Hemodynamic Changes with Umbilical Cord Milking in Nonvigorous Newborns: A Randomized Cluster Cross-over Trial.

OBJECTIVE: To assess the hemodynamic safety and efficacy of umbilical cord milking (UCM) compared with early cord clamping (ECC) in nonvigorous newborn infants enrolled in a large multicenter randomized cluster-crossover trial. STUDY DESIGN: Two hundred twenty-seven nonvigorous term or near-term infants who were enrolled in the parent UCM vs ECC trial consented for this substudy. An echocardiogram was performed at 12 ± 6 hours of age by ultrasound technicians blinded to randomization. The primary outcome was left ventricular output (LVO). Prespecified secondary outcomes included measured superior vena cava (SVC) flow, right ventricular output (RVO), peak systolic strain, and peak systolic velocity by tissue Doppler examination of the RV lateral wall and the interventricular septum. RESULTS: Nonvigorous infants receiving UCM had increased hemodynamic echocardiographic parameters as measured by higher LVO (225 ± 64 vs 187 ± 52 mL/kg/min; P < .001), RVO (284 ± 88 vs 222 ± 96 mL/kg/min; P < .001), and SVC flow (100 ± 36 vs 86 ± 40 mL/kg/min; P < .001) compared with the ECC group. Peak systolic strain was lower (-17 ± 3 vs -22 ± 3%; P < .001), but there was no difference in peak tissue Doppler flow (0.06 m/s [IQR, 0.05-0.07 m/s] vs 0.06 m/s [IQR, 0.05-0.08 m/s]). CONCLUSIONS: UCM increased cardiac output (as measured by LVO) compared with ECC in nonvigorous newborns. Overall increases in measures of cerebral and pulmonary blood flow (as measured by SVC and RVO flow, respectively) may explain improved outcomes associated with UCM (less cardiorespiratory support at birth and fewer cases of moderate-to-severe hypoxic ischemic encephalopathy) among nonvigorous newborn infants.

Umbilical cord milking in nonvigorous infants: a cluster-randomized crossover trial.

BACKGROUND: Delayed cord clamping and umbilical cord milking provide placental transfusion to vigorous newborns. Delayed cord clamping in nonvigorous newborns may not be provided owing to a perceived need for immediate resuscitation. Umbilical cord milking is an alternative, as it can be performed more quickly than delayed cord clamping and may confer similar benefits. OBJECTIVE: We hypothesized that umbilical cord milking would reduce admission to the neonatal intensive care unit compared with early cord clamping in nonvigorous newborns born between 35 and 42 weeks' gestation. STUDY DESIGN: This was a pragmatic cluster-randomized crossover trial of infants born at 35 to 42 weeks' gestation in 10 medical centers in 3 countries between January 2019 and May 2021. The centers were randomized to umbilical cord milking or early cord clamping for approximately 1 year and then crossed over for an additional year or until the required number of consented subjects was reached. Waiver of consent as obtained in all centers to implement the intervention. Infants were eligible if nonvigorous at birth (poor tone, pale color, or lack of breathing in the first 15 seconds after birth) and were assigned to umbilical cord milking or early cord clamping according to their birth hospital randomization assignment. The baseline characteristics and outcomes were collected following deferred informed consent. The primary outcome was admission to the neonatal intensive care unit for predefined criteria. The main safety outcome was hypoxic-ischemic encephalopathy. Data were analyzed by the intention-to-treat concept. RESULTS: Among 16,234 screened newborns, 1780 were eligible (905 umbilical cord milking, 875 early cord clamping), and 1730 had primary outcome data for analysis (97% of eligible; 872 umbilical cord milking, 858 early cord clamping) either via informed consent (606 umbilical cord milking, 601 early cord clamping) or waiver of informed consent (266 umbilical cord milking, 257 early cord clamping). The difference in the frequency of neonatal intensive care unit admission using predefined criteria between the umbilical cord milking (23%) and early cord clamping (28%) groups did not reach statistical significance (modeled odds ratio, 0.69; 95% confidence interval, 0.41-1.14). Umbilical cord milking was associated with predefined secondary outcomes, including higher hemoglobin (modeled mean difference between umbilical cord milking and early cord clamping groups 0.68 g/dL, 95% confidence interval, 0.31-1.05), lower odds of abnormal 1-minute Apgar scores (Apgar ≤3, 30% vs 34%, crude odds ratio, 0.72; 95% confidence interval, 0.56-0.92); cardiorespiratory support at delivery (61% vs 71%, modeled odds ratio, 0.57; 95% confidence interval, 0.33-0.99), and therapeutic hypothermia (3% vs 4%, crude odds ratio, 0.57; 95% confidence interval, 0.33-0.99). Moderate-to-severe hypoxic-ischemic encephalopathy was significantly less common with umbilical cord milking (1% vs 3%, crude odds ratio, 0.48; 95% confidence interval, 0.24-0.96). No significant differences were observed for normal saline bolus, phototherapy, abnormal 5-minute Apgar scores (Apgar ≤6, 15.7% vs 18.8%, crude odds ratio, 0.81; 95% confidence interval, 0.62-1.06), or a serious adverse event composite of death before discharge. CONCLUSION: Among nonvigorous infants born at 35 to 42 weeks' gestation, umbilical cord milking did not reduce neonatal intensive care unit admission for predefined criteria. However, infants in the umbilical cord milking arm had higher hemoglobin, received less delivery room cardiorespiratory support, had a lower incidence of moderate-to-severe hypoxic-ischemic encephalopathy, and received less therapeutic hypothermia. These data may provide the first randomized controlled trial evidence that umbilical cord milking in nonvigorous infants is feasible, safe and, superior to early cord clamping.

What does the evidence tell us? Revisiting optimal cord management at the time of birth.

A newborn who receives a placental transfusion at birth from delayed cord clamping (DCC) obtains about 30% more blood volume than those with immediate cord clamping (ICC). Benefits for term neonates include higher hemoglobin levels, less iron deficiency in infancy, improved myelination out to 12 months, and better motor and social development at 4 years of age especially in boys. For preterm infants, benefits include less intraventricular hemorrhage, fewer gastrointestinal issues, lower transfusion requirements, and less mortality in the neonatal intensive care unit by 30%. Ventilation before clamping the umbilical cord can reduce large swings in cardiovascular function and help to stabilize the neonate. Hypovolemia, often associated with nuchal cord or shoulder dystocia, may lead to an inflammatory cascade and subsequent ischemic injury. A sudden unexpected neonatal asystole at birth may occur from severe hypovolemia. The restoration of blood volume is an important action to protect the hearts and brains of neonates. Currently, protocols for resuscitation call for ICC. However, receiving an adequate blood volume via placental transfusion may be protective for distressed neonates as it prevents hypovolemia and supports optimal perfusion to all organs. Bringing the resuscitation to the mother's bedside is a novel concept and supports an intact umbilical cord. When one cannot wait, cord milking several times can be done quickly within the resuscitation guidelines. Cord blood gases can be collected with optimal cord management.   Conclusion: Adopting a policy for resuscitation with an intact cord in a hospital setting takes a coordinated effort and requires teamwork by obstetrics, pediatrics, midwifery, and nursing.

The Effects of Delayed Cord Clamping on 12-Month Brain Myelin Content and Neurodevelopment: A Randomized Controlled Trial.

OBJECTIVE: This study aimed to determine if delayed cord clamping (DCC) affected brain myelin water volume fraction (VFm) and neurodevelopment in term infants. STUDY DESIGN: This was a single-blinded randomized controlled trial of healthy pregnant women with term singleton fetuses randomized at birth to either immediate cord clamping (ICC) (≤ 20 seconds) or DCC (≥ 5 minutes). Follow-up at 12 months of age consisted of blood work for serum iron indices and lead levels, a nonsedated magnetic resonance imaging (MRI), followed within the week by neurodevelopmental testing. RESULTS: At birth, 73 women were randomized into one of two groups: ICC (the usual practice) or DCC (the intervention). At 12 months, among 58 active participants, 41 (80%) had usable MRIs. There were no differences between the two groups on maternal or infant demographic variables. At 12 months, infants who had DCC had increased white matter brain growth in regions localized within the right and left internal capsules, the right parietal, occipital, and prefrontal cortex. Gender exerted no difference on any variables. Developmental testing (Mullen Scales of Early Learning, nonverbal, and verbal composite scores) was not significantly different between the two groups. CONCLUSION: At 12 months of age, infants who received DCC had greater myelin content in important brain regions involved in motor function, visual/spatial, and sensory processing. A placental transfusion at birth appeared to increase myelin content in the early developing brain. KEY POINTS: · DCC resulted in higher hematocrits in newborn period.. · DCC appears to increase myelin at 12 months.. · Gender did not influence study outcomes..

Delayed Cord Clamping in Infants with Suspected Intrauterine Growth Restriction.

We evaluated a subset of infants with suspected intrauterine growth restriction or birth weights small for gestational age enrolled in a study of delayed cord clamping for preterm infants. Compared with immediate clamping, delayed cord clamping was associated with no apparent harm and less suspected necrotizing enterocolitis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00818220 and NCT01426698.

Effects of Delayed Cord Clamping on 4-Month Ferritin Levels, Brain Myelin Content, and Neurodevelopment: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether placental transfusion influences brain myelination at 4 months of age. STUDY DESIGN: A partially blinded, randomized controlled trial was conducted at a level III maternity hospital in the US. Seventy-three healthy term pregnant women and their singleton fetuses were randomized to either delayed umbilical cord clamping (DCC, >5 minutes) or immediate clamping (ICC, <20 seconds). At 4 months of age, blood was drawn for ferritin levels. Neurodevelopmental testing (Mullen Scales of Early Learning) was administered, and brain myelin content was measured with magnetic resonance imaging. Correlations between myelin content and ferritin levels and group-wise DCC vs ICC brain myelin content were completed. RESULTS: In the DCC and ICC groups, clamping time was 172 ± 188 seconds vs 28 ± 76 seconds (P < .002), respectively; the 48-hour hematocrit was 57.6% vs 53.1% (P < .01). At 4 months, infants with DCC had significantly greater ferritin levels (96.4 vs 65.3 ng/dL, P = .03). There was a positive relationship between ferritin and myelin content. Infants randomized to the DCC group had greater myelin content in the internal capsule and other early maturing brain regions associated with motor, visual, and sensory processing/function. No differences were seen between groups in the Mullen testing. CONCLUSION: At 4 months, infants born at term receiving DCC had greater ferritin levels and increased brain myelin in areas important for early life functional development. Endowment of iron-rich red blood cells obtained through DCC may offer a longitudinal advantage for early white matter development. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01620008.

Effects of Placental Transfusion on Neonatal and 18 Month Outcomes in Preterm Infants: A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of delayed cord clamping (DCC) vs immediate cord clamping (ICC) on intraventricular hemorrhage (IVH), late onset sepsis (LOS), and 18-month motor outcomes in preterm infants. STUDY DESIGN: Women (n = 208) in labor with singleton fetuses (<32 weeks gestation) were randomized to either DCC (30-45 seconds) or ICC (<10 seconds). The primary outcomes were IVH, LOS, and motor outcomes at 18-22 months corrected age. Intention-to-treat was used for primary analyses. RESULTS: Cord clamping time was 32 ± 16 (DCC) vs 6.6 ± 6 (ICC) seconds. Infants in the DCC and ICC groups weighed 1203 ± 352 and 1136 ± 350 g and mean gestational age was 28.3 ± 2 and 28.4 ± 2 weeks, respectively. There were no differences in rates of IVH or LOS between groups. At 18-22 months, DCC was protective against motor scores below 85 on the Bayley Scales of Infant Development, Third Edition (OR 0.32, 95% CI 0.10-0.90, P = .03). There were more women with preeclampsia in the ICC group (37% vs 22%, P = .02) and more women in the DCC group with premature rupture of membranes/preterm labor (54% vs 75%, P = .002). Preeclampsia halved the risk of IVH (OR 0.50, 95% CI 0.2-1.0) and premature rupture of membranes/preterm labor doubled the risk of IVH (OR 2.0, 95% CI 1.2-4.3). CONCLUSIONS: Although DCC did not alter the incidence of IVH or LOS in preterm infants, it improved motor function at 18-22 months corrected age. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00818220 and NCT01426698.

Effects of placental transfusion in extremely low birthweight infants: meta-analysis of long- and short-term outcomes.

BACKGROUND: Risks and benefits of increasing placental transfusion in extremely preterm infants (extremely low birthweight [ELBW], <1000 g) are ill defined. We performed a meta-analysis to compare long- and short-term outcomes of ELBW infants in trials of enhanced placental transfusion regimens. STUDY DESIGN AND METHODS: We conducted a meta-analysis of randomized controlled trials (RCTs) of delayed umbilical cord clamping or umbilical cord milking in compliance with PRISMA and Cochrane Collaborative guidelines for systematic reviews. We searched multiple databases for medical literature up to December 2012. Inclusion criteria were preterm infants less than 30 weeks and less than 1000 g birthweight, randomly assigned to enhanced placental transfusion (either delayed cord clamping or cord milking) versus immediate cord clamping. The primary outcome was standardized neurodevelopmental outcome at 18 to 24 months corrected age using a standardized scale. Several short-term outcomes were also evaluated as secondary variables. RESULTS: We found 19 studies of which 10 studies could be included (n = 199). Three reported neurodevelopmental outcomes, none of which showed significant rates of disability. Two reported these at 18 to 24 months (n = 42) but used different scales preventing pooling. Short-term benefits of enhanced placental strategies included better blood pressure and hemoglobin on admission, along with reduced blood transfusions, a trend to reduced intraventricular hemorrhage, and episodes of late-onset sepsis. CONCLUSIONS: Strategies to enhance placental transfusion may improve short-term outcomes of ELBW infants. However, paucity of data on neurodevelopmental outcomes and safety concerns tempers enthusiasm for these interventions. Appropriately designed RCTs to assess short-term and longterm outcomes are needed in ELBW infants.

Two-Year Outcomes of Umbilical Cord Milking in Nonvigorous Infants: A Secondary Analysis of the MINVI Randomized Clinical Trial.

Importance: Compared with early cord clamping (ECC), umbilical cord milking (UCM) reduces delivery room cardiorespiratory support, hypoxic-ischemic encephalopathy, and therapeutic hypothermia in nonvigorous near-term and full-term infants. However, UCM postdischarge outcomes are not known. Objective: To determine the 2-year outcomes of children randomized to UCM or ECC at birth in the Milking in Nonvigorous Infants (MINVI) trial. Design, Setting, and Participants: A secondary analysis to evaluate longer-term outcomes of a cluster-randomized crossover trial was conducted from January 9, 2021, to September 25, 2023. The primary trial took place in 10 medical centers in the US, Canada, and Poland from January 5, 2019, to June 1, 2021, and hypothesized that UCM would reduce admission to the neonatal intensive care unit compared with ECC; follow-up concluded September 26, 2023. The population included near-term and full-term infants aged 35 to 42 weeks' gestation at birth who were nonvigorous; families provided consent to complete developmental screening questionnaires through age 2 years. Intervention: UCM and ECC. Main Outcomes and Measures: Ages and Stages Questionnaire, 3rd Edition (ASQ-3) and Modified Checklist for Autism in Toddlers, Revised/Follow-Up (M-CHAT-R/F) questionnaires at ages 22 to 26 months. Intention-to-treat analysis and per-protocol analyses were used. Results: Among 1730 newborns from the primary trial, long-term outcomes were evaluated in 971 children (81%) who had ASQ-3 scores available at 2 years or died before age 2 years and 927 children (77%) who had M-CHAT-R/F scores or died before age 2 years. Maternal and neonatal characteristics by treatment group were similar, with median birth gestational age of 39 (IQR, 38-40) weeks in both groups; 224 infants (45%) in the UCM group and 201 (43%) in the ECC group were female. The median ASQ-3 total scores were similar (UCM: 255 [IQR, 225-280] vs ECC: 255 [IQR, 230-280]; P = .87), with no significant differences in the ASQ-3 subdomains. Medium- to high-risk M-CHAT-R/F scores were also similar (UCM, 9% [45 of 486] vs ECC, 8% [37 of 441]; P = .86). Conclusions and Relevance: In this secondary analysis of a randomized clinical trial among late near-term and full-term infants who were nonvigorous at birth, ASQ-3 scores at age 2 years were not significantly different between the UCM and ECC groups. Combined with previously reported important short-term benefits, this follow-up study suggests UCM is a feasible, no-cost intervention without longer-term neurodevelopmental risks of cord milking in nonvigorous near-term and term newborns. Trial Registration: ClinicalTrials.gov Identifier: NCT03631940.

Knowledge gaps in optimal umbilical cord management at birth.

In 2014 the World Health Organisation recommended providing placental blood to all newborn infants by waiting for at least one minute before clamping the umbilical cord. Mounting evidence supports providing a placental transfusion at the time of birth for all infants. The optimal time before clamping and cutting the umbilical cord is still not yet known, and debate exists around other cord management issues. The newborn's transition phase from intra- to extra-uterine life and the effects of blood volume on the many necessary adaptations are understudied. How best to support these adaptations guides our suggested research questions. Parents' perceptions of enrolling their unborn infant into a study play important parts in the conduct of such trials. This article aims to address these topics and suggest research questions for further studies.

Cardiac Asystole at Birth Re-Visited: Effects of Acute Hypovolemic Shock.

Births involving shoulder dystocia or tight nuchal cords can deteriorate rapidly. The fetus may have had a reassuring tracing just before birth yet may be born without any heartbeat (asystole). Since the publication of our first article on cardiac asystole with two cases, five similar cases have been published. We suggest that these infants shift blood to the placenta due to the tight squeeze of the birth canal during the second stage which compresses the cord. The squeeze transfers blood to the placenta via the firm-walled arteries but prevents blood returning to the infant via the soft-walled umbilical vein. These infants may then be born severely hypovolemic resulting in asystole secondary to the loss of blood. Immediate cord clamping (ICC) prevents the newborn's access to this blood after birth. Even if the infant is resuscitated, loss of this large amount of blood volume may initiate an inflammatory response that can enhance neuropathologic processes including seizures, hypoxic-ischemic encephalopathy (HIE), and death. We present the role of the autonomic nervous system in the development of asystole and suggest an alternative algorithm to address the need to provide these infants intact cord resuscitation. Leaving the cord intact (allowing for return of the umbilical cord circulation) for several minutes after birth may allow most of the sequestered blood to return to the infant. Umbilical cord milking may return enough of the blood volume to restart the heart but there are likely reparative functions that are carried out by the placenta during the continued neonatal-placental circulation allowed by an intact cord.

Midwifery and nursing: Considerations on cord management at birth.

Mounting evidence overwhelmingly supports the practice of the return of an infant's placental blood volume at the time of birth. Waiting just a few minutes before clamping the umbilical cord can provide health benefits to infants of all gestational ages. Despite the robust evidence, uptake of delayed cord clamping (DCC) into mainstream obstetrical practice is moving slowly. The practice of DCC is influenced by various factors that include the setting in which the birth takes place, the use of evidence-informed guidelines and other influences that facilitate or hinder the practice of DCC. Through communication, collaboration, and unique disciplinary perspectives, midwives and nurses work with other members of their respective care team to develop strategies for best practice to improve an infant's well-being through optimal cord management. Midwifery has been practiced for centuries throughout the world and midwives have supported DCC since the beginning of recorded history. An important tenet of midwifery philosophy is watchful waiting and non-intervention in normal processes. Nurses are vital to care of birthing families in- and out-of-hospitals as well as in prenatal and postpartum ambulatory care. Nurses and midwives are positioned to be involved in the process of adapting to the mounting evidence for DCC. Strategies to increase better utilization of the practice of DCC have been proposed. For all, teamwork and collaboration among disciplines participating in maternity care are essential for adapting to the new evidence. Involving midwives and nurses as partners in an interdisciplinary approach to plan, implement and sustain DCC at birth increases success.

Umbilical cord clamping in the early phases of the COVID-19 era - a systematic review and meta-analysis of reported practice and recommendations in guidelines.

OBJECTIVES: At the beginning of the COVID-19 pandemic, delayed umbilical cord clamping (CC) at birth may have been commonly discouraged despite a lack of convincing evidence of mother-to-neonate SARS-CoV-2 transmission. We aimed to systematically review guidelines, and reports of practice and to analyze associations between timing of CC and mother-to-neonate SARS-CoV-2 transmission during the early phases of the pandemic. METHODS: Major databases were searched from December 1, 2019, to July 20, 2021. INCLUSION: studies and guidelines describing CC practice in women with SARS-CoV-2 infection during pregnancy until 2 postnatal days, giving birth to live-born neonates. EXCLUSION: no extractable data. Two reviewers independently screened studies for eligibility and assessed study quality. Pooled prevalence rates were calculated. RESULTS: Forty-eight studies (1476 neonates) and 40 guidelines were included. Delayed CC was recommended in 70.0% of the guidelines. Nevertheless, delayed CC was reported less often than early CC: 262/1476 (17.8%) vs 511/1476 (34.6%). Neonatal SARS-CoV-2 positivity rates were similar following delayed (1.2%) and early CC (1.3%). Most SARS-CoV-2 transmissions (93.3%) occurred in utero. CONCLUSION: Delayed CC did not seem to increase mother-to-neonate SARS-CoV-2 transmission. Due to its benefits, it should be encouraged even in births where the mother has a SARS-CoV-2 infection. SYSTEMATIC REVIEW REGISTRATION: Prospero CRD42020199500.

Rethinking placental transfusion and cord clamping issues.

A brief delay in clamping the umbilical cord results in a placental transfusion that supplies the infant with a major source of iron during the first few months of life. Cord circulation continues for several minutes after birth and placental transfusion results in approximately 30% more blood volume. Gravity influences the amount of placental transfusion that an infant receives. Placing the infant skin-to-skin requires a longer delay of cord clamping (DCC) than current recommendations. Uterotonics are not contraindicated with DCC. Cord milking is a safe alternative to DCC when one must cut the cord prematurely. Recent randomized controlled trials demonstrate benefits for term and preterm infants from DCC. The belief that DCC causes hyperbilirubinemia or symptomatic polycythemia is unsupported by the available research. Delay of cord clamping substantively increases iron stores in early infancy. Inadequate iron stores in infancy may have an irreversible impact on the developing brain despite oral iron supplementation. Iron deficiency in infancy can lead to neurologic issues in older children including poor school performance, decreased cognitive abilities, and behavioral problems. The management of the umbilical cord in complex situations is inconsistent between birth settings. A change in practice requires collaboration between all types of providers who attend births.

Making the Argument for Intact Cord Resuscitation: A Case Report and Discussion.

We use a case of intact cord resuscitation to argue for the beneficial effects of an enhanced blood volume from placental transfusion for newborns needing resuscitation. We propose that intact cord resuscitation supports the process of physiologic neonatal transition, especially for many of those newborns appearing moribund. Transfer of the residual blood in the placenta provides the neonate with valuable access to otherwise lost blood volume while changing from placental respiration to breathing air. Our hypothesis is that the enhanced blood flow from placental transfusion initiates mechanical and chemical forces that directly, and indirectly through the vagus nerve, cause vasodilatation in the lung. Pulmonary vascular resistance is thereby reduced and facilitates the important increased entry of blood into the alveolar capillaries before breathing commences. In the presented case, enhanced perfusion to the brain by way of an intact cord likely led to regained consciousness, initiation of breathing, and return of tone and reflexes minutes after birth. Paramount to our hypothesis is the importance of keeping the umbilical cord circulation intact during the first several minutes of life to accommodate physiologic neonatal transition for all newborns and especially for those most compromised infants.

Cord Management of the Term Newborn.

Keeping the umbilical cord intact after delivery facilitates transition from fetal to neonatal circulation and allows a placental transfusion of a considerable amount of blood. A delay of at least 3 minutes improves neurodevelopmental outcomes in term infants. Although regarded as common sense and practiced by many midwives, implementation of delayed cord clamping into practice has been unduly slow, partly because of beliefs regarding theoretic risks of jaundice and lack of understanding regarding the long-term benefits. This article provides arguments for delaying cord clamping for a minimum of 3 minutes.

Placental transfusion: may the "force" be with the baby.

Placental transfusion results in a significant decrease in the risk of death for extremely preterm infants. With immediate cord clamping (ICC), these infants can leave up to one-half of their normal circulating in utero blood volume in the placenta. Extremely preterm infants are at highest risk of harm from ICC yet are currently the most likely to receive ICC. Receiving a placenta transfusion provides infants with life-saving components and enhanced perfusion. We present some lesser-known but important effects of placental transfusion. New research reveals that enhanced vascular perfusion causes an organ's endothelial cells to release angiocrine responses to guide essential functions. High progesterone levels and pulmonary artery pressure in the first few hours of life assist with neonatal adaptation. We propose that lack of essential blood volume may be a major factor contributing to inflammation, morbidities, and mortality that preterm infants frequently encounter.

Systematic review and network meta-analysis with individual participant data on cord management at preterm birth (iCOMP): study protocol.

INTRODUCTION: Timing of cord clamping and other cord management strategies may improve outcomes at preterm birth. However, it is unclear whether benefits apply to all preterm subgroups. Previous and current trials compare various policies, including time-based or physiology-based deferred cord clamping, and cord milking. Individual participant data (IPD) enable exploration of different strategies within subgroups. Network meta-analysis (NMA) enables comparison and ranking of all available interventions using a combination of direct and indirect comparisons. OBJECTIVES: (1) To evaluate the effectiveness of cord management strategies for preterm infants on neonatal mortality and morbidity overall and for different participant characteristics using IPD meta-analysis. (2) To evaluate and rank the effect of different cord management strategies for preterm births on mortality and other key outcomes using NMA. METHODS AND ANALYSIS: Systematic searches of Medline, Embase, clinical trial registries, and other sources for all ongoing and completed randomised controlled trials comparing cord management strategies at preterm birth (before 37 weeks' gestation) have been completed up to 13 February 2019, but will be updated regularly to include additional trials. IPD will be sought for all trials; aggregate summary data will be included where IPD are unavailable. First, deferred clamping and cord milking will be compared with immediate clamping in pairwise IPD meta-analyses. The primary outcome will be death prior to hospital discharge. Effect differences will be explored for prespecified participant subgroups. Second, all identified cord management strategies will be compared and ranked in an IPD NMA for the primary outcome and the key secondary outcomes. Treatment effect differences by participant characteristics will be identified. Inconsistency and heterogeneity will be explored. ETHICS AND DISSEMINATION: Ethics approval for this project has been granted by the University of Sydney Human Research Ethics Committee (2018/886). Results will be relevant to clinicians, guideline developers and policy-makers, and will be disseminated via publications, presentations and media releases. REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR) (ACTRN12619001305112) and International Prospective Register of Systematic Reviews (PROSPERO, CRD42019136640).