Consider the Source is a new series of interviews with prominent researchers working to improve the health outcomes of women and infants around the time of childbirth.

A member of the faculty at the University Rhode Island, Judith Mercer, PhD, CNM, FACNM, is the Principal Investigator on a randomized controlled trial at Women & Infants Hospital examining the effects of delayed cord clamping on outcomes of preterm, very low birth weight babies. She and her multi-disciplinary research team reported short-term outcomes in 2006 in the journal Pediatrics, and outcomes of infants at 7 months of age appear in an upcoming issue of the Journal of Perinatology.

Dr. Mercer graciously agreed to be the first to participate in our Consider the Source series, answering questions about her research in honor ofNational Prematurity Awareness Monthand the March of Dimes' Bloggers Unite to Fight for Preemies Event. I especially appreciate Dr. Mercer's research journey because it started with her observations of physiological birth. Her quest to more deeply understand normal physiology led her to improve care for sick and high-risk babies. Lamaze International would like to express our gratitude to Dr. Mercer, her research colleagues, and her collaborators at Women & Infants Hospital.

Science & Sensibility: You have studied how timing of umbilical cord clamping affects health outcomes in preterm infants. What compelled you to study this?

Judith Mercer: In 1975, I vividly remember reading Frederick Leboyer's book Birth Without Violence in which he advocates not cutting the umbilical cord until the infant has successfully completed her transition between her two worlds ' the fetal world of water and placental respiration and the neonatal world of air and breathing. He says 'For a few minutes the baby straddles two worlds... then, slowly, slowly she can cross the threshold from one to the other peacefully and easily with safety... as long as we don't interfere [by premature clamping of the cord].' I adopted the practice of delaying cord clamping to ensure a more gentle birth and have used it for more than 30 years.

I had an epiphany at a home birth in 1979. An infant was born very rapidly with the cord 2 and 1/2 times around his neck. He was as pale as the white sheet his mother had on her bed and limp and breathless. I was very afraid that I would not be able to resuscitate him. I placed him on the bed and immediately unwrapped the cord from around his neck and dried and stimulated him with no response. His heart rate was well over 100 and the cord was pulsating vigorously. I noticed that his color was changing from the pale white to pink as his body gained the blood back into it. His heart rate was always over 100. In about 1 and 1/2 minutes, he flexed his extremities, opened his eyes and took a gentle breath. He looked at us like 'What is the fuss?' and never cried. I tried as hard as I could to get him to cry as I believed at that time that he should do but I could not get him to. He nursed very well and was a normal child at one year of age when I last saw him.

I knew that I had seen a miracle and one that I would never have seen in the hospital. In the hospital, we would have cut the cord and taken the infant to a warmer to resuscitate him. In doing so, we would have denied him exactly what he needed - the opportunity for the blood squeezed out of him in the birth process due to the tight cord around his neck to flow back into his body. This event marked the beginning of my research career. I vowed that at some point in my life I would research what I had seen but did not fully understand.

So it was my personal clinical experience that lead me into my area of research. When I began to ask colleagues and other practitioner about their cord clamping practices, I found a wide variation in practice and beliefs. When I turned to the literature, I found a general lack of evidence-based recommendations for cord clamping practice. All appeared to be opinion-based or based on flawed or inconsistent research findings. Yet, at the same time, I noticed that the etiology of many newborn problems was not known and remain unknown today. The symptoms are often the opposite of what happens when one delays cord clamping. I also noticed that these problems rarely occur in settings where the infant has a normal physiologic transition. I wondered if immediate cord clamping may be causing some of these problems.

After midwifery jobs with no opportunity to do research, I joined the faculty at the University of Rhode Island where Dr. Margaret McGrath, a well-funded nurse-scientist, offered to mentor me. She introduced me to Dr. William Oh at Women and Infants Hospital who agreed to sponsor me. With their excellent support, I was able to build my research program.

In 2001, I published an integrative review of the literature on delayed versus immediate cord clamping and found many controlled trials demonstrating beneficial effects of delayed clamping in both term and preterm babies. These included increased blood volume of up to 40%, reduced likelihood of anemia, increased blood flow to vital organs and higher body temperatures in the delayed clamping groups. None of the studies demonstrated harm from delayed clamping and none replicated findings from a poorly-controlled - but often cited - study done in the 1960's that showed more jaundice and polycythemia in infants with delayed clamping.

At URI, I developed, with a colleague from Rochester, NY, the Blood Volume Model for Neonatal Transition and published Neonatal Transitional Physiology: A New Paradigm. While theoretical, it is entirely based on solid research from many different studies. We sought to develop a cohesive theoretical model that explained the relationships among oxygen transport, red blood cell volume, and initiation of breathing, and predicted the effects of early versus delayed cord clamping. We think that in the first one to two minutes, blood plays a larger role in physiological transition than air and that interrupting the process can harm the infant.

Judith Mercer, PhD, CNM

Based on these findings, my colleagues at URI, collaborators at Women and Infants Hospital, and I decided to do a pilot randomized controlled trial of delayed versus immediate cord clamping in babies born between 24 and 32 weeks. We had funding from the University and our local chapter of Sigma Theta Tau. We chose to focus on preterm infants because these infants have many problems after birth. Prevention or reduction in the occurrence of any of these problems would make a huge impact. Also, the preterm infants are followed very closely in our developmental follow-up clinic so we could examine their outcomes in a cost-effective manner.

Doing a small pilot allowed us to test the feasibility of a larger trial, develop an appropriate protocol and determine how many mothers we would need to recruit in the larger trial. Our study design proved feasible and findings were promising. We did not detect any harms of delayed clamping and the 16 babies in the delayed clamping group had higher blood pressure, higher initial blood glucose, and were less likely to be discharged on supplemental oxygen. With these initial findings, we were able to secure funding from the National Institute of Nursing Research for a larger clinical trial.

Science & Sensibility: How did you design the randomized controlled trial? What were your findings? Were there any surprises?

Judith Mercer: All women admitted to Women and Infants' Hospital between 24 and 31.6 weeks gestation with symptoms of preterm labor were candidates for inclusion in the study. From these women, 72 very low birth weight (VLBW) infants were delivered and represent the sample. Since gestational age is a major risk factor for preterm infants, we used block stratified randomization to assign the intervention to the subjects above and below 28 weeks with a pre-specified equal probability to help avoid unequal numbers of participants in each gestational age group as the study progressed. Exclusion criteria included: obstetrician's refusal to participate, prenatally-diagnosed major congenital anomalies or multiple gestations, intent to withhold or withdraw care, frank vaginal bleeding or placenta abruption, placenta previa. Women had to be admitted to the hospital at least 2 hours before delivery to allow time for screening enrollment.

Just prior to birth, eligible patients were randomized to receive either standard care (immediate cord clamping (ICC)) or the intervention (delayed cord clamping (DCC)). For the standard care group, the obstetrician clamped the umbilical cord immediately (< 5-10 seconds) For the intervention group, the obstetrician clamped the cord at 30 to 45 seconds and held the infant in a sterile towel or blanket approximately 10-15 inches below the mother's introitus or incision. Care was taken that no tension or traction was placed on the cord. A stopwatch was used to mark the time of birth and then the time elapsed was counted out in ten second intervals to the obstetrician. At 30 to 45 seconds, the obstetrician clamped and cut the umbilical cord, and the infant was moved to the warmer for neonatology management.

If the baby appeared jeopardized in any way, the obstetrician could alter the protocol for the safety of the infant and a protocol violation form was completed although no protocol violations occurred because of an infant's appearance. The subsequent clinical management of the infants was at the discretion of the neonatologists. Because of the obvious nature of the intervention, the study could not be blinded to those at the birth. Due to safety considerations for the infant, pediatric staff was always in attendance. However, staff who attended each birth adhered to the principal investigator's request not to reveal the infant's grouping in the infants' medical records.

Research assistants who were registered nurses and the Principle Investigator (PI) shared an on-call schedule to screen potentially eligible women, enroll them, or attend the births of enrolled women. Women had equal probability of assignment to the groups.

The primary outcomes we considered, based on our previous research and that of other researchers, were oxygen use at 36 weeks gestational age and suspected or confirmed necrotizing enterocolitis (NEC). We found no statistically significant differences between the groups in these primary outcomes. But additional planned data analyses revealed the most exciting findings. Infants in the delayed cord clamping group were found to have fewer incidences of any level of intraventricular hemorrhage (IVH) defined by the reports of cranial ultrasounds routinely ordered during the first 28 days in the NICU. The incidence of IVH was equally divided between the stratified groups (ICC 7/7, DCC 2/2) although the majority occurred in infants less than 30 weeks gestation. One infant in the DCC group was a protocol violation, meaning that the cord was clamped prior to 30 seconds in violation of the study protocol. In addition, infants in the DCC group were less likely to have blood culture-proven (confirmed) sepsis during the NICU stay.

For our follow-up study, we saw surviving babies at an average age of 7 months corrected age at our clinic. Trained, certified psychologists administered a validated test for motor and mental development, known as the Bayley Scales of Infant Development-II (BSID-II). A physician or nurse practitioner also conducted a complete medical history and physical examination. The staff was masked to the assigned study groups. In this phase of the study, we found no overall differences in the BSID scores between the DCC and ICC groups. However, after controlling for several factors, male infants in the DCC group had higher motor scores. Preterm male infants are known to be at higher risk for mortality and developmental delay than female infants, a phenomenon that is not well understood. Our study suggested that delayed cord clamping may be protective against motor delay in preterm male infants.

Science & Sensibility: Immediate cord clamping is the standard of care and is stubbornly defended despite a growing body of evidence of its harms. Did the attitudes of care providers or other staff get in the way of the conduct of your study? Have attitudes changed at your facility since the study began?

Judith Mercer: Due to the excellent cooperation of the obstetricians, fellows and residents, there were only 7 protocol violations. Six occurred in the DCC group with cord clamping time and were mainly as a result of miscommunication.

This study was a Phase I trial. Phase I trials are generally small and test the safety of a particular intervention. Institutional changes are not usually instituted on the basis of outcomes from a Phase I study. We used the information gained from this study to design a Phase II study which tests the protocol on a much larger group. We were awarded a $2.5 million dollar grant from NIH, National Institute for Nursing Research, to carry out this study which is now underway. Our sample size is 212 infants and we are current almost half-way through. To determine the mechanism of effect, we will measure red cell volume, cytokines, and stem cells, each of which may play a role. We expect that this trial will confirm our findings and we hope it will also help us understand why IVH is more common with immediate clamping.

Science & Sensibility: What other research is needed to improve transitional care of newborns? What studies are you hoping to conduct next?

Judith Mercer: In addition to our Phase II trial, a group of Australian neonatologists and others is beginning a large government-funded multi-center trial on delayed cord clamping in preterm infants. I serve on there advisory board. They plan to publish a meta-analysis of their data, my data, and any other data generated in the meantime.

My colleague, Dr. Debra Erickson-Owens and I plan to submit a proposal to fund research on term infants in the near future. Well designed trials and meta-analyses have documented more anemia of infancy at two and three months in full-term infants with immediate cord clamping. Betsy Lozoff, MD, at the University of Michigan has documented a relationship between anemia and poorer developmental outcomes in several publications displaying her body of work. She had found that perinatal iron deficiency harms the developing brain in animal studies interfering with the myelination that must take place in the first few months of life for the brain to develop fully. She was able to demonstrate poorer behavioral and developmental outcome (10 points less IQ when controlling for confounding variables) more than 10 years after treatment for iron deficiency in infancy. She also found evidence of altered central nervous system development in infants with iron deficiency anemia at 6 mo in that they had delayed maturation of auditory brainstem responses. These findings raise concern about possible adverse developmental and behavioral effects from immediate cord clamping, but no one has studied these effects, which we are planning to do. As with the preterm study, we plan to conduct a pilot study on full term infants and, later, a funded full study.

Published: November 16, 2009

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