.84 - 1.38) 1.07 (0.84 - 1.37) IUFD: intrauterine death; BPD: bronchopulmonary dysplasia; IVH: intraventricular hemorrhage; PVL: periventricular leukomalacia; NEC: necrotizing enterocolitis; ROP: retinopathy of prematurity; OP: operation; ; RR: relative risk, AOR: adjusted relative risk Model 1: Adjusted for IVF, Oligohydramnios, Antenatal steroid, and pathological chorioamnionitis of mother; Model 2: Adjusted for sex, gestational age, Apgar score at 1 minute of infant; Model 3: Adjusted for Model 1+ Model 2; *p-value <0.05; We evaluated the impact of one triplet’s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal. We evaluated the impact of one triplet’s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal. Table 3 Long-term growth and neurodevelopmental outcomes by IUFD multiple and normal multiple Outcomes IUFD multiple # (n=1 45 ) Normal multiple # (n=1 ,009 ) IUFD multiple vs. Normal multiple (reference) Crude RR (95% CI) Model 1 Adjusted RR a (95% CI) Model 2 Adjusted RR a (95% CI) Model 3 Adjusted RR a (95% CI) Corrected age at 18 to 24 months Neurodevelopmental impairment Mental development delay (%) 13/54 (24.1) 85/397 (21.4) 1.12 (0.66 - 1.89) 1.06 (0.61 - 1.86) 0.98 (0.55 - 1.72) 1.01 (0.56 - 1.78) Motor development delay (%) 11/54 (20.4) 74/397 (18.6) 1.09 (0.61 - 1.95) 1.05 (0.57- 1.94) 0.92(0.50 - 1.72) 0.96 (0.51 - 1.81) Social development delay (%) 1/12 (8.3) 10/116 (8.6) 0.70 (0.09 - 5.44) 0.68 (0.08 - 5.46) 0.75 (0.09 - 6.28) 0.82 (0.09 - 7.06) Total development delay (%) 15/54 (27.7) 111/397 (27.9) 0.99 (0.62 - 1.58) 0.96 (0.58 - 1.61) 0.86 (0.52 - 1.44) 0.91 (0.54 - 1.53) Blindness (%) 3/89 (3.4) 4/618 (0.6) 5.21 (1.18 - 22.89)* 4.94 (1.27 - 19.17)* 4.08 (1.11 - 15.05)* 4.56 (1.35 - 15.34)* Wearing glasses (%) 6/88 (6.8) 29/613 (4.7) 1.44 (0.61 - 3.41) 1.63 (0.66 - 4.02) 1.21 (0.50 - 2.90) 1.50 (0.59 - 3.78) Hearing aid (%) 3/71 (4.2) 21/532 (3.9) 1.07 (0.32 - 3.54) 1.11 (0.34 - 3.63) 0.95 (0.27 - 3.26) 1.06 (0.31 - 3.57) Cerebral palsy (%) 9/89 (10.1) 59/618 (9.5) 1.05 (0.54 - 2.07) 1.17 (0.60 - 2.31) 0.97 (0.49 - 1.89) 1.12 (0.57 - 2.19) Postnatal growth failure (Z-score< -2.0) Weight (%) 13/77 (16.8) 81/539 (15.0) 1.22 (0.86 - 1.74) 1.26 (0.89 - 1.80) 1.17 (0.84 - 1.63) 1.22 (0.87 - 1.71) Height (%) 16/72 (22.2) 81/511 (15.8) 1.01 (0.81 - 1.26) 1.00 (0.80 - 1.25) 0.97 (0.79 - 1.19) 0.96 (0.78 - 1.19) Head circumference (%) 16/64 (25.0) 105/432 (24.3) 1.41 (0.99 - 1.99) 1.38 (0.97 - 1.95) 1.31 (0.93 - 1.81) 1.30 (0.93 - 1.81) Corrected age at 36 months Neurodevelopmental impairment Mental development delay (%) 11/26 (42.3) 37/133 (27.8) 1.52 (0.88 - 2.61) 2.01 (1.06 - 3.79) 1.90 (1.01 - 3.58) 1.89 (1.00 - 3.59) Motor development delay (%) 12/26 (46.1) 48/133 (36.1) 1.27 (0.78 - 2.08) 1.79 (0.98 - 3.27) 1.46 (0.81 - 2.61) 1.61 (0.89 - 2.91) Social development delay (%) 1 /10 (10.0) 11/41 (26.8) 0.37 (0.05 - 2.61) 0.58 (0.07 - 4.49) 0.66 (0.09 - 4.54) 0.60 (0.09 - 3.88) Total development delay (%) 14/26 (53.8) 58/133 (43.6) 1.23 (0.81 - 1.87) 1.65 (0.96 - 2.84) 1.44 (0.87 - 2.38) 1.50 (0.89 - 2.50) Postnatal growth failure (Z-score< -2.0) Weight (%) 17/53 (32.1) 76/361 (21.0) 1.52 (0.97 - 2.38) 1.46 (0.95 - 2.24) 1.49 (0.91 - 2.45) 1.45 (0.91 - 2.33) Height (%) 27/53 (50.9) 188/361 (52.1) 0.97 (0.73 - 1.30) 0.93 (0.71 - 1.21) 0.96 (0.72 - 1.28) 0.92 (0.71 - 1.21) Head circumference (%) 17/53 (32.1) 67/361 (18.5) 1.72 (1.09 - 2.73)* 1.60 (1.02 - 2.51)* 1.66 (1.03 - 2.67)* 1.58 (1.01 - 2.48)* IUFD: intrauterine death; RR: relative risk, AOR: adjusted relative risk; The number of long-term growth and neurodevelopmental follow-ups at CA of 18-24 months are 503 in normal multiple and 59 in IUFD multiple, respectively; # The number of long-term growth and neurodevelopmental follow-ups at 3 years old are 237 in normal multiple and 35 in IUFD multiple, respectively; We evaluated the impact of one triplet’s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal. Model 1: Adjusted for IVF, Oligohydramnios, Antenatal steroid, and pathological chorioamnionitis of mother; Model 2: Adjusted for sex, gestational age, Apgar score at 1 minute of infant; Model 3: Adjusted for Model 1+ Model 2; We evaluated the impact of one triplet’s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal. Additional Declarations No competing interests reported. Supplementary Files KNNIUFDSupplements2026.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9281364","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":624585927,"identity":"1daf4ea6-b628-426d-9f06-5a0aab88ec3f","order_by":0,"name":"Sumin Kim","email":"","orcid":"","institution":"Samsung Advanced Institute for Health Sciences \u0026 Technology (","correspondingAuthor":false,"prefix":"","firstName":"Sumin","middleName":"","lastName":"Kim","suffix":""},{"id":624585932,"identity":"9915eb11-c31f-4699-a29f-f67c09f22f69","order_by":1,"name":"So Yoon Ahn","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"So","middleName":"Yoon","lastName":"Ahn","suffix":""},{"id":624585937,"identity":"8fe580f4-859f-42cf-bea8-96a059625006","order_by":2,"name":"Danbee Kang","email":"","orcid":"","institution":"Samsung Advanced Institute for Health Sciences \u0026 Technology (","correspondingAuthor":false,"prefix":"","firstName":"Danbee","middleName":"","lastName":"Kang","suffix":""},{"id":624585940,"identity":"47cae4be-0283-4a54-8627-54e8f7e1c334","order_by":3,"name":"Misun Yang","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Misun","middleName":"","lastName":"Yang","suffix":""},{"id":624585944,"identity":"6a7a1e1d-d056-4883-8063-a365f4bff291","order_by":4,"name":"Sein Sung","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Sein","middleName":"","lastName":"Sung","suffix":""},{"id":624585949,"identity":"65ca6702-2e1a-4a43-9578-0736add919e2","order_by":5,"name":"Juhee Cho","email":"","orcid":"","institution":"Samsung Advanced Institute for Health Sciences \u0026 Technology (","correspondingAuthor":false,"prefix":"","firstName":"Juhee","middleName":"","lastName":"Cho","suffix":""},{"id":624585954,"identity":"8100b6e9-a674-44c8-baea-9fa57dd983ef","order_by":6,"name":"Yun Sil Chang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYLCChAIGBgMQ4wMQs7ETpcUAooVxBkgLM1HWQLUw84A4hLQY3Mg9/OGBAYO8OfvZw69tfm2T52NmYPzwMQeflrw0CaDDDHf25KVZ5/bdNmxjZmCWnLkNn5YcM5BfEgwO5JgZ5/bcZgRqYWPmxa/F+ANYy/k3ZsaWPbftidFiIAHWAtT7mOHH7USCWiTPvDEDapEw3HDjjRljb8Pt5DZmxma8fuE7nmP88UeFjbzBeaALf/y5bTu/vfngh494tCgcAFMSIIJNgrENRDM24FYPBPJI0swfGP7gVTwKRsEoGAUjFAAA/YFPgULr5EkAAAAASUVORK5CYII=","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Yun","middleName":"Sil","lastName":"Chang","suffix":""}],"badges":[],"createdAt":"2026-03-31 14:38:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9281364/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9281364/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107254697,"identity":"ea5e5487-4a95-4f98-9019-2e06126c6840","added_by":"auto","created_at":"2026-04-19 12:04:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":155772,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of the study population\u003c/p\u003e\n\u003cp\u003eKNN: Korea neonatal network; ELBWI: extremely low birth weight infant; Normal multiples: two infants share nearly identical birth times and exactly identical maternal demographic information including the mother’s initial, and the maternal records indicate a twin pregnancy; IUFD multiple: maternal information indicates twin but only one surviving infant is identified, without the presence of other infants with the same maternal initials, nearly identical birth time, and identical maternal demographic information; NICU: neonatal intensive care unit; CA: corrected age\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9281364/v1/a7cd2a812706f51628c59e24.jpg"},{"id":107254699,"identity":"557a55ab-aeb6-46cb-ac5c-2c29232987c4","added_by":"auto","created_at":"2026-04-19 12:04:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":240004,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup analyses for in-hospital mortality\u003c/p\u003e\n\u003cp\u003eIVF: in vitro fertilization; IUFD: intrauterine death; RRs: relative risks; CI: confidence interval; NICU: neonatal intensive care unit; Model 3: Adjusted for Model 1+ Model 2; We evaluated the impact of one triplet’s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal.\u003c/p\u003e","description":"","filename":"Fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9281364/v1/3f458e016194628688476658.jpg"},{"id":107254700,"identity":"dca9e594-8261-467b-8978-cf50022a9211","added_by":"auto","created_at":"2026-04-19 12:04:42","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":165114,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival estimates for in-hospital mortality in IUFD multiple and normal multiple\u003c/p\u003e","description":"","filename":"Fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9281364/v1/ef753fefe882c35bd748f218.jpg"},{"id":109249326,"identity":"8605788f-6de0-40a4-831b-a17b756f5032","added_by":"auto","created_at":"2026-05-14 08:48:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":984918,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9281364/v1/7e35edbb-7aed-4d66-9155-a481caf3530e.pdf"},{"id":107482411,"identity":"f24e8630-81f0-43b3-a668-00fef4f059d7","added_by":"auto","created_at":"2026-04-22 02:23:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":377311,"visible":true,"origin":"","legend":"","description":"","filename":"KNNIUFDSupplements2026.docx","url":"https://assets-eu.researchsquare.com/files/rs-9281364/v1/c340e29988c30d7e27ebb985.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Outcomes After Co-Twin Intrauterine Fetal Death in Extremely Preterm Infants From Multiple Pregnancies","fulltext":[{"header":"Article Summary ","content":"\u003cp\u003eIn a large national cohort, co-twin intrauterine fetal death was associated with increased in-hospital mortality, NEC, blindness, and restricted head growth in extremely preterm infants. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat\u0026rsquo;s Known on This Subject\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eExtremely preterm infants exposed to co-twin intrauterine fetal death have higher mortality but evidence on long-term outcomes remains limited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat This Study Adds\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePreterm infants from multiple pregnancies exposed to co-twin intrauterine fetal death may be at risk for adverse short- and long-term outcomes, underscoring the importance of careful monitoring and follow-up.\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eRecent global trends indicate a notable increase in multiple pregnancies, including twins and higher-order multiples, driven largely by advanced maternal age \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and the widespread application of assisted reproductive technologies (ART), particularly in vitro fertilization (IVF) \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Multiple pregnancies inherently carry elevated risks of adverse perinatal outcomes, such as preterm birth, stillbirth, and associated neonatal complications, in comparison to singleton pregnancies \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Consequently, this phenomenon has contributed significantly to the rising prevalence of preterm deliveries and the corresponding increase in extremely preterm infants (EPIs) \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIntrauterine fetal death (IUFD) occurred with an incidence of approximately 3.7% to 6.8% in multiple pregnancies \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Notably, the rate of stillbirth in multiple pregnancies exceeded that of singletons by approximately fourfold \u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. When IUFD occurs in the second and third trimesters, it markedly influences the survival and clinical outcomes of the surviving co-twin, with the impact varying according to chorionicity \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. In particular, IUFD occurring before 28 weeks of gestation in monochorionic twins was strongly associated with increased mortality among surviving co-twins compared with cases where IUFD occurred later in gestation \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. A prospective cohort study also demonstrated higher mortality and morbidity rates among multiples than singletons in EPIs, especially among those born below 26 weeks\u0026rsquo; gestation \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite significant advances in neonatal intensive care and perinatal management, EPIs with IUFD-affected co-twins represent a particularly vulnerable population, facing considerable risks for mortality, severe short-term morbidities, and long-term neurodevelopmental impairment (NDI) \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. However, previous studies have predominantly relied on small case series, limiting the reliability of their findings. To address this gap and expand on previous studies, we conducted a systematic evaluation of the impact of IUFD on mortality, short-term morbidities, and long-term growth and neurodevelopment in EPIs. By stratifying our large cohort into meaningful subgroups based on perinatal and maternal factors, we aimed to identify potential heterogeneity in treatment effects and uncover differential impacts of IUFD on specific patient populations, ultimately informing more personalized care strategies.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Data Source\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted this cohort study using a deidentified data set from the Korea Neonatal Network (KNN). The KNN registry was approved by the Samsung Medical Center Institutional Review Board (2013-03-002) and informed consent was obtained from the parents when their infants were enrolled in the registry. All methods were performed in accordance with the relevant guidelines and regulations of the this study\u003csup\u003e14\u003c/sup\u003e. This included data on growth and neurodevelopment at discharge, during NICU hospitalization, and at 18\u0026ndash;24 months\u0026rsquo; corrected age (CA) and 3 years old. The data collection followed the pre-set KNN Manual of Operation (MOP) \u003csup\u003e14\u003c/sup\u003e. After ensuring data quality through inquiries and site visit monitoring, the KNN registry data are saved annually on the Korea National Institute of Health server.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified all twins or triplets with gestational age (GA) of 21 to 27 weeks, born as EPIs [22] between January 2013 to December 2021 and registered in the KNN. Among the 2,060 EPIs from KNN data, we excluded 42 EPIs with severe congenital anomalies, then the eligible participants were 2,018 (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIUFD\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe criteria for defining IUFD in multiple pregnancies differed between two periods according to the KNN MOP \u003csup\u003e15\u003c/sup\u003e. During phase 1 (2013\u0026ndash;2018), IUFD was recorded based on obstetric clinicians\u0026rsquo; documentation. Typically, fetal demise occurring before 12 weeks of gestation was not considered as IUFD in multiple pregnancies, whereas demise at or beyond 20 weeks was consistently classified as IUFD in multiple pregnancies. For fetal demise between 12 and 20 weeks of gestation, classification depended on clinical judgment.\u003c/p\u003e\n\u003cp\u003eDuring phase 2 (2019\u0026ndash;2021), following the revised KNN MOP guidelines, only fetal demise occurring at or beyond 16^+0 weeks of gestation was classified as IUFD in twin or triplet pregnancies.\u003c/p\u003e\n\u003cp\u003eIn both periods, pregnancies were consistently categorized into two groups: IUFD multiple, defined as twin or triplet pregnancies in which the number of live-born infants was fewer than the original number of fetuses identified during pregnancy, and normal multiple, defined as pregnancies in which all fetuses survived. This definition was uniformly applied to twins and triplets throughout the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome was in-hospital mortality, defined as death at NICU discharge. Secondary outcomes were short-term morbidities, long-term growth and NDI at a CA of 18-24 months (follow-up 1) and 3 years old (follow-up 2). Short-term morbidities included periventricular leukomalacia (PVL) \u003csup\u003e16\u003c/sup\u003e, bronchopulmonary dysplasia (BPD) of moderate or greater severity \u003csup\u003e17\u003c/sup\u003e, retinopathy of prematurity (ROP) over stage3 or requiring laser treatment \u003csup\u003e18\u003c/sup\u003e, necrotizing enterocolitis (NEC) at Bell\u0026apos;s stage 2 or higher \u003csup\u003e19\u003c/sup\u003e, culture-proven sepsis, intraventricular hemorrhage (IVH) of grade 3 or higher, length of hospitalization, and mortality at NICU discharge were obtained from KNN database (Supplementary Table 1).\u003c/p\u003e\n\u003cp\u003eThe long-term NDI assessed at a CA of 18-24 months and 3 years old using Bayley Scales of Infant Development (BSID) II \u0026amp; III, and Korean Developmental Screening Test for infants and children (K-DST) \u003csup\u003e20\u003c/sup\u003e. Cerebral palsy (Gross Motor Function Classification System \u0026ge;2) \u003csup\u003e21\u003c/sup\u003e, blindness, wearing glasses, hearing aid. Postnatal growth failure (PGF) \u003csup\u003e22\u003c/sup\u003e were defined as below z-score of \u0026ndash;2 (2.3rd percentile) in weight, height, or head circumference for gestational ages between 22 and 50 weeks were calculated using the Fenton Lambda-Mu-Sigma (LMS) tables with 2013 Fenton growth chart \u003csup\u003e23\u003c/sup\u003e and \u0026nbsp; according to the 2006 World Health Organization (WHO) child growth standards for children aged 0 to 5 years \u003csup\u003e22,24\u003c/sup\u003e. Based on the findings of each assessment that was available, we classified NDI into three unique domains: the mental, motor, and social domains. The determination of NDI in the Mental domain was based on the following criteria: 1) a mental developmental index of less than 70 on the BSID II; 2) a cognitive or language score of less than 70 on the BSID III; or 3) a cognition, language, or self-help score that falls below the threshold on the K-DST for those who were assessed only with the K-DST but not with the BSID. For the Motor domain, NDI was identified by: 1) a psychomotor developmental index of less than 70 on the BSID II; 2) a motor score of less than 70 on the BSID III; or 3) a gross motor or fine motor score that is below the threshold on the K-DST for those who were assessed only with the K-DST but not with the BSID. In the Social domain, NDI was determined by a social interaction score that falls below the cut-off value on the K-DST. Therefore, regardless of screening results from K-DST, NDI in each domain was defined mainly when the BSID scores was \u0026lt;70, and secondly when at least one of the scores in a particular domain from K-DST was \u0026lt;-2 standard deviations (SD) if BSID data were missing \u003csup\u003e20\u003c/sup\u003e. The total domain was labeled as NDI if any of the three domains showed abnormalities \u003csup\u003e20,25,26\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfounding factors\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInfant characteristic including gestational age (GA), birth weight, small for gestational age (SGA) (\u0026lt;10\u003csup\u003eth\u003c/sup\u003e percentile of the Fenton growth chart) \u003csup\u003e23\u003c/sup\u003e, sex, Apgar scores at 1 and 5 minutes was obtained from KNN database. Maternal characteristics included maternal age, oligohydramnios, polyhydramnios, use of antenatal steroid, cesarean section (C/S), pathologic chorioamnionitis, diabetes mellitus (DM), maternal hypertension, preterm rupture of membranes (PROM) within a 24-hour timeframe, and IVF were also obtained from KNN database. All the variables were measured by standard manual of operation (Supplementary Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were presented as a mean \u0026plusmn; standard deviation for continuous variables and as a number or percentage for categorical variables. The chi-squared or Fisher\u0026rsquo;s exact test was performed for categorical variables, and the t-test or Mann\u0026ndash;Whitney U test was used for continuous variables accordingly. To compare mortality, short-term and long-term outcomes by IUFD and normal multiple, a generalized linear model with a modified Poisson regression and robust error variance was used. Then we estimated relative risk (RR) for common binary outcomes. Adjusted RRs with 95% confidence intervals (CIs) were calculated to account for potential confounders including IVF, Oligohydramnios, use of antenatal steroids, and pathological chorioamnionitis of mother as Model 1; sex, gestational age, Apgar score at 1 minute of infant as Model 2; Model 1+ Model 2 as Model 3. We evaluated the impact of one triplet\u0026rsquo;s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal. A subgroup analysis to analyze the heterogeneity of rates, presenting the results in a forest plot with the p-value for interaction. We conducted survival and cumulative incidence analyses to compare the outcomes between the two groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo compare cumulative incidence of long-term mortality, Kaplan-Meier analysis was used. The log-rank test was used to compare cumulative survival and incidence differences between the groups. Hazard ratios (HRs) and adjusted HRs with 95% CIs were estimated using the Cox proportional hazards model to assess the relative risk between the two groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using STATA 17.0 version [StataCorp., College Station, TX, USA], and R version 4.1.3. P-values \u0026lt;0.05 were considered statistically significant.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eClinical characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong 2,018 participants, 274 (13.6%) were live-born EPIs from IUFD-complicated multiple pregnancies (IUFD multiple group), and 1,744 (86.4%) were infants from uncomplicated multiple pregnancies (Normal multiple group). Compared to the normal multiple group, the IUFD multiple group demonstrated a significantly lower gestational age and birth weight. \u0026nbsp;Mothers of IUFD multiple group were less likely to have maternal diabetes, cesarean sections, and use of antenatal steroids compared to those of normal multiple group (Table 1). In contrast, the incidence of oligohydramnios and pathological chorioamnionitis occurred significantly more frequently in the IUFD multiple group than in the normal multiple group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eShort-term outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In-hospital mortality rate was 43.1% and 29.2%, in IUFD multiple group and normal multiple group, respectively with RR 1.47 (95% CI, 1.25\u0026ndash;1. 73). Even after adjustment for confounders of lower gestational age, sex, lower Apgar score at 1min, IVF, oligohydramnios, antenatal steroid, and pathological chorioamnionitis, fully adjusted RR of IUFD was 1.17 (95% CI, 1.01\u0026ndash;1.37). The incidence of NEC \u0026ge; stage II was also significantly higher in the IUFD multiple (65.8% vs. 57.1%, adjusted RR = 1.37, 95% CI, 1.01\u0026ndash;1.87) when compared to normal multiple (Table 2). The association between co-twin IUFD and increased in-hospital mortality among live born infants was consistent in all subgroups of sex, gestational age, Apgar score at 1 minute, IVF, use of antenatal steroid, and pathological chorioamnionitis (p for interaction \u0026gt; 0.05) (Figure 2). In contrast, in the olilgohydramnios subgroups, the association between co-twin IUFD and higher in-hospital mortality after live-born seems to be inconstant (Figure 2). From a clinical perspective, oligohydramnios appears to have a substantial impact on mortality, and this strong influence might affect this association between co-twin IUFD and mortality of live-born EPI.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLong-term outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIUFD multiple group infants were associated with significantly lower cumulative 1-year survival than normal multiple group infants (log-rank test, p \u0026lt; 0.001). \u0026nbsp;The adjusted HR for in-hospital mortality was 1.56 (95% CI, 1.3\u0026ndash;1.9) (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor the long-term growth and neurodevelopmental outcomes, among 1,391 NICU survivors, 740 infants (53.1%) were followed up at a corrected age of 18 to 24 months and 414 infants (29.8%) were followed up at corrected age of 3 years (Figure 1). Although gestational age and birth weight were lower in infants lost in normal multiple, there was no difference between infants who had follow-up or loss (Supplementary Table 3). At corrected ages of 18\u0026ndash;24 months (follow-up 1), although blindness was more frequent in the IUFD multiple group compared to the normal multiple group (3.4% vs. 0.6%; RR, 4.56; 95% CI, 1.35 \u0026ndash; 15.34), other outcomes were not differences between the IUFD multiple and normal multiple (Table 3). At corrected ages of 3 years (follow-up 2), neurodevelopmental impairment or growth outcomes were similar between IUFD multiple and normal multiple except head circumference growth restriction (32.1% vs. 18.5%; RR, 1.58; 95% CI, 1.01 \u0026ndash; 2.48) (Table 3).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study examined the impact of second-trimester IUFD on live-born premature infants from multiple pregnancies, focusing on short-term morbidities and long-term growth and neurodevelopmental outcomes. In the extremely premature infants, IUFD was strongly associated with increased in-hospital NICU mortality among live-born infants. Regarding short-term morbidities, EPIs with IUFD-affected co-twins were associated with a higher incidence of NEC\u0026thinsp;\u0026ge;\u0026thinsp;stage II. For long-term outcomes, growth and neurodevelopmental parameters did not differ significantly, apart from an elevated risk of blindness at 18\u0026ndash;24 months follow-up and restricted head growth at 3 years follow-up in live-born EPIs with IUFD-affected co-twins.\u003c/p\u003e \u003cp\u003eA systematic review and meta-analysis by Hillman et al. reported that the rate of co-twin perinatal death after single fetal demise was 15% in monochorionic twins versus 3% in dichorionic twins and thus monochorionic twins are at substantially increased risk of co-twin demise following single fetal death compared to dichorionic twins due to shared placental circulation \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. However, the meta-analysis was limited by the inclusion of very small-scale studies, such as case series reports. In other population-based study using the data obtained from Vital Statistics Branch at the US National Center for Health Statistics, demonstrated that fetal death at 20 weeks\u0026rsquo; gestation or later is uncommon, occurring in 2.6% of twin and 4.3% of triplet gestations and the probability of survival for the remaining fetuses improved dramatically with increasing gestational age at the time of the fetal death \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. However, in this population-based data, there was several limitations of excluding fetal death occurred before 20 weeks\u0026rsquo; gestation and thus it is unlikely that majority of fetal losses occurring in the 2nd trimester were included. In addition, the Matched Multiple Birth File did not contain information regarding chorionicity and infertility treatment.\u003c/p\u003e \u003cp\u003eThe results data of our present study based on nine years of prospective national VLBWI registry data and thus the finding that higher mortality rate and increased NEC incidence in live-born EPIs with IUFD-affected co-twins than normal unaffected multiples can be considered highly reliable. Moreover, this is the first study to demonstrate outcomes of live-born premature infants following IUFD exposure in a cohort composed of extremely preterm infants, a population at high risk for adverse clinical outcomes. In addition, this national registry data set includes the majority of 2nd trimester fetal loss because the information of fetal demise was defined as the fetal death after 14 weeks\u0026rsquo; gestation and the analyzed EPI population was limited to the live-born premature infants lower than 28 gestational weeks. However, the absence of chorionicity data in multiple pregnancies induced an inevitable limitation, limiting the evaluation of the association between chorionicity and mortality in live-born EPIs with IUFD-affected co-twins. Accordingly, there is a need for further meticulously designed study to analyze whether IVF-related procedures such as selective abortion and chorionicity influence the outcomes of live-born EPIs with IUFD-affected co-twins\u003c/p\u003e \u003cp\u003eAlso, the prevalence of NEC\u0026thinsp;\u0026ge;\u0026thinsp;stage II was significantly higher among live-born EPIs with IUFD-affected co-twins (17.1%) compared to normal unaffected multiples (11.3%). Previous studies on IUFD have not reported an association between IUFD and an increased risk of NEC in live-born EPIs with IUFD-affected co-twins and our present study provides the first evidence suggesting this relationship. In the recent national cohort study about maternal chorioamnionitis and NEC, maternal chorioamnionitis is associated with increased incidence of NEC in the infants of birth weight 2500-4499g\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Another multicenter cohort study in very preterm infants and VLBWI also presented positive association between maternal chorioamnionitis and NEC or death\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Given these reports above, antenatal inflammation may be associated with the development of NEC and thus further studies are warranted to elucidate the association between IUFD-related antenatal inflammation and the development of NEC.\u003c/p\u003e \u003cp\u003eLong-term follow-up at 18\u0026ndash;24 months corrected age showed no significant differences in neurodevelopmental outcomes between groups, apart from a higher incidence of blindness among live-born EPIs with IUFD-affected co-twins. This increased risk of blindness may not solely result from sensory pathway disruptions but could also reflect the compounding effects of neurological injuries, such as IVH\u0026thinsp;\u0026ge;\u0026thinsp;grade III \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e or PVL those were more prevalent in IUFD multiple compared to normal multiples, though there was not any statistical significance.\u003c/p\u003e \u003cp\u003eA study based on national registrations by Pharoan et al. showed that surviving co-twins of fetuses who experienced intrauterine death have an elevated risk of cerebral impairment, with an overall risk estimated at 20%. The prevalence of cerebral palsy, adjusted for gestational age, was found to be significantly higher in these cases compared to the general twin population \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. However, in the Swedish national registry, with a 50% loss to follow-up, the disability rate at 8 years of age was recorded as 46 per 1000, which was lower than that reported in other studies. The differences in disability rates might be attributed to variations in definitions, methodologies, including the use of questionnaires sent to rehabilitation centers, and population bases \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Though these above reports with national registry thoroughly performed survey about long-term developmental delays in survived co-twins of fetuses who experienced intrauterine death, there was no comparison with twins or triplets all survived as a control group. Our current study targeted only premature infants born at \u0026lt;\u0026thinsp;29 weeks\u0026rsquo; gestation, the cerebral palsy rates at 2 years were 9.6% and 9.5% in IUFD multiples and all live-born multiples, respectively and the motor development delay at 3 years old also showed 35.2% and 28.5% in IUFD multiples and all live-born normal multiples, respectively. Though there was no statistically significant difference between groups, it is hard to say that IUFD co-twin exposure did not seem to induce developmental delay, because of substantial amount of follow-up loss in this cohort. Future studies should link this cohort with national health insurance data to minimize loss to follow-up and to accurately assess the developmental outcomes between IUFD multiples and normal multiples.\u003c/p\u003e \u003cp\u003eRecent societal shifts, including delayed marriage and the increased use of assisted ART, have led to a significant rise in multiple pregnancies, particularly among older mothers \u003csup\u003e\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. ART procedures, including IVF and intracytoplasmic sperm injection (ICSI), have become more accessible and successful, contributing further to the rise \u003csup\u003e\u003cspan additionalcitationids=\"CR36 CR37\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. However, these pregnancies are inherently associated with increased risks, such as preterm birth, low birth weight, and congenital anomalies \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e, leading to a 2- to 4-fold higher risk of maternal or neonatal death. In response to declining fertility rates and delayed marriage, South Korea has implemented policies such as ART insurance coverage since October 2017 to reverse population decline \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e. In addition, in South Korea, where a policy mandating single embryo transfer is not in place, the incidence of IVF-induced multiple pregnancies is increasing annually [51]. These policies, while beneficial in promoting ART, have inadvertently increased the rate of multiple pregnancies and, consequently, the risks associated with in-utero fetal demise \u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Our study demonstrated that the proportion of infants conceived via IVF (59.6%) was higher compared to those conceived spontaneously (40.4%).\u003c/p\u003e \u003cp\u003eA retrospective cohort study indicated that the survival rate of MCDA twins conceived via IVF/ICSI is lower (79%) compared to those conceived spontaneously (90%). Additionally, the risk of losing one or both twins is twice as high in IVF/ICSI pregnancies (29% vs. 14%) compared to spontaneous pregnancies \u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. Notably, the increased risk of adverse outcomes in IVF pregnancies appears to be mediated by the higher prevalence of monochorionic rather than by IVF itself \u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. Thus, the increased incidence of adverse outcomes in IVF twins may be mediated by chorionicity, underscoring the importance of placental type in predicting fetal loss and neonatal outcomes \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. The sub-group analysis data of our present study, co-twin IUFD exposure seems to increase mortality rate of live-born EPI among infants from multiple pregnancies conceived by IVF; adjusted RR (95% CI), 1.36 (1.12\u0026ndash;1.66), but not in the infants from multiple pregnancies conceived spontaneously; adjusted RR (95% CI), 1.06 (0.83\u0026ndash;1.35).\u003c/p\u003e \u003cp\u003eIn the present study has several limitations. First, we could not the identify between fetal death in the delivery room, type of placenta and membranes including chorionicity with dichorionic diamniotic, monochorionic diamniotic and fetal death time due to lack of information in KNN registry. Second, the study population enrolled a loss of follow-up rate of neurodevelopmental assessment which might decrease the strength of adverse impact of EPIs on long-terms results. Although, a significant number of EPIs were included in our study after IUFD. This was accomplished at the national level by examining the real long-term clinical course under well-supervised quality \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, including neurodevelopmental features, using data obtained from a large prospective cohort. Finally, due to the nature of the multi-center registry, this study utilized various neurodevelopmental assessment tools. To include all available data and reduce selection bias, we created a composite score by integrating BSID-II and III as confirmatory tests, along with K-DST \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Despite K-DST is reported to be valid and show strong correlation with BSID \u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e, it is important to recognize the potential for bias due to the variability between tests. Although questionnaires like we used a consistent cut-off value (\u0026lt;\u0026thinsp;70 for NDI) for both BSID-II and III, as done in previous studies \u003csup\u003e\u003cspan additionalcitationids=\"CR47\" citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e, but debates continue regarding the use of different cut-off values for these tests \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis large-scale national study demonstrated that second-trimester IUFD was strongly associated with higher in-hospital mortality, increased risks of NEC\u0026thinsp;\u0026ge;\u0026thinsp;stage II, and blindness among EPIs. In contrast, other short-term morbidities and long-term growth and neurodevelopmental outcomes were not significantly affected. Therefore, we suggest that second-trimester IUFD is a crucial risk factor affecting the surviving EPI. Consequently, this study provides evidence to support comprehensive counseling for patients, after a fetal demise in a multifetal gestation and the need for meticulous clinical management of the surviving live-born EPI after co-twin IUFD exposure.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eEPIs, extremely preterm infants; BPD, bronchopulmonary dysplasia; NICU, neonatal intensive care unit; CA, corrected age; NDI, neurodevelopmental impairment; KNN, Korean Neonatal Network; MOP, manual of operation; GA, gestational age; BW, birth weight; C/S, cesarean section; SGA, small for gestational age; PDA, patent ductus arteriosus; IVH, intraventricular hemorrhage; PVL, periventricular leukomalacia; BSID, Bayley Scales of Infant Development; K-DST, Korean Developmental Screening Test for infants and children; aOR, adjusted odds ratio; RR, relative risk; CI, confidence intervals;\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interest Disclosures:\u003c/strong\u003e The authors have indicated no conflicts of interest relevant to this article to be disclosed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding/Support:\u003c/strong\u003e This research was supported by a fund by Research of the Korea National Institute of Health (2022-ER0603-02#), Future Medicine 2030 project of the Samsung Medical Center (#SMX1220081) and grant from SMC-Ottogi Research Fund (SMX1210881).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003eThe data that support the findings of this study are available from the corresponding author ([email protected]) upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributors Statement Page\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSumin Kim, So Yoon Ahn, Juhee Cho, Danbee Kang and Yun Sil Chang conceptualized and designed the study, drafted the initial manuscript, coordinated and supervised data collection, and critically reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eSumin Kim and So Yoon Ahn designed the data collection instruments, collected data, carried out the initial analyses, and critically reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003eMisun Yang, Se In Sung, Danbee Kang, Juhee Cho and Yun Sil Chang critically reviewed and revised the manuscript, and supervised data collection.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePettersson ML, Bladh M, Nedstrand E, Svanberg AS, Lampic C, Sydsj\u0026ouml; G. 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Revision of a parent-completed development screening tool: Ages and Stages Questionnaires. \u003cem\u003eJ Pediatr Psychol\u003c/em\u003e. 1997;22(3):313-328\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Characteristics of infants and their mothers\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"614\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003cstrong\u003eharacteristic\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (n=2\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e\u003cstrong\u003e018)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIUFD multiple\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=274)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal multiple\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=1\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e\u003cstrong\u003e744)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInfant\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eMale (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e1074 (53.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e143 (52.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e931 (53.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.713\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eGestational age\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e25.2\u0026plusmn;1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e24.6\u0026plusmn;1.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e25.3\u0026plusmn;1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eSGA (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e149 (7.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e28 (10.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e121 (6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.054\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eBirth weight (g)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e800.1\u0026plusmn;197.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e740.4\u0026plusmn;207.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e809.4\u0026plusmn;194.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eApgar scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e1 minute\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e3.6\u0026plusmn;1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e3.5\u0026plusmn;1.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e3.7\u0026plusmn;1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.294\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e5 minutes\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e5.9\u0026plusmn;2.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e5.7\u0026plusmn;1.9 \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e5.9\u0026plusmn;1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.065\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eZ-score at birth\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cem\u003eWeight\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e-0.01\u0026plusmn;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-0.04\u0026plusmn; 0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-0.01\u0026plusmn;0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.733\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cem\u003eHeight\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e-0.3\u0026plusmn;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-0.4\u0026plusmn;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e-0.3\u0026plusmn;1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.527\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cem\u003eHead circumference\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e0.1\u0026plusmn;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.03\u0026plusmn;1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.09\u0026plusmn;1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.200\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eM\u003c/strong\u003e\u003cstrong\u003eother\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eMaternal age\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e33.2\u0026plusmn;3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e33.2\u0026plusmn;3.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e33.2\u0026plusmn; 3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.891\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eIVF (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e1\u003cstrong\u003e,\u003c/strong\u003e203 (59.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e155 (56.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1\u003cstrong\u003e,\u003c/strong\u003e048 (60.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eDiabetes (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e181 (8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e15 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e166 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eHypertension (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e133 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e15 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e118 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.423\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eCesarean section (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e1\u003cstrong\u003e,\u003c/strong\u003e612 (79.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e170 (62.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1\u003cstrong\u003e,\u003c/strong\u003e442 (82.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003ePROM, cut off 24h (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e367/622 (59.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e75/112 (66.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e292/510 (57.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eOligohydramnios\u0026nbsp;(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e215/1\u003cstrong\u003e,\u003c/strong\u003e819 (11.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e42/241 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e173/1\u003cstrong\u003e,\u003c/strong\u003e578 (10.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003ePolyhydramnios (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e54/1\u003cstrong\u003e,\u003c/strong\u003e819 (2.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e11/241 (4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e43/1\u003cstrong\u003e,\u003c/strong\u003e578 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.117\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003eAntenatal steroid (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e1\u003cstrong\u003e,\u003c/strong\u003e700/1\u003cstrong\u003e,\u003c/strong\u003e984 (85.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e215/269 (79.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1\u003cstrong\u003e,\u003c/strong\u003e485/1\u003cstrong\u003e,\u003c/strong\u003e715 (86.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 189px;\"\u003e\n \u003cp\u003ePathological chorioamnionitis (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e713/1\u003cstrong\u003e,\u003c/strong\u003e721 (41.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e129/233 (55.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e584/1\u003cstrong\u003e,\u003c/strong\u003e488 (39.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 73px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eContinuous variables are presented as means (standard deviation). Categorical variables are presented as N (%). IUFD: intrauterine fetal death; SGA: small for gestational age; PROM: premature rupture of membrane; IVF: in vitro fertilization. We evaluated the impact of one triplet\u0026rsquo;s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal. \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Short-term morbidities by IUFD multiple and normal multiple\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"907\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIUFD multiple\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=274)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal multiple\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=1\u003c/strong\u003e\u003cstrong\u003e,\u003c/strong\u003e\u003cstrong\u003e744)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 416px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIUFD multiple vs.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eNormal multiple\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(reference)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCrude RR\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted RR\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted RR\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 3\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted RR\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIn-hospital mortality\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e118 (43.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e509 (29.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.47 (1.25 -\u0026nbsp;1.73)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.42 (1.21 - 1.67)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.17 (1.01 - 1.36)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.17 (1.01 - 1.37)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBPD \u0026ge; moderate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e108/164 (65.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e708/1,238 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.15 (1.01 - 1.30)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.98 (0.83 - 1.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.01 (0.86 - 1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.02 (0.87 - 1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIVH \u0026ge; grade III\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e67/239 (28.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e359/1,597 (22.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.24 (0.99 - 1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.15 (0.91 - 1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.03 (0.81 - 1.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.03 (0.81 - 1.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSepsis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e97/272 (35.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e561/1,734 (32.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.10 (0.92 - 1.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.09 (0.91 - 1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.04 (0.87 - 1.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.04 (0.86 - 1.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePVL\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e33/237 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e184/1,589 (11.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.20 (0.84 - 1.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.15 (0.80 - 1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.11 (0.77 - 1.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.12 (0.78 - 1.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNEC \u0026ge; stage Ⅱ\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e46/268 (17.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e194/1,711 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.51 (1.12 - 2.04) *\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.52 (1.12 - 2.07)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.33 (0.98 - 1.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.37 (1.01 - 1.87)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eROP \u0026ge; stage III\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e58/165 (21.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e424 (24.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.06 (0.84 - 1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.88 (0.69 - 1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.83 (0.64 - 1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.84 (0.65 - 1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eROP OP.\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e51/168 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e326/1,074 (30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.00 (0.77 - 1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.97 (0.74 - 1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.92 (0.70 - 1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.92 (0.70 - 1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostnatal growth failure at NICU discharge (Z-score\u0026lt; -2.0)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cem\u003eWeight\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e52 (18.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e333 (19.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.99 (0.76 -\u0026nbsp;1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.03 (0.78 - 1.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.98 (0.75 - 1.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.02 (0.77 -\u0026nbsp;1.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cem\u003eHeight\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e102 (37.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e678 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.65 (0.81 -\u0026nbsp;1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.97 (0.82 - 1.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.95 (0.80 -\u0026nbsp;1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.95 (0.81 -\u0026nbsp;1.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cem\u003eHead circumference\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e62 (22.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e348 (19.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.13 (0.88 - 1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.11 (0.87 - 1.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.08 (0.84 - 1.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e1.07 (0.84 - 1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIUFD: intrauterine death; BPD: bronchopulmonary dysplasia; IVH: intraventricular hemorrhage; PVL: periventricular leukomalacia; NEC: necrotizing enterocolitis; ROP: retinopathy of prematurity; OP: operation; ; RR: relative risk, AOR: adjusted relative risk\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eModel 1: Adjusted for IVF, Oligohydramnios, Antenatal steroid, and pathological chorioamnionitis of mother; \u0026nbsp;Model 2: Adjusted for sex, gestational age, Apgar score at 1 minute of infant; Model 3: \u0026nbsp;Adjusted for Model 1+ Model 2; *p-value \u0026lt;0.05; We evaluated the impact of one triplet\u0026rsquo;s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal.\u003c/p\u003e\n\u003cp\u003eWe evaluated the impact of one triplet\u0026rsquo;s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003eLong-term growth and neurodevelopmental outcomes by IUFD multiple and normal multiple\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"916\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIUFD multiple\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e#\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=1\u003c/strong\u003e\u003cstrong\u003e45\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNormal multiple\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003e#\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=1\u003c/strong\u003e\u003cstrong\u003e,009\u003c/strong\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 509px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIUFD multiple vs.\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eNormal multiple\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(reference)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCrude RR\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted RR\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted RR\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ea\u0026nbsp;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eModel 3\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted RR\u003c/strong\u003e\u003cstrong\u003e\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCorrected age at 18 to 24 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurodevelopmental impairment\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eMental development delay\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e(%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e13/54 (24.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e85/397 (21.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.12 (0.66 - 1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.06 (0.61 - 1.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.98 (0.55 - 1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.01 (0.56 - 1.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eMotor development delay\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e(%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e11/54 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e74/397 (18.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.09 (0.61 - 1.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.05 (0.57- 1.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.92(0.50 - 1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.96 (0.51 - 1.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eSocial development delay\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e(%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e1/12 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e10/116 (8.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.70 (0.09 - 5.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.68 (0.08 - 5.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.75 (0.09 - 6.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.82 (0.09 - 7.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eTotal\u0026nbsp;\u003c/em\u003e\u003cem\u003edevelopment delay\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e(%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e15/54 (27.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e111/397 (27.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.99 (0.62 - 1.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.96 (0.58 - 1.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.86 (0.52 - 1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.91 (0.54 - 1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBlindness\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e3/89 (3.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e4/618 (0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e5.21 (1.18 - 22.89)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e4.94 (1.27 - 19.17)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e4.08 (1.11 - 15.05)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e4.56 (1.35 - 15.34)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWearing glasses\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e6/88 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e29/613 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.44 (0.61 - 3.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.63 (0.66 - 4.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.21 (0.50 - 2.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.50 (0.59 - 3.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHearing aid\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e3/71 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e21/532 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.07 (0.32 - 3.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.11 (0.34 - 3.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.95 (0.27 - 3.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.06 (0.31 - 3.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCerebral palsy\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e9/89 (10.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e59/618 (9.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.05 (0.54 - 2.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.17 (0.60 - 2.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.97 (0.49 - 1.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.12 (0.57 - 2.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostnatal growth failure (Z-score\u0026lt; -2.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eWeight (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e13/77 (16.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e81/539 (15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.22 (0.86 - 1.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.26 (0.89 - 1.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.17 (0.84 - 1.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.22 (0.87 - 1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eHeight (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e16/72 (22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e81/511 (15.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.01 (0.81 - 1.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.00 (0.80 - 1.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.97 (0.79 - 1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.96 (0.78 - 1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eHead circumference (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e16/64 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e105/432 (24.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.41 (0.99 - 1.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.38 (0.97 - 1.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.31 (0.93 - 1.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.30 (0.93 - 1.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCorrected age at 36 months\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeurodevelopmental impairment\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eMental development delay\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e(%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e11/26 (42.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e37/133 (27.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.52 (0.88 - 2.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e2.01 (1.06 - 3.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.90 (1.01 - 3.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.89 (1.00 - 3.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eMotor development delay\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e(%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e12/26 (46.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e48/133 (36.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.27 (0.78 - 2.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.79 (0.98 - 3.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.46 (0.81 - 2.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.61 (0.89 - 2.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eSocial development delay\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e(%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e1 /10 (10.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e11/41 (26.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.37 (0.05 - 2.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.58 (0.07 - 4.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.66 (0.09 - 4.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.60 (0.09 - 3.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eTotal\u0026nbsp;\u003c/em\u003e\u003cem\u003edevelopment delay\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003e(%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e14/26 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e58/133 (43.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.23 (0.81 - 1.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.65 (0.96 - 2.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.44 (0.87 - 2.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.50 (0.89 - 2.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePostnatal growth failure (Z-score\u0026lt; -2.0)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eWeight (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e17/53 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e76/361 (21.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.52 (0.97 - 2.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.46 (0.95 - 2.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.49 (0.91 - 2.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.45 (0.91 - 2.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eHeight (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e27/53 (50.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e188/361 (52.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.97 (0.73 - 1.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.93 (0.71 - 1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e0.96 (0.72 - 1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e0.92 (0.71 - 1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 204px;\"\u003e\n \u003cp\u003e\u003cem\u003eHead circumference (%)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 98px;\"\u003e\n \u003cp\u003e17/53 (32.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e67/361 (18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.72 (1.09 - 2.73)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.60 (1.02 - 2.51)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e1.66 (1.03 - 2.67)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 122px;\"\u003e\n \u003cp\u003e1.58 (1.01 - 2.48)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eIUFD: intrauterine death; RR: relative risk, AOR: adjusted relative risk;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe number of long-term growth and neurodevelopmental follow-ups at CA of 18-24 months are 503 in normal multiple and 59 in IUFD multiple, respectively; \u003csup\u003e#\u003c/sup\u003eThe number of long-term growth and neurodevelopmental follow-ups at 3 years old are 237 in normal multiple and 35 in IUFD multiple, respectively; We evaluated the impact of one triplet\u0026rsquo;s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal.\u003c/p\u003e\n\u003cp\u003eModel 1: Adjusted for IVF, Oligohydramnios, Antenatal steroid, and pathological chorioamnionitis of mother; \u0026nbsp;Model 2: Adjusted for sex, gestational age, Apgar score at 1 minute of infant; Model 3: \u0026nbsp;Adjusted for Model 1+ Model 2; \u0026nbsp;We evaluated the impact of one triplet\u0026rsquo;s death on the surviving siblings, using maternal ID as a clustering variable, accounting for interdependent outcomes within the same maternal.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Infant, Extremely Premature, Pregnancy, Fetal Death","lastPublishedDoi":"10.21203/rs.3.rs-9281364/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9281364/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThis study examines the effects of exposure to second-trimester intrauterine fetal death (IUFD) on extremely preterm infants (EPIs) from twin or triplet pregnancies, specifically comparing the outcomes of surviving co-twin or co-triplet based on IUFD status.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eTwins or triplets of EPIs within the Korean Neonatal Network (KNN) from 2013 to 2021 were analyzed, focusing on the morbidities and mortality of surviving infants after IUFD. Long-term growth and neurodevelopmental impairment (NDI) were evaluated using composite scores from the Bayley Scales of Infant Development II \u0026amp; III, the Korean Developmental Screening Test.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 2 018 EPIs, IUFD multiple (surviving EPIs with fetal death) had no significant differences in comparison to normal multiple (surviving EPIs without fetal death). However, the mortality rate at NICU discharge was higher in IUFD multiple than in normal multiples. Long-term growth and NDI revealed no significant differences among groups, but IUFD multiple had higher postnatal growth failure (PGF) than normal multiple.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEPIs following intrauterine co-twin or co-triplet fetal death exhibited a significantly higher mortality rate than EPIs from twin or triplet pregnancies where all survived.\u003c/p\u003e","manuscriptTitle":"Outcomes After Co-Twin Intrauterine Fetal Death in Extremely Preterm Infants From Multiple Pregnancies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 12:04:38","doi":"10.21203/rs.3.rs-9281364/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0fc35f1f-acc4-4aa8-8f4f-950042e21e9e","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":66478978,"name":"Biological sciences/Developmental biology"},{"id":66478979,"name":"Health sciences/Diseases"},{"id":66478980,"name":"Health sciences/Health care"},{"id":66478981,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-04-21T09:56:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 12:04:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9281364","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9281364","identity":"rs-9281364","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}