Early versus delayed cord clamping in term and preterm births: a review

The optimal timing for cord clamping, early versus delayed, in the third stage of labour is a controversial subject. Issues surrounding the timing of cord clamping include gestational age and maternal and neonatal considerations. Delayed cord clamping (DCC) has been shown to increase placental transfusion, leading to an increase in neonatal blood volume at birth of approximately 30%. In the term infant, although this may result in an increase in iron stores, thereby decreasing the risk of anemia, it may adversely increase the risk of jaundice and the need for phototherapy. In the preterm infant, DCC (or even milking of the cord) decreases the need for blood transfusions for anemia, the number of such transfusions, and the risks of intraventricular hemorrhage and late-onset sepsis. Advantages of DCC also include a reduction in alloimmunization in Rh-negative women, although this advantage is theoretical and unproven. We searched multiple databases including PubMed Clinical Queries, Trip Database, Cochrane Systematic Reviews, and UpToDate, as well as published guidelines from the Society of Obstetricians and Gynaecologists of Canada, the American Congress of Obstetricians and Gynecologists, and the Royal College of Obstetricians and Gynaecologists. We preferentially selected systematic reviews and randomized controlled trials for this literature review. Overall, the available evidence appears to suggest that DCC is likely to result in better neonatal outcomes in both term and preterm infants, even in areas where neonatal iron deficiency anemia is rare. However, there is insufficient evidence to date to support a recommendation to delay cord clamping in non-vigorous infants requiring resuscitation.     

延迟脐带结扎对极早产儿的临床意义

目的：评价延迟脐带结扎（delayed cord clamping,DCC）对极早产儿预后的影响。方法：选取2019年5月—2021年5月郑州大学第三附属医院阴道分娩的极早产儿,随机分为早期脐带结扎（early cord clamping,ECC）组和DCC组。比较2组的血常规、胆红素值、Apgar评分、平均动脉压、血气、体温,以及新生儿低氧血症、急性呼吸窘迫综合征（acute respiratory distress syndrome,ARDS）、输血、脑室内出血、坏死性小肠炎、败血症、低血糖、新生儿死亡、高胆红素血症及光疗的发生率。比较2组极早产儿平均住院日和平均住院费用,并比较2组产妇的第三产程和产后出血量。结果：DCC组极早产儿出生时血红蛋白、72 h血红蛋白、出生时红细胞压积、72 h红细胞压积、平均动脉压、出生时胆红素、胆红素峰值均高于ECC组,差异有统计学意义（P<0.05）。DCC组的新生儿低氧血症、ARDS、输血、脑室内出血、坏死性小肠炎、新生儿败血症、低血糖的发生率,以及极早产儿平均住院日、平均住院费用均低于ECC组,差异有统计学意义（P<0.05）。2组极早产儿的Apgar评分、体温、酸中毒发生率、高胆红素血症发生率、光疗发生率、红细胞增多症发生率及新生儿死亡率比较,差异无统计学意义（P>0.05）。2组产妇的第三产程及产后出血量比较,差异无统计学意义（P>0.05）。结论：DCC是一项可以有效改善极早产儿分娩结局且不增加其他并发症的临床干预措施。     

Delayed cord clamping and inotrope use in preterm infants

Objective: To evaluate the impact of delayed cord clamping (DCC) on need for inotropic support and mean arterial blood pressure (MABP).

Methods: This is a single-center, prospective case-control study of premature infants, born <32 weeks gestation, who underwent DCC in comparison to a matched control group who underwent immediate cord clamping (ICC). The primary outcomes were the differences in MABP and inotropic medication used over the first week of life. Secondary outcomes included the admission hemoglobin, need for blood transfusion, and rates of intraventricular hemorrhage (IVH). Infants were matched on EGA, birth weight, sex, antenatal corticosteroid and magnesium exposure, and presence of chorioamnionitis.

Results: Hundred and fifty-eight infants (DCC n?=?79, ICC n?=?79) were included. Demographic factors were similar between groups. DCC infants had a higher admission hemoglobin (p?p?=?.03), fewer median transfusions (p?=?.03), and were discharged at an earlier post-menstrual age (p?=?.04). When controlling for other factors, DCC was not associated with a reduction in inotrope use (p?=?.22) but was associated with a reduction in high-grade IVH (p?=?.01). There was no difference in MABP between the groups.

Conclusions: DCC is not associated with a reduction in the use of inotropes or a difference in MABP.     

A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants

BACKGROUND: The optimal timing of clamping the umbilical cord in preterm infants at birth is the subject of continuing debate. Objective: To investigate the effects of a brief delay in cord clamping on the outcome of babies born prematurely. METHODS: A retrospective meta-analysis of randomised trials in preterm infants was conducted. Data were collected from published studies identified by a structured literature search in EMBASE, PubMed, CINAHL and the Cochrane Library. All infants born below 37 weeks gestation and enrolled into a randomised study of delayed cord clamping (30 s or more) versus immediate cord clamping (less than 20 s) after birth were included. Systematic search and analysis of the data were done according to the methodology of the Cochrane collaboration. RESULTS: Ten studies describing a total of 454 preterm infants were identified which met the inclusion and assessment criteria. Major benefits of the intervention were higher circulating blood volume during the first 24 h of life, less need for blood transfusions (p = 0.004) and less incidence of intraventricular hemorrhage (p = 0.002). CONCLUSIONS: The procedure of a delayed cord clamping time of at least 30 s is safe to use and does not compromise the preterm infant in the initial post-partum adaptation phase.     

Prophylactic indomethacin reduces grades III and IV intraventricular hemorrhages when compared to early indomethacin treatment of a patent ductus arteriosus.

OBJECTIVE: To determine the relative risk of severe intraventricular hemorrhage (IVH) between two very early indomethacin treatment strategies. STUDY DESIGN: Retrospective chart review of infants <29 weeks gestation and <1350 g who received either indomethacin prophylaxis or very early echocardiography with indomethacin treatment only if the ductus arteriosus was patent. RESULTS: A total of one hundred and two infants received prophylactic indomethacin (pINDO). Echochardiography was performed on 158 infants, of whom 117 received indomethacin. Infants receiving pINDO had lower gestational age, but similar birth weight, gender, race, antenatal steroid exposure, delivery mode, Apgar scores, and need for resuscitation as infants evaluated by echocardiography. Grades III to IV IVH was observed less frequently in infants who received pINDO (OR 0.27, 95% CI 0.10 to 0.77, p=0.014). Frequency of side effects and recurrent patent ductus arteriosus did not differ between treatment groups. CONCLUSION: pINDO reduces severe IVH when compared to an early echocardiography strategy.     

高频振荡通气治疗新生儿呼吸窘迫综合征的临床对照研究

目的　观察高频振荡通气 (HFV)对新生儿呼吸窘迫综合征 (NRDS)的治疗效果。　方法　采用高频振荡通气治疗 NRDS患儿 2 5例 ,并与同期一般常规通气治疗的 2 5例 NRDS患儿进行前瞻性临床对照研究。　结果　察组存活 2 0例 ,并发肺炎 12例 ,脑室内出血 (IVH ) 3例 ,肺出血4例 ,动脉导管未闭 (PDA) 4例 ,支气管 -肺发育不良 (BPD) 2例 ,无气漏发生 ;死亡 5例。存活儿使用呼吸机平均时间 88.6 h。对照组存活 14例 ,并发肺炎 12例 ,IVH 3例 ,肺出血 11例 ,PDA 8例 ,BPD6例 ,气漏 3例 ,死亡 11例。存活儿平均呼吸机使用时间为 15 4.7h。　结论　高频振荡通气可有效地减少了气压伤 ,缩短了使用呼吸机的时间 ,较常频呼吸机使用更为安全。     

Clamp late and maintain perfusion (CLAMP) policy: delayed cord clamping in preterm infants

Objective: Randomized controlled trials have demonstrated that delayed umbilical cord clamping (DCC) in preterm infants results in improved neonatal outcomes, including increased hematocrit, and decreased rates of intraventricular hemorrhage (IVH) and packed red blood cell transfusions. We hypothesized that implementation of a DCC policy in preterm infants would result in similarly improved outcomes, despite initial clinician resistance.

Study design: A DCC policy (30–60?s) for singleton infants <35 weeks gestation was implemented in September 2011. We conducted a pre-test/post-test analysis of neonatal outcomes among singletons delivered between 24 0/7 weeks and 34 6/7 weeks gestation from 2009 to 2013 (2 years pre-implementation and 2 years post-implementation). The primary outcomes were rates of policy compliance and four neonatal outcomes.

Results: Despite multiple routes of policy dissemination, DCC was attempted in only 49% of the deliveries. In spite of this, infants delivered post-policy implementation (n?=?196) had a significant decrease in IVH, significant increase in initial hematocrits, and improved temperatures compared with infants delivered pre-implementation (n?=?204).

Conclusion: After implementation of a DCC policy, preterm singleton infants had improved temperatures, increased hematocrits and a decreased prevalence of IVH without significant differences in adverse outcomes, suggesting that the benefits of DCC outweighed the risks.     

延迟脐带结扎对新生儿及产妇的影响

足月儿和早产儿的适宜脐带结扎时间是多年来的争议话题。目前,各个国家、地区在临床实践中脐带结扎时间不一,主要分为2种：即刻脐带结扎指胎儿娩出后15 s内结扎脐带;延迟脐带结扎指胎儿娩出后至少30 s或等待脐带搏动停止后结扎脐带。延迟脐带结扎可增加胎盘内储血向新生儿体内的输血量,近期可提高新生儿血红蛋白水平,减少新生儿脑室内出血及晚期脓毒症的发生,且不增加产后出血发生率,远期可增加铁储备,降低贫血发生率。     

Timing of cord clamping revisited

Although cord cutting has been performed since the beginning of mankind, the timing and advantages of early versus delayed cord clamping are still controversial. Early cord clamping (within the first 30 s after birth) is usually justified for potential prevention of postpartum hemorrhage and for immediate treatment of the newborn, but at the same time, may increase Rh-sensitization. Delayed cord clamping is performed after a period of 30 s during which 'placental transfusion' of approximately 80 mL of blood occurs. This amount seems to protect the baby from childhood anemia without increasing hypervolemia-related risks. In preterm infants, delayed clamping appears to reduce the risk of intraventricular hemorrhage and the need for neonatal transfusion. Obtaining cord blood for future autologous transplantation of stem cells needs early clamping and seems to conflict with the infant's best interest. Although a tailored approach is required in the case of cord clamping, the balance of available data suggests that delayed cord clamping should be the method of choice.     

Immediate and delayed cord clamping in infants born between 24 and 32 weeks: a pilot randomized controlled trial.

OBJECTIVE: This pilot study's aim was to establish feasibility of a protocol for delayed cord clamping (DCC) versus immediate cord clamping (ICC) at preterm birth and to examine its effects on initial blood pressure and other outcomes. STUDY DESIGN: A randomized controlled trial recruited 32 infants between 24 and 32 weeks. Immediately before delivery, mothers were randomized to ICC (cord clamped at 5 to 10 seconds) or DCC (30- to 45-second delay in cord clamping) groups. RESULTS: Intention-to-treat analyses revealed that the DCC group were more likely to have higher initial mean blood pressures (adjusted OR 3.4) and less likely to be discharged on oxygen (adjusted OR 8.6). DCC group infants had higher initial glucose levels (ICC=36 mg/dl, DCC=73.1 mg/dl; p=0.02). CONCLUSION: The research design is feasible. The immediate benefit of improved blood pressure was confirmed and other findings deserve consideration for further study.     

Effect of placental transfusion on the blood volume and clinical outcome of infants born by cesarean section

Delay in cord clamping up to 30 to 40 seconds is feasible and should be practiced in preterm and term infants born by cesarean section. In term infants, this maneuver may decrease iron deficiency anemia at 6 months of age. Premature infants may have a higher blood volume and hematocrit initially requiring fewer transfusions. They also have a decreased incidence of intraventricular hemorrhage. The effect of compounding factors, such as maternal blood pressure, uterine contraction, medications, bleeding, and their effects on the infant's immediate and long-term outcome are unclear.     

Outcome of very low birth weight infants exposed to antenatal indomethacin for tocolysis.

OBJECTIVE: Beginning in October 1995, and for several years thereafter, our institution used indomethacin as a first-line tocolytic drug. Our purpose is to compare the outcomes of very low birth weight infants who were exposed to antenatal indomethacin with those who were not exposed to this therapy. STUDY DESIGN: We used our center's component of the NICHD Neonatal Research Network's Generic Data Base which recorded the outcomes of all live born infants weighing less than 1500 g over a 5-year period. We abstracted data concerning neonatal morbidity (death, Grades III to IV intraventricular hemorrhage (IVH), necrotizing enterocolitis and patent ductus arteriosus), as well as other factors including gestational age, birth weight, antenatal corticosteroid treatment and maternal hypertension or pre-eclampsia. Univariate analysis was performed using Fisher's exact test. Multivariate analysis using logistic regression was performed to control for confounding factors. RESULTS: A total of 85 infants who were exposed to antenatal indomethacin were compared to 464 infants who were not exposed to the drug. In the univariate analysis, antenatal indomethacin exposure was not associated with a significant increase in the incidence of necrotizing enterocolitis or patent ductus arteriosus. The incidence of Grades III to IV IVH was 17.9% in those infants exposed to antenatal indomethacin compared to 7.1% in the nonexposed infants (p=0.008). The incidence of neonatal death in the exposed infants was 27.7 versus 16.4 in the nonexposed infants (p=0.02).After controlling for antenatal corticosteroids, maternal pre-eclampsia, gestational age and birth weight, antenatal indomethacin was significantly associated with an increased incidence of IVH, but not neonatal death. CONCLUSION: Antenatal indomethacin was associated with significantly higher rates of IVH. Additional studies assessing the potential risks of indomethacin tocolysis are needed before it is used as a first-line tocolytic therapy.     

Chest physiotherapy in preterm infants with RDS in the first 24 hours of life

To evaluate if chest physiotherapy is beneficial to premature infants with respiratory distress syndrome (RDS) during the first 24 hours of life, 20 infants were randomly assigned to two groups; 10 infants in Group I received routine chest physiotherapy and suction, and 10 infants in Group II received suction only. The birth weight, gestational age, postnatal age, Apgar scores, blood gases, acid-base status, and ventilatory requirements prior to study were comparable between the two groups. There were no significant differences between the groups in the amount of endotracheal secretions removed, the PO2/FIO2 ratio, blood gases, and pH during the study. The incidence of patent ductus arteriosus (PDA), bronchopulmonary dysplasia (BPD), Grade I and II intraventricular hemorrhage (IVH), and mortality was comparable. However, five of 10 Group I and zero of 10 Group II infants developed Grade III or IV IVH (P less than 0.05).     

Regulation of cerebral blood flow velocity in nonasphyxiated, very low birth weight infants with hyaline membrane disease

Previous studies of cerebral blood flow (CBF) and blood flow velocity regulation in stressed neonates, both term and preterm, have suggested that CBF is pressure passive. These studies are in conflict with data obtained from fetal and newborn animals. To determine if autoregulation of CBF is present in preterm infants, we studied eight very low birth weight infants (gestational age, 29.1 +/- 1.5 weeks; birth weight, 1117 +/- 278 g), all of whom had hyaline membrane disease that necessitated mechanical ventilation. None of the infants suffered from perinatal asphyxia, intraventricular hemorrhage, or patent ductus arteriosus. All infants demonstrated appropriate changes in cerebral blood flow velocity (CBFV) in response to changes in arterial oxygen content and pCO2. CBFV was not affected by changes in systemic mean arterial blood pressure. The data indicate that nonasphyxiated very low birth weight infants regulate their CBF in a manner similar to that observed in adults.     

The effects of indomethacin tocolysis on the postnatal response of the ductus arteriosus to indomethacin in extremely low birth weight infants.

BACKGROUND: Antenal indomethacin reportedly decreases the responses of a symptomatic patent ductus arteriosus (sPDA) to postnatal indomethacin treatment. Whether a similar exposure affects the responses to indomethacin prophylaxis is unknown. OBJECTIVE: To evaluate the clinical responsiveness of ductus arteriosus to indomethacin prophylaxis and to the treatment of sPDA in extremely low birth weight (ELBW) infants following indomethacin tocolysis. METHODS: Retrospective cohort study of 58 ELBW infants whose mothers received indomethacin tocolysis (study) and 58 ELBW infants whose mothers did not (controls), matched by gender, gestational age (GA), birth weight and postnatal sPDA management (prophylaxis or early treatment). RESULTS: Indomethacin was used as a tocolytic at a median dose of 250 mg, for a duration of 2 days, and ending 1 day before delivery. Study and control mothers were comparable in demographics, antenatal steroid use, cesarean delivery, but were different in the incidence of preeclampsia and preterm labor. Study and control infants were similar in birth weight, GA, indomethacin prophylaxis, early sPDA treatment, mortality, necrotizing enterocolitis, severe intraventricular hemorrhage and stage 3-5 retinopathy of prematurity. Seventeen of 43 study and 16 of 43 control infants who received indomethacin prophylaxis developed sPDA and were combined with early treatment sPDA infants (15 to each group). Two of 32 study and two of 31 control infants underwent surgical ligation whereas the remaining were treated with indomethacin. Sixteen of 30 (53%) and 13 of 29 (45%) were successfully treated and did not require ligation. Study infants were divided according to their mothers' indomethacin total dose (28 infants received 225 mg). Both subgroups were demographically and clinically comparable and their response to indomethacin prophylaxis and treatment were similar. CONCLUSION: In ELBW infants, exposure to indomethacin tocolysis does not affect the clinical responsiveness of the ductus arteriosus to prophylaxis or that of the sPDA to indomethacin treatment.     

Maternal outcomes following the initiation of an institutional delayed cord clamping protocol: an observational case–control study

Objective: The objective of this study is to evaluate maternal outcomes before and after implementation of an institutional delayed cord clamping (DCC) protocol.

Study design: We performed a secondary analysis of a retrospective cohort study of deliveries occurring at <34 weeks at a tertiary care center in 2013–2014. About 139 women who underwent early cord clamping were compared with 130 women delivered after DCC protocol implementation. Maternal estimated blood loss (EBL) was the primary outcome of interest. Operative times, post-Cesarean decrease in hemoglobin (Hgb), and rates of post-partum hemorrhage and transfusion were also examined in bivariate and multivariable analyses.

Results: About 75% of post-guideline deliveries had actual DCC. In regression analyses, only Cesarean delivery and multifetal gestation increased EBL. No trends were identified in EBL over time. In post-hoc analysis, the study had over 80% power to detect a difference in post-partum hemorrhage rates of 20%.

Conclusion: An institutional DCC protocol for deliveries <34 weeks was not associated with an identifiable increase in adverse maternal outcomes.     

极低出生体重早产儿动脉导管未闭的治疗

目的探讨极低出生体重早产儿有临床表现的动脉导管未闭的治疗方法方法 本研究为前瞻性队列研究.2008年1月1日至2010年12月31日间出生体重＜1500 g的确诊有临床表现的动脉导管未闭早产儿78例,其中42例采用口服吲哚美辛治疗者作为治疗组,36例未治疗者为对照组.观察吲哚美辛的疗效、副作用以及对早产儿的近远期预后.结果治疗组及对照组在性别比例、胎龄、动脉导管直径、合并心力衰竭、败血症、新生儿呼吸窘迫综合征、脑室内出血的差异均无统计学意义(P均＞0.05).治疗组治疗后动脉导管关闭33例,关闭率为78.6%,高于对照组,自发关闭9例,关闭率25.0%,差异有统计学意义(χ2=22.39,P=0.000).治疗组治疗前后的血肌酐、血小板差异无统计学意义(P均＞0.05).治疗组较对照组有较少的脑室内出血发生比例(z=1.167,P=0.030)、较短的总用氧时间[分别为(8.0±5.5) d和(13.3±9.3) d,t=2.225,P=0.032]及住院时间[(39.0±7.7) d和(43.6±10.6) d,t=2.229,P=0.029],且支气管肺发育不良、坏死性小肠结肠炎的发生情况组间差异无统计学意义(P均＞0.05).治疗组中有5例药物治疗失败后使用胸腔镜钳闭动脉导管,术后3例发生肺部感染,1例出现胸腔积液,无死亡及气胸发生.结论极低出生体重早产儿有临床表现的动脉导管未闭应积极干预,口服吲哚美辛可有效关闭动脉导管,胸腔镜钳闭动脉导管可作为药物治疗失败后的一种选择.

Abstract：

Objective To investigate the treatment of symptomatic patent ductus arteriosus (PDA) in very low birth weight preterm infants. Methods From January 1, 2008 to December 31, 2010, 78 very low birth weight preterm infants (birth weight＜1500 g) were diagnosed as symptomatic PDA. Among which, 42 cases administered orally with indomethacin (0.2 mg/kg, every 12 hrs for three times) were taken as treatment group, while five cases in this group who failed to indomethacin treatment were interrupted with video-assisted thoracoscopic surgery. And 36 cases who did not receive treatment for ductus arteriosus were taken as control group. The clinical outcomes, complications and prognosis of these patients were observed. Results There were no significant differences between the gentle percentage, gestational age, diameter of ductus arteriosus, rate of complicated with heart failure, sepsis, neonatal respiratory distress syndrome and intraventricular hemorrhage of two groups (P>0.05, respectively). The ductus arteriosus closed in 33 patients of treatment group (78.6%) and in nine patients of control group (25.0%)(χ2=22.39,P=0.000). There were no significant differences in serum creatinine level and platelet count between before and after the treatment in treatment group(P>0.05). Compared with control group, the treatment group had lower incidence of intraventricular hemorrhage (z=1.167, P=0.030), shorter duration of oxygen therapy [(8.0±5.5) d vs (13.3±9.3) d, t=2.225, P=0.032] and shorter hospital stay [(39.0±7.7) d vs (43.6±10.6) d, t=2.229, P=0.029]; while the incidence of bronchopulmonary dysplasia and necrotizing enterocolitis were similar (P>0.05). The five cases of PDA who received video-assisted thoracoscopic surgery were successfully interrupted with no residual shunt left, while three of them had lung infections and one had pleural effusion, but no pneumothorax and infant death associated with surgery occurred. Conclusions Symptomatic PDA of very low birth weight preterm infants should be treated actively. Oral indomethacin was an effective and safe method to cure the PDA in these infants. Surgical ligation under video-assisted thoracoscopic surgery after failure of indomethacin treatment might be a good option.     

Immediate versus delayed umbilical cord clamping in premature neonates born < 35 weeks: a prospective, randomized, controlled study

The purpose of this study was to test whether delayed versus immediate cord clamping would result in higher blood pressure (BP) and hematocrit (Hct), and to assess its clinical effects on the neonatal course in premature neonates (< 35 weeks). This was a prospective, masked, randomized, controlled study. Prior to delivery, 35 neonates were randomly assigned to immediate cord clamping (ICC) at 5 to 10 seconds, and a comparable group of 30 neonates were randomly assigned to delayed cord clamping (DCC) at 30 to 45 seconds. Intention-to-treat analyses revealed that the DCC group tended to have higher initial diastolic BP and higher Hct (especially in vaginally delivered neonates). Infants weighing < 1500 g with DCC tended to have higher mean BP, and needed less mechanical ventilation and surfactant compared with ICC neonates. Infants with DCC did not experience more polycythemia (Hct > 60%), but had a trend toward higher bilirubin levels with no differences in the phototherapy needs. DCC seems to be safe and may be beneficial when compared with ICC in premature neonates. However, the differences between the two methods were modest and the clinical relevance needs to be assessed further by larger studies and additional meta-analysis of randomized trials.     

Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit

Indomethacin and ibuprofen are potent inhibitors of prostaglandin synthesis. Neonates have been exposed to these compounds for more than 3 decades. Indomethacin is commonly used to prevent intraventricular hemorrhage (IVH), and both drugs are prescribed for the treatment or prevention of patent ductus arteriosus (PDA). This review examines the basis for indomethacin and ibuprofen use in the neonatal intensive care population. Despite the call for restrained use of each drug, the most immature infants are likely to need pharmacologic approaches to reduce high-grade IVH, avoid the need for PDA ligation, and preserve the opportunity for an optimal outcome.     

Associations between "early" red blood cell transfusion and severe intraventricular hemorrhage, and between "late" red blood cell transfusion and necrotizing enterocolitis

Transfusion of banked donor erythrocytes can be life saving for small and ill neonates with severe anemia or active hemorrhage. However, risks of transfusions exist and must be weighed against potential benefits each time a transfusion is considered. The present review seeks to bring together the published data supporting 2 newly postulated risks of transfusions among very low-birth-weight neonates. The first is an association between "early" red blood cell transfusions, those administered in the first few days after birth, and the subsequent occurrence of a grade 3 or 4 intraventricular hemorrhage. The second is an association between "late" RBC transfusions and the subsequent occurrence of necrotizing enterocolitis. Much remains to be discovered about the pathogenetic links between transfusion and these adverse outcomes. Moreover, work is needed to clearly establish whether transfusions are causatively associated with these adverse outcomes or are covariables. The purpose of this chapter is to review the associations between transfusion and intraventricular hemorrhage and between transfusions and necrotizing enterocolitis and to use these associations to hypothesize that evidence-based improvements in transfusion practice have the potential to improve neonatal intensive care unit outcomes.