Background
Infants with restricted growth for age are frequently exposed to insufficient placental circulation and are more likely to develop postnatal complications. Delayed cord clamping at birth for these infants requires further exploration.
Objective
This study aimed to compare the short-term neonatal outcomes of delayed cord clamping with that of early cord clamping in small for gestational age preterm infants and to explore whether the effects of delayed cord clamping in small for gestational age preterm infants are different from that in non–small for gestational age preterm infants.
Study Design
We conducted a national retrospective cohort study, including infants born at <33 weeks’ gestation and admitted to the Canadian Neonatal Network units between January 2015 and December 2017. Small for gestational age infants (birthweight of <10th percentile for gestational age and sex) who received delayed cord clamping ≥30 seconds were compared with those who received early cord clamping. In addition, non–small for gestational age infants who received delayed cord clamping were compared with those who received early cord clamping. The main study outcomes included composite outcome of mortality or major morbidity, neonatal morbidity rate, mortality rate, peak serum bilirubin, and number of blood transfusions. Multivariable logistic and linear regression models with a generalized estimation equation approach were used to account for the clustering of infants within centers.
Results
Overall, 9722 infants met the inclusion criteria. Of those infants, 1027 (10.6%) were small for gestational age. The median (interquartile range) gestational age was 31 weeks (range, 28–32 weeks). After adjusting for potential confounders, delayed cord clamping in small for gestational age infants was associated with a reduction in the composite outcome of mortality or major morbidity (adjusted odds ratio, 0.60; 95% confidence interval, 0.42–0.86) compared with early cord clamping. There was no difference between the 2 groups in peak serum bilirubin. Many associated benefits of delayed cord clamping in small for gestational age infants were similar to those in non–small for gestational age infants.
Conclusion
Delayed cord clamping in small for gestational age preterm infants was associated with decreased odds of mortality or major morbidity. Many of the benefits of delayed cord clamping in the small for gestational age preterm infants were similar to those identified in the non–small for gestational age preterm infants.
Introduction
Placental transfusion refers to the transfer of residual placental blood to the neonate during the first few minutes after birth, which can be accomplished by delayed cord clamping (DCC). When DCC is performed, the neonate receives an additional transfusion of 10 to 15 mL/kg of residual placental blood during the first few minutes after birth. The additional blood volume and physiological postnatal transition facilitated by DCC have been shown to improve hematocrit levels, reduce the need for blood transfusions, and reduce the mortality in preterm infants. As such, national and international governing bodies currently recommend DCC for at least 30 to 60 seconds after birth in most preterm infants.
Although DCC incurs important benefits, there are some adverse effects and limitations, including a possible increase in the incidence of polycythemia and hyperbilirubinemia. Furthermore, there is currently a lack of evidence regarding the impact of DCC on infants with intrauterine growth restriction (IUGR) or small for gestational age (SGA). Previous cord management studies either have excluded such infants or did not report their outcomes separately. , Given the already restrictive placental blood flow in utero experienced by some of this population, it is unclear if these infants will receive adequate placental blood transfusion through DCC, if they will have an efficient physiological transition at birth, and if they will be more likely to experience polycythemia and hyperbilirubinemia compared with non-SGA infants. It is known that SGA infants have higher rates of morbidity and mortality than non-SGA infants, and thus, the potential benefits of DCC may be greater if other adverse effects are not proven to be sustained or experienced in this population.
Why was this study conducted?
This study aimed to evaluate the short-term neonatal outcomes of delayed cord clamping (DCC) vs early cord clamping (ECC) in small for gestational age (SGA) preterm infants.
Key findings
The odds of mortality or major morbidity were significantly lower (aOR, 0.6; 95% CI, 0.42–0.86) in SGA preterm infants who received DCC than in those who received ECC. DCC was not associated with an increased risk of adverse outcomes.
What does this add to what is known?
This large national cohort study supported the limited published evidence that DCC in SGA preterm infants is associated with improved neonatal outcomes, in the absence of increased risk.
Evidence for DCC in the SGA preterm population is limited. A secondary subgroup analysis by Wang et al and a small randomized controlled trial (RCT) by Digal et al suggest that DCC in the SGA preterm population incurs no harm and increases serum ferritin levels without increasing the incidence of polycythemia or the need for phototherapy. In 2020, the American College of Obstetricians and Gynecologists identified cord management in infants with risk factors for neonatal polycythemia as an area in need of research. Thus, we aimed to compare the composite outcome of mortality or major morbidity, neonatal morbidity rate, mortality rate, peak serum bilirubin, and number of blood transfusions between DCC and ECC in SGA preterm infants and to compare the effects of DCC in SGA preterm infants with that in non-SGA preterm infants.
Materials and Methods
Study population
We conducted a retrospective cohort study of preterm infants admitted to neonatal intensive care units (NICUs) using the Canadian Neonatal Network (CNN) database between January 1, 2015, and December 31, 2017. Preterm infants born at <33 weeks’ gestation were identified. SGA preterm infants (defined as infants with a birthweight of <10th percentile for gestational age and sex) within this cohort who received DCC (≥30 seconds) were identified and compared with SGA infants who received ECC (<30 seconds). In addition, non-SGA preterm infants born at <33 weeks’ gestation who received DCC were compared with non-SGA infants who received ECC, to compare the effects of DCC in the SGA cohort with the non-SGA cohort. Infants who were moribund on admission, were to receive palliative care at birth, had major congenital anomalies, or were missing cord clamping data, were excluded.
Study variables and outcomes
We analyzed maternal and infant characteristics, delivery and resuscitation data, peak serum bilirubin, number of blood transfusions, rates of short-term neonatal morbidity and mortality, composite outcome of mortality or major morbidity (bronchopulmonary dysplasia [BPD], severe intraventricular hemorrhage [IVH], late-onset sepsis, and necrotizing enterocolitis [NEC] ≥stage 2), and severe retinopathy of prematurity (ROP; ≥stage 3). The short-term clinical outcomes examined included patent ductus arteriosus (PDA), NEC, BPD, IVH, late-onset sepsis, severe ROP, mortality, and length of hospital stay. These were compared between the DCC and ECC groups for both SGA and non-SGA infants. Gestational age was defined as the best estimate based on obstetrical history, obstetrical examination, and first prenatal ultrasound examination. PDA was defined as those receiving medical or surgical treatment. BPD was defined as supplemental oxygen treatment at 36 weeks’ corrected age or at the time of transfer to another medical facility if that occurred before 36 weeks’ corrected age. IVH was defined according to Papile et al. Late-onset sepsis was defined as any positive blood and/or cerebral spinal fluid culture for bacteria, virus, or fungi after 2 days of age. ROP was defined according to the international classification. NEC was defined according to the Bell criteria. Length of stay was defined as the total number of days that an infant stayed in the NICU before death, discharge to home, or transfer to another hospital. Mortality was defined as any death before discharge from the NICU.
Source of data collection
Data on individual infants were collected as part of the ongoing CNN data collection system. Overall, 30 NICUs were part of the CNN database during the study period from January 2015 to December 2017. At the affiliated sites, demographics and outcome data were collected from patient medical records by trained research assistants using a computerized data entry program according to the standardized outcome definitions. Data were collected on each infant until death or discharge from the NICU and were transmitted electronically to the CNN coordinating center where they were stored. The database has been reported to have very high reproducibility and internal consistency.
Ethics
For the CNN, data collection was approved by each institution’s research ethics board or institutional quality improvement committee. This study was approved by the research ethics board of the IWK Health Centre (project number 1024102) and the executive committee of the CNN.
Statistical analysis
Descriptive statistical methods were used for the clinical characteristics of the population. For maternal and infant characteristic comparisons, the chi-square test was used for categorical variables, whereas the Student t test or Wilcoxon rank-sum test was used for continuous variables. To examine the association of DCC on the outcomes, the outcomes were compared between the DCC and ECC groups for SGA and non-SGA infants separately using similar methods. We compared the outcomes between the 2 intervention groups stratified by SGA using multiple logistic or linear or quantile regression models adjusted for potential confounders. Variables for adjustment included the most considerably different baseline characteristics between the DCC and ECC groups in the SGA and non-SGA cohorts. We conducted subgroup analyses for infants with severe SGA (birthweight of less than third percentile for gestational age and sex) and for infants with a gestational age of <28 weeks using similar methods. Data management and all statistical analyses were performed using SAS (version 9.4; SAS Institute Inc, Cary, NC). Significance was defined as P <.05.
Results
Among 12,749 infants admitted to participating NICUs during the 3-year study period, 9722 met the inclusion criteria. Of those infants, 1027 (10.6%) were SGA (577 received ECC and 450 received DCC), and 8695 were non-SGA (4609 received ECC and 4086 received DCC) ( Figure ).
The maternal and infant baseline characteristics in the SGA and non-SGA cohorts are described in Table 1 . In univariate analyses of the SGA cohort, considerable differences were seen in gestational age and antenatal magnesium sulfate receipt between the DCC and ECC groups. In the non-SGA cohort, considerable differences were seen in gestational age, maternal hypertension, preeclampsia, antenatal corticosteroids, prolonged rupture of membranes, outborn, and mode of delivery between DCC and ECC groups.
| Variable | SGA-ECC n=577 | SGA-DCC n=450 | P value | Non–SGA-ECC n=4609 | Non–SGA-DCC n=4086 | P value |
|---|---|---|---|---|---|---|
| Maternal diabetes mellitus | 14 (81/561) | 12 (54/444) | .29 | 15 (664/4458) | 16 (640/4031) | .21 |
| Maternal hypertension | 51 (292/574) | 56 (251/447) | .09 | 15 (681/4537) | 17 (684/4054) | .02 |
| Preeclampsia | 37 (213/577) | 36 (160/450) | .65 | 10 (458/4609) | 11 (464/4086) | .03 |
| Singleton | 73 (423/577) | 76 (342/450) | .33 | 69 (3202/4609) | 71 (2889/4086) | .21 |
| Antenatal steroids | 92 (523/569) | 95 (427/450) | .06 | 87 (3971/4546) | 93 (3795/4065) | <.01 |
| Magnesium sulfate | 50 (290/577) | 43 (194/450) | .02 | 46 (2105/4609) | 47 (1938/4086) | .1 |
| PROM >24 h | 8 (45/567) | 6 (28/441) | .33 | 25 (1121/4516) | 27 (1103/4037) | <.01 |
| Cesarean delivery | 91 (527/577) | 92 (413/449) | .71 | 65 (2997/4605) | 52 (2107/4082) | <.01 |
| Gestational age (wk) | 29 (27–31) | 31 (28–32) | <.01 | 29 (26–31) | 30 (28–31) | <.01 |
| Gestational age <29 wk | 38 (218/577) | 26 (119/450) | <.01 | 44 (2042/4609) | 35 (1447/4086) | <.01 |
| Male | 58 (335/575) | 58 (260/449) | .91 | 54 (2507/4609) | 55 (2234/4086) | .79 |
| Outborn | 6 (36/577) | 5 (23/450) | .44 | 13 (602/4609) | 5 (202/4086) | <.01 |
The clinical outcomes at birth and during hospital stay are described in Table 2 . After adjusting for potential confounders in the SGA cohort, the DCC group had lower odds of mortality or major morbidity (adjusted odds ratio [aOR], 0.60; 95% confidence interval [CI], 0.42–0.86) than the ECC group ( Table 3 ). There was a lower odds of mechanical ventilation (aOR, 0.61; 95% CI, 0.42–0.87), BPD (aOR, 0.61; 95% CI, 0.45–0.82), IVH (aOR, 0.70; 95% CI, 0.52–0.92), and severe ROP (aOR, 0.35; 95% CI, 0.18–0.67). There was no difference in mortality, other morbidities, admission temperature, or peak serum bilirubin.
| Variable | SGA-ECC n=577 | SGA-DCC n=450 | P value | Non–SGA-ECC n=4609 | Non–SGA-DCC n=4086 | P value |
|---|---|---|---|---|---|---|
| Apgar score of <4 at 5 min | 9 (50/574) | 2 (8/449) | <.01 | 8 (386/4559) | 3 (135/4073) | <.01 |
| Birthweight (g) | 860±279 | 938±267 | <.01 | 1312±457 | 1417±430 | <.01 |
| Intubation at birth | 32 (182/575) | 12 (55/449) | <.01 | 30 (1378/4589) | 14 (587/4081) | <.01 |
| Chest compressions | 2 (12/577) | 2 (7/450) | .53 | 3 (142/4609) | 2 (92/4086) | .02 |
| Epinephrine | 2 (12/575) | 0 (0/449) | <.01 | 2 (110/4589) | 0.2 (10/4081) | <.01 |
| Surfactant use | 44 (256/577) | 28 (128/450) | <.01 | 48 (2228/4609) | 35 (1420/4086) | <.01 |
| Admission temperature in °C | 36.40±0.68 | 36.50±0.58 | .01 | 36.60±0.78 | 36.70±0.70 | <.01 |
| SNAP II score of >20 | 18 (105/571) | 9 (41/449) | <.01 | 18 (822/4557) | 11 (432/4063) | <.01 |
| Inotropic support in the first 48 h | 9 (54/577) | 4 (17/450) | <.01 | 8 (386/4609) | 3 (141/4086) | <.01 |
| Peak serum bilirubin (μmol/L) | 143.7±44.8 | 147.6±39.0 | .16 | 157.8±45.7 | 163.2±45.8 | <.01 |
| Number of transfusions | 3 (2–7) | 3 (1–6) | .01 | 3 (1–6) | 2 (1–4) | <.01 |
| NEC | 4 (23/577) | 5 (22/450) | .48 | 4 (187/4607) | 3 (126/4085) | .02 |
| Mechanical ventilation | 52 (299/577) | 35 (158/450) | <.01 | 54 (2478/4609) | 38 (1546/4086) | <.01 |
| BPD | 41 (212/511) | 31 (127/414) | <.01 | 27 (1163/4263) | 24 (958/3935) | <.01 |
| Postnatal steroids | 24 (140/577) | 16 (71/450) | <.01 | 18 (836/4609) | 10 (395/4086) | <.01 |
| IVH | 24 (126/521) | 17(67/390) | .01 | 33 (1261/3837) | 26 (832/3186) | <.01 |
| Severe IVH | 5 (24/521) | 3 (13/390) | .34 | 9 (345/3837) | 6 (184/3186) | <.01 |
| Late-onset sepsis | 16 (91/577) | 10 (43/450) | <.01 | 12 (559/4609) | 7 (302/4086) | <.01 |
| Severe ROP | 13 (45/349) | 7 (17/229) | .04 | 11 (224/2100) | 7 (117/1597) | <.01 |
| PDA | 33 (189/572) | 21 (94/447) | <.01 | 32 (1454/4576) | 22 (915/4074) | <.01 |
| Length of hospital stay | 46 (18–85) | 37 (15–64) | <.01 | 38 (16–71) | 32 (13–58) | <.01 |
| Mortality | 12 (69/577) | 6 (28/450) | <.01 | 7 (341/4609) | 3 (135/4086) | <.01 |
| Composite outcome a | 52 (303/577) | 38 (173/450) | <.01 | 39 (1802/4609) | 32 (1310/4086) | <.01 |
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