Mortality and short-term outcomes of preterm infants of multiple versus singleton gestations

doi:10.21203/rs.3.rs-2440008/v1

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Mortality and short-term outcomes of preterm infants of multiple versus singleton gestations

https://doi.org/10.21203/rs.3.rs-2440008/v1

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Objective

To compare mortality and major neonatal morbidities between singleton preterm infants and preterm infants of multiple gestations born between 23 + 0 to 32 + 6 weeks.

Method

This is a retrospective cohort study of preterm infants (23 + 0 to 32 + 6 weeks gestational age) born at King Abdul-Aziz Medical City Riyadh (KAMC-R) between January 2016 to December 2020.

Results

Total of 803 preterm infants were included: 567 (70.6%) were singletons, 158 (19.6%) were twins and 36 (4.5%) infants were triplets and higher multiples. The mortality was significantly higher in preterm infants of multiple gestations compared to singleton (12.3% vs. 7.9%; p = 0.003; OR, 2.2; CI, 1.3–3.7). Preterm infants of multiple gestations had an increased risk of ROP (11% vs. 6.5%; P = 0.033; OR, 1.1, CI, 1.04–2.99), BPD at 36 weeks PMA (29.7% vs. 20.5%; P = 0.003; OR, 1.7; CI, 1.2–2.5) and sepsis (24.2% vs 17.5%, P = 0.044; OR, 1.5; CI, 1.01–2.2) compared to preterm singletons. There were no differences in mortality and adverse neonatal outcomes between twins and higher multiples.

Conclusion

Preterm infants of multiple gestations suffered higher mortality and neonatal morbidities compared to preterm singleton infants despite a higher utilization of maternal antenatal steroids and better antenatal care.

Multiple pregnancies

singleton

twins

preterm birth

neonate

mortality

Multiple pregnancy birth rates have been increasing in recent decades due to advanced maternal age (1, 2) and assisted reproductive technology (3, 4). Indeed, this has increased interest in better measuring and understanding multiple births’ impact on maternal and neonatal outcomes.

Previous data on the survival outcomes of twins have shown that twins are 4.9-times more likely than singletons to die during the neonatal period (5). Others have shown that mortality risks vary according to the gestational age at birth. For instance, Papiernik et al. (6) found that, while twins are more likely than singletons to die when the age of gestation is < 28 weeks, twins were more likely to survive when born > 28 weeks gestation (6).

Nevertheless, other studies have not found significant differences in neonatal outcomes

between singleton and multiple births (7) (8).

Maternal health in the setting of multiple pregnancies was also a focus of some studies. For instance, Waites et al. (9) found that late preterm twin pregnancies were more likely to be associated with adverse maternal outcomes, such as delivery by cesarean delivery, occurrence of postpartum hemorrhage, and the need for transfusion (9). Nevertheless, neonatal mortality and intrauterine fetal death (IUFD) were less common in late preterm twins compared to singletons (9).

In summary, there are variations in the existing literature regarding whether singleton vs. multiple births pose added risks of adverse neonatal and maternal outcomes.

The purpose of this study was to compare neonatal mortality and major neonatal morbidities between infants of singleton and multiple pregnancies born before 33 weeks completed gestational age. We wished to test the hypothesis that prematurely born infants of multiple gestations would have higher mortality and significantly greater neonatal morbidities.

The study was conducted at King Abdulaziz Medical City (KAMC), Riyadh, Kingdom of Saudi Arabia, covering 4 years, from January 2017 to December 2020. The Neonatal Intensive Care Unit (NICU) at KAMC is a 40-bed, level III critical care unit and a 36-bed intermediate care nursery with an average of 2300 admissions per year.

Newborn infants (gestational age < 33 weeks) born at KAMC were included in the study. Outborn infants and those with lethal anomalies were excluded from the study. King Abdullah International Medical Research Centre (KAMRC) institutional review board approved the study (IRB: RC20/283/R) and waived the patient consent as the study design was a retrospective chart review and no patients identifiables were kept in the database.

Gestational age, chorionicity, and amnionicity were determined from prenatal records. In uncertain last menstrual period, gestational age from the earliest ultrasound scan was used to determine the gestational age.

Demographic data for mothers and infants were abstracted from the prenatal and inpatient records. Maternal and neonatal variables investigated for the description of the population were: prenatal use of corticosteroids, presence of gestational diabetes and hypertension, mode of delivery, gender, birthweight, and gestational age at birth. The following neonatal morbidities were evaluated: Bronchopulmonary Dysplasia (BPD) at 36 weeks PMA (10), major intraventricular hemorrhage (IVH) (grade III & IV) based on the Papile classification (11), retinopathy of prematurity (ROP) based on pediatric ophthalmologic examination using the international classification of ROP (12) that needed intravitreal injection therapy and/or laser photocoagulation, necrotizing enterocolitis (NEC) based on Bell’s classification (13) that needed surgical intervention with insertion of intraabdominal drain or laparotomy, cystic or diffuse periventricular leukomalacia (PVL) by ultrasound and/or MRI (14) and culture-positive sepsis of the blood, CSF, or urine. Duration of mechanical ventilation in days and the length of hospital stay to the point of home discharge were also determined.

Statistical analysis

Data were tested for normality using the Kolmogorov-Smirnov (KS) test and found to be normally distributed. Comparisons were made between preterm infants with multiple gestations versus those preterms of singleton gestation. Furthermore, we compared the outcomes of preterm twins versus preterm of higher multiple gestations. Finally, a subgroups analysis for preterms (multiples and singletons) was carried out for two gestational age groups (above and below 29 weeks gestation).

Comparison of categorical variables was analyzed with bivariate analysis using chi-square test and description of unadjusted odds ratios (ORs). This was followed by multivariate logistic regression and presentation of adjusted Odds Ratios (AOR) with 95% confidence intervals (CI) to minimize confounding. All risk factors with a significant (p < 0.05) association in the bivariate analysis were included in the multivariate analysis. The following covariables were considered for the multivariate models: gender, gestational age (to remove the effect of collinearity with birthweight), prenatal corticosteroids, maternal arterial hypertension, maternal diabetes, and cesarean delivery. A comparison of means was analyzed using independent, two-sided t-tests. Statistical Package for the Social Sciences (SPSS) version 26.0 was used for analysis.

Eight-hundred-three preterm infants < 33 weeks gestation were born during the 4-years study period, of which 467 (70.6%) were preterm singletons and a further 236 (29.4%) were preterm multiples. Table 1 shows the maternal and neonatal outcomes of the study population.

Table (1) Pregnancy and neonatal outcomes of the study population

	Frequency	Percentage
Maternal hypertensive disorders	119/803	14.80%
Maternal diabetes	134/803	16.70%
Maternal Prolonged Rupture of Membranes (PROM)	217/803	27%
Complete antenatal steroids	525/803	65.50%
Incomplete antenatal steroids	139/803	17.30%
No antenatal steroids	138/803	17.20%
Delivery by Cesarean Section (CS)	523/803	66.30%
Multiple preterm	236/803	29.40%
Singleton preterm	467/803	70.60%
Survived to hospital discharge	728/803	90.70%
Died before discharge	75/803	9.30%
Major IVH(Grade3-4)	111/803	13.80%
Cystic PVL	70/803	8.70%
ROP needing treatment	63/803	7.80%
Surgical NEC	39/803	4.90%
BPD at 36 wks. PMA	186/803	23.20%
Culture positive sepsis	159/803	19.80%

*IVH=Intraventricular Hemorrhage

*PVL=Periventricular Luekomalacia

*ROP= Retinopathy of Prematurity

*NEC= Necrotizing Enterocolitis

*BPD=Bronchopulmonary Dysplasia

Of the 236 preterm infants in the multiple gestation group, 19.6% were twins, 4.5% were triplets, 4.5% were quadruplets and 0.7% were of a sextuplet pregnancy (Table 2).

Table 2

Distribution of infants in the study by number of fetuses
Frequency	Percent	Cumulative Percent
singleton	567	70.6	70.6
DCDA	120	14.9	85.6
MCDA	22	2.7	88.3
MCMA	16	2.0	90.3
Triplets	36	4.5	94.8
Quadruplets	36	4.5	99.3
Sextuplets	6	0.7	100.0
Total	803	100.0
∗ DCDA = Dichorionic-Diamniotic
∗ MCDA = Monochorionic-Diamniotic
∗MCMA = Monochorionic-Monoamniotic

Table 3

Maternal and infant’s demographics (multiple vs singleton)
Demographic	Singleton	Multiple	P value
Maternal HT	96/567(16.9%)	23/236(9.7%)	0.009
Gestational DM	99/567(17.5%)	35/236(14.8%)	0.357
PROM	175/567(30.9%)	42/236(17.8%)	< 0.001
Complete antenatal steroids	348/567(61.5%)	177/236(75%)	0.001
Cesarean section delivery	334/567(58.9%)	198/236(83.9%)	< 0.001
Assisted conception	30/567(5.3%)	117/236(49.6%)	< 0.001
Maternal age	30.5(6.6)	30.2(5.6)	0.424
Gender (male)	315/567(55.5%)	137/236(58.1%)	0.516
Gestational age (weeks)	29(3.3)	29(3.0)	0.952
Birth weight (grams)	1282(438)	1259(448)	0.514

Maternal hypertension (p = 0.009) and maternal PROM (p < 0.001) were significantly higher among mothers of infants in the singleton pregnancy group. On the other hand, antenatal corticosteroids (75% vs. 61.5%, p = 0.001), use of assisted reproductive therapy (49.6% vs. 5.3%, p < 0.001), and delivery by cesarean section (83.9% vs. 58.9%, p < 0.001) were all significantly higher among mothers of infants in the multiple pregnancy group. There were no statistically significant differences in gender, gestational age at birth, birthweight, and maternal diabetes between the two groups (Table.3).

Adjusted mortality before hospital discharge was significantly higher among preterm infants of multiple gestations compared to preterm singletons (12.3% vs. 7.9%; p = 0.003; OR, 2.2; 95%CI, 1.3–3.7). Retinopathy of prematurity (ROP) needing treatment was significantly higher among preterm infants of multiple pregnancies compared to preterm singletons (11% vs. 6.5%, p = 0.033, OR 1.1, 95%CI 1.04–2.99). In addition, the incidence of BPD at 36 weeks PMA (29.7% vs 20.5%; p = 0.003; OR, 1.7; 95%CI, 1.2–2.5) and culture positive sepsis (24.2% vs 17.5%; p = 0.044; OR, 1.5; 95%CI, 1.01–2.2) were significantly higher among preterm infants of multiple pregnancy (Table 4). There were no statistically significant differences between preterm infants of multiple and singleton pregnancies regarding the occurrence of severe IVH, cystic PVL, and surgical NEC (Table 4).

Table 4

Univariate and multivariate analysis of neonatal outcomes (multiples vs singleton)
Outcome	singleton	Multiple	Unadjusted P value	Unadjusted OR (95%CI)	Adjusted p value, OR (95%CI)
Mortality	45/567(7.9%)	29/236(12.3%)	0.034	1.7(1.04–2.75)	0.003,2.2(1.3–3.7)
Major IVH	77/567(13.6%)	34/236(14.4%)	0.757	1.1(0.69–1.65)	0.327,1.3(0.79–2.02)
PVL	46/567(8.1%)	24/236(10.2%)	0.347	1.3(0.76–2.15)	0.438,1.2(0.72–2.15)
ROP	37/567(6.5%)	26/236(11%)	0.031	1.8(1.04-3.0)	0.033,1.1(1.04–2.99)
Surgical NEC	25/567(4.4%)	14/236(5.9%)	0.360	1.4(0.69–2.7)	0.286,1.5(0.74–1.9)
BPD	116/567(20.5%)	70/236(29.7%)	0.005	1.6(1.15–2.3)	0.003,1.7(1.2–2.5)
Sepsis	99/567(17.5%)	57/236(24.2%)	0.030	1.5(1.03–2.2)	0.044,1.5(1.01–2.2)
∗Adjustments were made for antenatal steroids, maternal hypertension, maternal PROM and mode of delivery
∗IVH = Intraventricular Hemorrhage
∗PVL = Periventricular Leukomalacia
∗ROP = Retinopathy of Prematurity
∗NEC = Necrotizing Enterocolitis
∗BPD = Bronchopulmonary Dysplasia

Of the multiple pregnancy group infants, 158 (12%) were twins and 78 (5.1%) were of higher multiples. Uptake of antenatal corticosteroids (85.9% vs. 69.6%, p = 0.003) and delivery by cesarean section (97.4%vs 77.2%, p < 0.001) were significantly higher among infants of the higher multiples compared to twins (Table 5). There were no statistically significant differences between twins and higher multiples with regard to maternal hypertension, maternal diabetes, and maternal PROM (Table 5). Gestational age at birth, birthweight, and gender did not differ between the two groups (Table 5). There were no statistically significant differences in the adjusted mortality and all major neonatal morbidities between twins and higher multiples (Table 6).

Table 5

Maternal and infants’ demographics (twins vs triplets &higher multiples)
Demographic	Twins	Triplets & higher multiples	P value
Maternal hypertension	19/158(12%)	4/78(5.1%)	0.093
Gestational Diabetes	25/158(15.8%)	10/78(12.8%)	0.542
Maternal PROM	31/158(19.6%)	11/78(14.1%)	0.297
Complete antenatal steroids	110/158(69.6%)	67/78(85.9%)	0.003
Cesarean section delivery	122/158(77.2%)	76/78(97.4%)	< 0.001
Gender (male)	92/158(58.2%)	45/78(57.7%)	0.937
Gestational age (weeks)	29.1(2.7)	28.9(3.4)	0.652
Birthweight (grams)	1298(441)	1182(457)	0.068

Table 6

Univariate and multivariate analysis of neonatal outcomes (twins vs triplets and higher multiples)
Outcome	Twins	Triplets & higher multiples	Unadjusted P value	Unadjusted OR (95%CI)	Adjusted p value, OR (95%CI)
Mortality	17/158(10.7%)	12/78(15.6%)	0.238	0.65(0.3–1.4)	0.145,1.95(0.79–4.80)
Major IVH	20/158(12.6%)	14/78(18.2%)	0.250	1.5(0.73–3.3)	0.376,0.69(0.31–1.55)
PVL	18/158(11.3%)	6/78(7.8%)	0.400	0.66(0.52–1.7)	0.305,1.7(0.62–4.69)
ROP	14/158(8.8%)	12/78(15.6%)	0.119	1.91(0.84–4.4)	0.075,0.42(0.16–1.09)
Surgical NEC	9/158(5.7%)	5/78(6.5%)	0.799	1.2(0.37–3.6)	0.334,0.52(0.14–1.94)
BPD at 36wk PMA	49/158(30.8%)	21/78(27.3%)	0.576	0.84(0.46–1.5)	0.458,1.28(0.59–2.43)
Sepsis	35/158(22%)	22/78(28.6%)	0.270	1.42(0.76–2.6)	0.381,0.740(0.38–1.45)
∗IVH = Intraventricular Hemorrhage
∗PVL = Periventricular Leukomalacia
∗ROP = Retinopathy of Prematurity
∗NEC = Necrotizing Enterocolitis
∗BPD = Bronchopulmonary Dysplasia

Subgroup analysis of singletons and multiples born between 23 + 0 and 28 + 6 weeks showed that 208 singletons and a further 78 multiples were born during the study period. In this subgroup, maternal hypertension was significantly higher among mothers of preterm singletons (16.8% vs. 3.4%, p = 0.002). On the other hand, antenatal steroids uptake (74.4% vs. 60.1%, p = 0.013), delivery by cesarean section (77% vs. 51.9%, p < 0.001) and rates of assisted conception (52.9% vs. 6.7%, p < 0.001) were significantly higher among multiples compared to singletons (Table 7). At the gestational age of < 29 weeks. Preterm multiples are of smaller birthweight (796 vs. 891 g, p < 0.001) (Table 7).

Table 7

Maternal and infants’ demographics (singleton vs multiples for infants born between 23 + 2–28 + 6 weeks’ gestation)
Demographic	Singleton < 29 weeks	Multiple < 29 weeks	P value
Maternal Hypertension	35/208(16.8%)	3/87(3.4%)	0.002
Gestational diabetes	32/208(15.4%)	13/87(14.9%)	0.923
Maternal PROM	68/208(32.7%)	21/87(23.1%)	0.144
Complete antenatal steroids	125/208(60.1%)	65/87(74.4%)	0.013
Cesarean section delivery	108/208(51.9%)	67/87(77%)	< 0.001
Assisted conception	14/208(6.7%)	46/87(52.9%)	< 0.001
Maternal age	30.2(6.5)	29.0(5.8)	0.126
Gender (male)	95/208(45.7%)	59/87(67.8%)	0.001
Gestational age (weeks)	26.3(1.7)	25.6(1.9)	0.001
Birthweight (grams)	891(230)	796(240)	0.002

Morality before hospital discharge was significantly higher among preterm multiples compared to preterm singletons born at a gestational age between 23 + 0 and 28 + 6 weeks (26.4% vs. 13.9% p = 0.003; OR, 2.9; 95%CI, 1.4–5.9). Rates of PVL (p = 0.041; OR, 2.2; 95%, 1.03–4.7), ROP needing treatment (p = 0.005, OR 2.7, 95%CI, 1.4–5.3), BPD at 36 weeks, PMA (p = 0.002; OR, 2.5; 95%CI, 1.4–4.3) and culture-positive sepsis (p = 0.034; OR, 1.8; 95%CI, 1.04–3.2) were significantly higher among preterm infants of multiple pregnancies in comparison to preterm singletons in this gestational age group (Table 8). Duration of mechanical ventilation (Fig. 1) and length of hospital stay (Fig. 2) were significantly longer among multiples compared to singletons born at a gestational age between 23 + 0 and 28 + 6 weeks.

Table 8

Univariate and multivariate analysis of neonatal outcomes (singletons vs multiples born between 23 + 0–28 + 6 gestation)
Outcome	Singletons 23 + 0–28 + 6wks.	Multiples 23 + 0–28 + 6wks.	Unadjusted P value	Unadjusted OR (95%CI)	Adjusted p value, OR (95%CI)
Mortality	29/208(13.9%)	23/87(26.4%)	0.010	2.2(1.2–4.1)	0.003,2.9(1.4–5.9)
Major IVH	54/208(26%)	30/87(34.5%)	0.139	1.5(0.87–2.6)	0.269,1.4(0.8–3.5)
PVL	20/208(9.6%)	21/87(24.1%)	0.001	2.9(1.5–5.9)	0.041,2.2(1.03–4.7)
ROP	33/208(15.9%)	25/87(28.7%)	0.011	2.1(1.2–3.9)	0.005,2.7(1.35–5.3)
Surgical NEC	17/208(8.2%)	9/87(10.3%)	0.549	1.3(0.55-3.0)	0.638,1.3(0.49–3.2)
BPD at 36wks PMA	87/208(42%)	55/87(63.2%)	0.001	2.4(1.4–3.97)	0.002,2.45(1.4–4.3)
Sepsis	61/208(29.3%)	39/87(44.8%)	0.010	1.9(1.2–3.3)	0.034,1.8(1.04–3.2)
∗Adjustments were made for gender, antenatal steroids, maternal hypertension and mode of delivery
∗IVH = Intraventricular Hemorrhage
∗PVL = Periventricular Leukomalacia
∗ROP = Retinopathy of Prematurity
∗NEC = Necrotizing Enterocolitis
∗BPD = Bronchopulmonary Dysplasia

Subgroup analysis of singletons and multiples born between 29 + 0 weeks and 32 + 6 weeks showed that there were 360 singletons and a further 149 multiples born during the study period. In this subgroup, maternal PROM was significantly higher among mothers of preterm singletons (29.7% vs. 14.1%, p < 0.001). On the other hand, antenatal steroids uptake (75.2% vs. 62.4%, p = 0.03), delivery by cesarean section (87.9% vs. 63.1%, p < 0.001), and rates of assisted conception (47.7% vs. 4.4%, p < 0.001) were significantly higher among multiples compared to singletons (Table 9). There were no statistically significant differences in mortality and major neonatal morbidities between preterm multiples and singletons born between 29 + 0- and 32 + 6-weeks’ gestation (Table 10). The duration of mechanical ventilation did not differ between the two groups (13.5 vs. 11, p = 0.43). The length of hospital stay was significantly longer in preterm singletons compared to preterm multiples in infants born between 29 + 0–32 + 6 weeks (Fig. 3).

Table 9

Maternal and infants’ demographics (singleton vs multiples for infants born between 29 + 0–32 + 6 weeks’ gestation)
Demographic	Singleton 29–32 + 6 weeks	Multiple 29–32 + 6 weeks	P value
Maternal hypertension	61/360(16.9%)	20/149(13.4%)	0.323
Maternal Diabetes	67/360(18.7%)	22/149(14.8%)	0.293
Maternal PROM	107/360(29.7%)	21/149(14.1%)	< 0.001
Complete antenatal steroids	224/360(62.4%)	112/149(75.2%)	0.030
Cesarean section delivery	227/360(63.1%)	131/149(87.9%)	< 0.001
Assisted conception	16/360(4.4%)	71/149(47.7%)	< 0.001
Maternal age (years)	30.7(6.6)	30.8(5.3)	0.869
Gestational age (weeks)	30.7(1.2)	31.1(0.94)	0.007
Gender (male)	221/360(61.4%)	78/149(52.3%)	0.074
Birthweight (grams)	1508(365)	1530(293)	0.461

Table 10

Univariate and multivariate analysis of neonatal outcomes (singletons vs multiples born between29 -32 + 6wks. gestation)
Outcome	Singletons 29–32 + 6 wks.	Multiples 29–32 + 6 wks.	Unadjusted P value	Unadjusted OR (95%CI)	Adjusted p value, OR (95%CI)
Mortality	16/360(4.4%)	6/149 (4%)	0.833	0.90(0.35–2.35)	0.80,1.14(0.41–3.16)
Major IVH	23/360 (6.4%)	4/149 (2.7%)	0.090	2.47(0.84–7.28)	0.39,1.6(0.52–5.04)
PVL	26/360(7.2%)	3/149 (2%)	0.036	3.78(1.12–12.71)	0.065,3.2(0.92–10.8)
ROP	4/360(1.1%)	1/149(0.7%)	0.647	1.66(0.18-15.0)	0.99,1.07(0.09–10.8)
Surgical NEC	8/360(2.2%)	5/149(3.4%)	0.461	0.655(0.21–2.03)	0.18,2.4(0.67–8.2)
BPD at 36wks PMA	30/360(8.3%)	15/149(10.1%)	0.531	0.81(0.42–1.55)	0.35,1.4(0.69–2.7)
Sepsis	38/360(10.6%)	18/149(12.1%)	0.671	0.86(0.47–1.56)	0.37,1.3(0.71–2.5)
∗IVH = Intraventricular Hemorrhage
∗PVL = Periventricular Leukomalacia
∗ROP = Retinopathy of Prematurity
∗NEC = Necrotizing Enterocolitis
∗BPD = Bronchopulmonary Dysplasia

This single-center study comprising 236 multiple preterm pregnancies focused on maternal and fetal factors that affect perinatal morbidities and neonatal mortality before maternity unit discharge. The objective of the present study was to investigate the clinical outcomes in preterm births of multiple pregnancies and to find out if any perinatal factors are related to clinical outcomes.

Our study showed a significantly higher neonatal mortality rate for multiple preterm pregnancies compared to preterm singletons at gestational age < 33 weeks. This finding is similar to large international databases from Europe (15) and the USA (16), which have also shown that neonatal mortality for multiple preterm infants was higher compared to singletons (15, 16). Nevertheless, other studies have shown no differences in mortality between preterm singletons and multiples (17, 18). On the other hand, contrary to our findings, others have reported lower neonatal mortality among preterm multiples compared to singletons (19).

We have also reported a significantly higher incidence of BPD among preterm multiples compared to a singleton at a gestational age between 23–28 + 6 weeks. In addition, we also found that preterm multiples born before 29 weeks’ gestation required a longer duration of mechanical ventilation, which is likely to reflect the severity of the initial respiratory distress syndrome among these infants. These findings agree with a recent multicenter national study that showed similar adverse short- and long-term respiratory outcomes among preterm multiples (20). Others have shown lower rates of BPD among twins compared to singleton preterm born between 22- and 31-weeks’ gestation despite a higher incidence of RDS among the preterm multiples group (21).

Our study showed that the risk of severe ROP needing therapy was significantly higher in preterm multiples compared to singletons at gestational age < 29 weeks. This risk remained significant after adjustments for differences in birthweight, antenatal steroids use, maternal hypertension and PROM. This suggests that multiple pregnancy is a risk factor for severe ROP. Our finding of increased ROP among preterms of multiple gestations agrees with results from other studies (22). Yet, our finding of higher rates of severe ROP among preterm multiples contrasts data from other studies showing no association between multiple births and the incidence and severity of ROP (19, 23, 24). Interestingly, others have shown a higher risk of severe ROP among singletons than preterm multiples (25).

In our study, we report higher rates of PVL on USS/MRI in preterm multiples born at gestational age < 29 weeks compared to singletons. Nevertheless, major IVH (grades 3 and 4) was not significantly different between multiples and singletons in the same gestational age group. This finding is similar to a recent large trial that reported a higher incidence of major neurological injury among twin preterm infants compared to preterm singletons (20).

With regard to LOS, our study has shown that although LOS was longer for multiples born at GA < 29 weeks, those preterm multiples born > 29 weeks’ gestation had a significantly shorter LOS in comparison to singletons of a similar gestation. In a study of late preterm infants of multiple gestations, the LOS for multiples born at 34 weeks but not 35 and 36 weeks was significantly longer for multiples compared to singletons of matched gestation (26). Indeed, the age range of preterm infants included in that study was not similar to our study, which did not include late preterm infants. Nevertheless, another study from Canada with a similar gestational age profile to our study did not show differences in LOS between multiple and singleton preterm infants (27).

We report higher rates of culture-positive sepsis in preterm multiples born at GA < 29 weeks compared to singletons of a similar gestation. This contradicts a recent study that showed a lower risk of sepsis in preterm multiples (20). Other studies that examined the sepsis outcome concerning multiple gestations did not find differences between singletons and multiples (19, 28, 29). There were no statistically significant differences in the incidence of surgical NEC between preterm infants of singleton and multiple pregnancies in our study.

Interestingly, the survival and major neonatal morbidities of moderately preterm infants (29–32 weeks gestations) of multiple pregnancies were similar to the singletons born in the same gestational age group. Furthermore, our study has not detected any statistically significant differences in mortality and major morbidities between twins and infants of higher multiples.

Our study has some strengths and limitations. First, this was a retrospective study, and the data for both mothers and infants were obtained from charts and medical records. Therefore, some maternal and infant data were missing for the study population. Secondly, this data reflects the experience of a single institution. Therefore, extrapolations and interpretations of our results must be made with caution. This study compared neonatal mortality and major morbidities between singleton infants and multiple births. Our analysis controlled for baseline characteristics and identified variables that could affect the neonatal outcome, such as maternal hypertension, maternal antenatal corticosteroid uptake, and mode of delivery. We believe these results are valuable in counseling parents in the case of multiple gestation pregnancies.

∗ DCDA

Dichorionic-Diamniotic

∗ MCDA

Monochorionic-Diamniotic

∗MCMA

Monochorionic-Monoamniotic

∗IVH

Intraventricular Hemorrhage

∗PVL

Periventricular Leukomalacia

∗ROP

Retinopathy of Prematurity

∗NEC

Necrotizing Enterocolitis

∗BPD

Bronchopulmonary Dysplasia

Ethics approval and consent to participate

King Abdullah International Medical Research Centre (KAMRC) approved the study with IRB number: (RC20/283/R). All methods were carried out in accordance with relevant guidelines and regulations and the study was conducted in accordance with the Declaration of Helsinki. The study was a retrospective chart review and no patients identifiable were kept. Patient consent was waived by the ethical committee.

Competing interest

The authors declare that they have no conflict of interest.

Consent for publication

All of the authors in this study have consented for publication of this study

Funding

None.

Availability of data and materials

The datasets used and analyzed during this current study is available from the corresponding author on reasonable request

Acknowledgment

The authors would like to acknowledge the assistance of the personnel in the Neonatal Intensive Care department at King Abdulaziz Medical City, Riyadh, Ministry of National Guard.

Conflict of interest Statement:

The authors declare that they have no conflict of interest.

Authors contribution

Kamal Ali and Mohammad Alhasson designed the study and analyzed the data. Bader M Alqahtani, Mohammad A Alreefi collected the data. All of the authors made a significant contribution to writing of the manuscript.

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No competing interests reported.

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Mortality and short-term outcomes of preterm infants of multiple versus singleton gestations

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