Design

This is a retrospective, observational single-centre study. Data collection was approved by our institutional review board as a quality improvement (QI) project.

Setting and subjects

This study was conducted at a public safety-net hospital in California with a regional level III NICU. Our study included preterm infants <33 weeks’ GA who received ≥30 s DCC and were born January 2008–December 2017. Infants receiving <30 s DCC and multiples with intrauterine fetal demise (IUFD) of one twin were excluded.

Standardised DR management of preterm infants

In 2007, we implemented ≥30 s DCC for all very preterm infants as standardised DR management. DCC duration increased to ≥60 s in March 2011 and ≥120 s in July 2016. Our DCC procedure was based on the Mercer trial11 and was previously published.12 During DCC, an infant was placed on a portable warming mattress, and gentle stimulation and airway suctioning with a bulb syringe were performed as needed. After the first multiple was delivered, many obstetricians delivered second/third multiples while the first received DCC. This allowed providers to evaluate the well-being of all multiples during DCC. Occasionally, obstetricians delivered the first multiple and waited to deliver the next multiple until the first multiple’s cord was clamped. DCC was contraindicated if there was active maternal bleeding from abruption/placental disruption at time of delivery, cord tear/avulsion, en caul delivery, hydrops fetalis, recipient twin of severe twin-to-twin transfusion syndrome (TTTS) or severe anaemia from isoimmunisation. DCC was discontinued if an infant appeared lifeless or apnoeic despite stimulation and bulb suctioning for 30–45 s. Continuous positive airway pressure was initiated in all preterm infants after the cord was clamped as a DR standard.

Data collection

Maternal and neonatal demographics, and neonatal outcomes were obtained from our prospectively collected NICU database. Haematocrits, obtained when clinically indicated, and maternal estimated blood loss (EBL), documented in electronic medical records, were collected retrospectively. Haematocrits measured after packed red blood cell (RBC) transfusion were excluded.

Demographic variables included GA, birth weight (BW), antenatal steroids, C-section and sex; DR measures included 1 min Apgar <3 and 5 min Apgar <7, admission temperature, intubation, chest compressions and maternal EBL; respiratory outcomes included surfactant administration, any intubation during NICU stay and pneumothorax; haematological outcomes included haematocrits at 0–2 and 12–24 hours of life, polycythaemia (haematocrit >65%), peak bilirubin, exchange transfusion and RBC transfusions; and neonatal outcomes included severe IVH (grade 3 or 4), NEC (Bell stage ≥2), late-onset sepsis (LOS) (positive blood or cerebro spinal fluid culture >72 hours), chronic lung disease (CLD) (requiring oxygen/respiratory support at 36 weeks postmenstrual age), severe retinopathy of prematurity (ROP) (≥stage 3, plus disease or received anti-Vascular Endothelial Growth Factor), survival without major morbidity (survival without severe IVH, NEC, LOS, CLD and severe ROP) and death.

Analysis

DCC in multiples

During the study period, there were 640 preterm infants born at <33 weeks’ GA: 520 singletons and 120 multiples. Infants who did not receive DCC (n=103 [16%]: 87 singletons and 16 multiples), and multiples with IUFD of one twin (n=8) were excluded. The study included 529 infants (433 [82%] singletons, 96 [86%] multiples) who received ≥30 s DCC (figure 1). Fifty-four sets of multiples (n=112) were born: 50 sets of twins and 4 sets of triplets. There were 21 pairs of dichorionic-diamniotic twins, 27 pairs of monochorionic-diamniotic twins, 2 pairs of monochorionic-monoamniotic twins and 4 pairs of trichorionic-triamniotic triplets. Table 1 shows DCC achievement across all multiple types. Twenty-two pairs of monochorionic twins that received DCC were included. Eleven monochorionic twin pairs had >20% BW discordance; of those 11, 7 pairs had >5% haematocrit difference, and of those 7, 5 pairs had higher haematocrits in larger twins, suggestive of TTTS. None of these infants had polycythaemia, and only one had anaemia. Second-born twins were smaller in four of five pairs with TTTS.

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Figure 1

Study subject selection for infants <33 weeks’ gestational age (GA). DCC, delayed cord clamping.

Singletons versus multiples

Neonatal and maternal demographics, DR measures, respiratory and haematological outcomes and neonatal mortality and morbidity of singletons and multiples are shown in table 2. Multiples had a higher GA (31.0 weeks vs 30.6 weeks, p=0.001), more C-sections (91% vs 54%, p<0.0001), fewer males (48% vs 62%, p=0.02) and higher 12–24 hour haematocrits (54.3 vs 50.5, p=0.01). The haematocrit difference remained significant after adjusting for BW, delivery type and sex (p=0.02). Mothers in the multiples group had higher EBL than those from the singletons group (800 mL vs 650 mL, p<0.0001) and higher risk of PPH (EBL >1000 mL) (23% vs 16%, p=0.04). These differences were not significant after adjusting for delivery type (EBL: p=0.1, PPH: p=0.3).

First-born versus second-born multiples

Neonatal and maternal demographics, DR measures, respiratory and haematological outcomes and neonatal mortality and morbidity of first-born and second-born multiples are shown in table 3. Second-born multiples had a lower BW compared with first-born multiples (1438 g vs 1550 g, p<0.02). Second-born multiples had lower survival without major morbidity (77% vs 91%, p=0.03). This difference was not significant after adjusting for BW (p=0.1).

Subgroup analysis between first-born and second-born monochorionic multiples showed that second-born multiples were smaller (1380 g vs 1510 g, p=0.008). Second-born twins had less surfactant administration (18% vs 36%, p=0.02) and higher 12–24 hour haematocrits (56.0 vs 52.7, p=0.02) after adjusting for BW.

Monochorionic versus dichorionic/trichorionic multiples

Neonatal and maternal demographics, DR measures, respiratory and haematological outcomes and neonatal mortality and morbidity of monochorionic and dichorionic/trichorionic multiples are shown in table 4. Monochorionic multiples had lower admission temperatures than dichorionic/trichorionic multiples (36.8°C vs 37.0°C, p=0.046), however this difference is not clinically significant.

Singletons versus multiples

Of many DCC RCTs, only a few included multiples.6 7 13 The Australian Placental Transfusion Study (APTS) is the largest DCC RCT, having 196 preterm multiples <30 weeks’ GA in their DCC group. In 2017, a meta-analysis including APTS showed a 32% reduction in mortality in preterm infants who received DCC.2 A QI study showed successful implementation of DCC in 77% of preterm singletons and multiples. Their DCC cohort, which included 25% multiples (n=41), had fewer DR intubations, less metabolic acidosis and higher haematocrits.9 A pre/postintervention study showed that preterm twins receiving DCC required fewer transfusions and surfactant treatment for RDS compared with infants receiving early cord clamping.8

Our study showed that DCC was feasible in 86% multiples, and outcomes were comparable with singletons who received DCC. DCC was beneficial to singletons and multiples; in fact, multiples had higher haematocrits than singletons. We did not compare outcomes between multiples who received DCC versus no DCC because 23% of our infants did not receive DCC due to needing immediate resuscitation, and 40% due to maternal bleeding/placental disruption. Hence, multiples who did and did not receive DCC are not comparable.

Maternal haemorrhage

One study found no difference in maternal EBL in vaginal or C-section deliveries in preterm multiples who received 30–60 s DCC compared with multiples with no DCC (<30 s).10 In our study, maternal EBL was higher during delivery of multiples than singletons. However, this difference was not significant after adjusting for delivery type. During our 10-year study period, DCC duration was gradually increased from 30 s to 2 min. Our obstetricians developed a practice of delivering both or all multiples and leaving them side-by-side outside of the uterus to evaluate the well-being of second-born and third-born multiples when present. This practice allowed the overall time between the first multiple’s delivery and the last multiple’s cord clamping to be shorter than the additive duration of DCC for each infant.

First-born versus second-born multiples

Studies have shown that second-born multiples have worse outcomes in almost every category compared with first-born including mortality, Apgars, RDS, intubation and resuscitation.3–5 One study showed that second-born multiples had more neonatal complications, especially in infants with BW <1500 g and non-vertex presentation in the second twin.3 Major contributors of morbidity in second twins have been birth asphyxia and RDS.4 5 Biological sex has contributed to first and second twin outcome discrepancy, with male second twins generally having worse outcomes than female second twins.4

We did not observe a significant difference in DR measures, haematological and respiratory outcomes or neonatal mortality and morbidity when both first-born and second-born multiples received DCC. Second-born multiples in our cohort had lower survival without major morbidity; however, second-born multiples were smaller than first-born (BW 1438 g vs 1550 g). The difference in survival without major morbidity between first-born and second-born multiples disappeared after adjusting for BW. Our study suggests that in the cohort where both first-born and second-born preterm infants received DCC, the second-born may not be at an increased risk for worse outcomes. During our study period, first-born and second-born multiples received DCC in 80% multiple births. The 20% who did not receive DCC may have additional risk factors, and second-born multiples in that population may have worse outcomes than first. Regardless, in those multiples who receive DCC, it is reassuring that second-born multiples do not have worse outcomes.

Monochorionic versus dichorionic/trichorionic multiples

Monochorionic multiples present a unique challenge to implementing DCC due to TTTS complications and concerns about putting the second twin’s well-being at risk while performing DCC on the first. Many studies excluded monochorionic multiples or a subset of those who fit TTTS diagnostic criteria.4 7 9 Studies including monochorionic multiples had very small sample sizes.8 10 Another study with more multiples did not specify results according to chorionicity.6 Our study had 22 pairs of monochorionic multiples who both received DCC. We compared outcomes between monochorionic first-born and second-born multiples and showed that second-born multiples had less surfactant administration and higher haematocrits, while all other outcomes were comparable. There was no difference between first-born and second-born multiples in the dichorionic/trichorionic subgroup.

BW discordance from TTTS contributes to adverse outcomes in second twins.4 5 Rates of neonatal morbidity are highest in twins with BW discordance >20%.4 This is especially significant when second twins have a higher BW, contributing to fetal distress, oxygen insufficiency, RDS and lower Apgars in second twins.4 However, second twins <1500 g require more intubation and resuscitation, and are more likely to die of complications.3 Many prior DCC studies excluded monochorionic twins with >20% BW discordance. Eleven of our monochorionic twins had >20% BW discordance. Of the five pairs who had haematocrits suggestive of TTTS, only one pair was prenatally identified as having TTTS, and others were noted as having discordant twins. Neonatal mortality and morbidity outcomes were not different between first-born and second-born multiples in the monochorionic subgroup, although there is suggestion of second twins having worse outcomes (CLD and survival without major morbidity).

Limitations

Our study has limitations as a single-centre observational study. Selection bias related to implementing DCC could influence internal and external validity of results. Neonatal outcomes were not analysed for approximately 20% of infants born in our centre who did not receive DCC. Since the study was conducted over a decade, our goal for minimum DCC duration increased from 30 s in 2008 to 120 s in 2016. Because our centre’s obstetric and neonatal teams became more comfortable implementing DCC over time, generalisability of results may be limited to centres with similar experience implementing DCC. Our sample size of multiples was relatively small to be confident about subgroup analysis results for different multiple types.