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New Cochrane Review: Delayed Cord Clamping Likely Beneficial for Healthy Term Newborns

July 25th, 2013 by avatar

By Mark Sloan, M.D.

Last fall, Dr. Mark Sloan wrote an extremely well-received post on Science & Sensibility, Common Objections to Delayed Cord Clamping; What’s the Evidence Say? that both professionals and consumers could use to understand and discuss the benefits of delayed cord clamping. From that post, we read that early cord clamping is an intervention that needs to change.  Yet, early cord clamping is still observed in L&D rooms across the United States, despite the mounting evidence for waiting at least 1-3 minutes before clamping occurs.  A new Cochrane review was just released in July, 2013, and I am grateful to Dr. Sloan for summarizing this review and sharing the  new information on this topic. – Sharon Muza, Community Manager, Science & Sensibility

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flickr.com/photos/lovemybunnies/4740682244/

A new Cochrane review of the timing of cord clamping in healthy term neonates was released earlier this month: Effect of timing of umbilical cord clamping of term infants on mother and baby outcomes. It’s an update of a 2009 review on the subject, and the language is more pro-delayed cord clamping (ie, clamping the cord at 1-3 minutes after birth) this time around. Here’s an excerpt from the Author’s Conclusions:

 “A more liberal approach to delaying clamping of the umbilical cord in healthy term infants appears to be warranted, particularly in light of growing evidence that delayed cord clamping increases early haemoglobin concentrations and iron stores in infants. Delayed cord clamping is likely to be beneficial as long as access to treatment for jaundice requiring phototherapy is available.”

To understand why this change in emphasis since the 2009 Cochrane review is important, let’s first look at why the timing of cord clamping is important to newborns, how current obstetric practice came to be, and what the Cochrane review did (and didn’t) find. 

A brief physiology review

At term, roughly 1/3 of a fetus’s blood supply resides in the placenta. In the course of labor and delivery, much of that blood is transfused from the placenta into the fetus/newborn, driven by the force of uterine contractions. That transfusion continues beyond the moment of birth; if left undisturbed for 1 to 3 minutes, the placenta will deliver about three additional ounces of blood to the newborn.

That may not sound like much, but three ounces of blood is equivalent to a three month supply of iron for the newborn. Iron is critical to brain growth and development; iron deficiency is a known cause of cognitive and social-emotional deficits in infants, which may be permanent. As breast milk alone may not supply a baby with all the iron he or she needs, it’s that additional iron that makes delayed cord clamping (DCC) so important. 

A brief history of cord clamping

Until the relatively recent past, the umbilical cord was generally allowed to stop pulsating before it was cut and tied off. Aristotle and Hippocrates, among many other medical and science writers, wrote approvingly of the practice. The first mention of early cord clamping (ECC)—cutting the cord before pulsation has ceased—is found in the 1600s, when management of the third stage of labor changed with the rise of male midwives, flat-on-the-back birthing practices, and forceps. 

Though ECC gained in popularity, controversy dogged the practice from the beginning. To give just one example, the prominent British physician Erasmus Darwin (Charles’s grandfather) condemned the practice, declaring in 1801 that early cord clamping was “a very injurious thing” that left babies “much weaker than [they] ought to be.” 

Despite ongoing objections, ECC became the obstetrical standard of care in the mid-1960s, promoted primarily as a tool to prevent maternal postpartum hemorrhage (PPH). Though subsequent research has shown that ECC is of no benefit in postpartum hemorrhage (PPH) prevention, the practice remains a firmly entrenched part of obstetrical care in the U.S. 

What did the 2013 Cochrane review find?

The review found that DCC babies had significantly higher body iron stores than ECC babies, an increase that persisted for months.

What didn’t the Cochrane review find?

Maternal adverse outcomes: The review found no significant ECC-versus-DCC differences in any maternal outcomes, including postpartum hemorrhage, length of the third stage of labor, need for blood transfusion, and need for manual removal of the placenta.

Neonatal adverse outcomes: Similarly, with the single exception of a slight increase in the need for phototherapy to treat hyperbilirubinemia (discussed below), there were no significant differences between ECC and DCC babies in neonatal outcomes such as mortality, Apgar scores < 7 at five minutes, need for resuscitation, NICU admission, respiratory distress, polycythemia, and clinical jaundice.

The apparent association between DCC and an increased need for phototherapy is a bit controversial. As pointed out by Dr. Judith Mercer, an expert on the benefits of delayed clamping, this concern is based largely on a single unpublished 1996 study performed by one of the Cochrane review’s authors (McDonald).  McDonald’s study is one of only two of the nearly forty studies considered for inclusion in the current review that includes unpublished data; when that data is removed, the difference between groups loses significance.   

Of note, the two studies added since the 2009 review found no association between delayed clamping and hyperbilirubinemia requiring phototherapy (Al-Tawil 2012, Andersson 2011). It should also be pointed out that none of the babies in these studies was harmed by hyperbilirubinemia. All recovered completely; there were no cases of kernicterus—brain damage caused by severe neonatal jaundice.

Whatever the case regarding delayed clamping and phototherapy, there’s no doubt that iron deficiency in infancy can lead to permanent cognitive and social-emotional deficits. The global benefits of increased iron stores during a critical period of brain development would seem to outweigh that concern.

The bottom line

For healthy term babies, a delay of 1-3 minutes before cord clamping has been shown to increase neonatal iron stores at a critical period of brain development, with virtually no risk of harm to mother and baby. Conversely, there is no convincing argument in support of clamping the umbilical cord before a minute of age.

Given that ECC has been shown to have no impact on maternal PPH, and that it offers no demonstrable benefit to healthy term newborns (and may in fact be harmful, by reducing body iron stores during a critical period of brain development), the question isn’t “Why switch to delayed cord clamping?” It’s this: “Why continue to intervene?”

Will obstetric practice change? Not immediately, if the recent Huffington Post comments of Dr. Jeffrey Ecker, ACOG chair of obstetric practice, are any indication: 

“Over time, I believe we’ll see an evolution in practice with appropriate women and babies — babies that don’t otherwise need immediate attention,” Ecker said. “I don’t think it is all going to change in a year. But in five, 10 years, we’ll look back and say, ‘Boy, this is different.’”

The best way to speed up that process is for pregnant women and providers of maternity care services to press their local hospitals for change now.

References

Al-Tawil, M. M., Abdel-Aal, M. R., & Kaddah, M. A. (2012). A randomized controlled trial on delayed cord clamping and iron status at 3–5 months in term neonates held at the level of maternal pelvis. Journal of Neonatal-Perinatal Medicine5(4), 319-326.

Andersson, O., Hellström-Westas, L., Andersson, D., & Domellöf, M. (2011). Effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months: a randomised controlled trial. BMJ: British Medical Journal343.

California WIC Association and the UC Davis Human Lactation Center. (2012) Maternity Care Matters; Overcoming Barriers to Breastfeeding. A Policy Update on California Breastfeeding and Hospital Performance. Retrieved from http://calwic.org/storage/restricted/hospitalreport/Maternity%20Care%20Matters_2012.pdf

McDonald, S. J., Middleton, P., Dowswell, T., & Morris, P. S. (2013). Effect of timing of umbilical cord clamping of term infants on mother and baby outcomes. Health.

Pearson, Catherine. “Cord Clamping: How Delaying Helps Babies.” The Huffington Post. TheHuffingtonPost.com, 11 July 2013. Web. 24 July 2013.

About Mark Sloan, MD

Mark Sloan has been a pediatrician and a Fellow of the American Academy of Pediatrics for more than 25 years. Since 1982, he has practiced with the Permanente Medical Group in Sacramento and Santa Rosa, California, where he was Chief of Pediatrics from 1997 to 2002. He is an Assistant Clinical Professor in the Department of Community and Family Medicine at the University of California, San Francisco. Dr. Sloan’s first book, Birth Day: A Pediatrician Explores the Science, the History and the Wonder of Childbirth was published in 2009 by Ballantine BooksHis writing has appeared in the Chicago Tribune, the San Francisco Chronicle, the San Francisco Examiner, and Notre Dame Magazine, among other publications.  Dr. Sloan can be reached through his blog.

 

Babies, Childbirth Education, Delayed Cord Clamping, Do No Harm, Evidence Based Medicine, Guest Posts, informed Consent, Medical Interventions, New Research, Newborns, Practice Guidelines, Research, Third Stage , , , , , , , , ,

Common Objections to Delayed Cord Clamping – What’s The Evidence Say?

November 13th, 2012 by avatar

by Mark Sloan M.D.

Today’s guest post is written by Dr. Mark Sloan, pediatrician and author of Birth Day: A Pediatrician Explores the Science, the History and the Wonder of Childbirth.  Dr. Sloan shares information and current research on delayed cord clamping after birth, in a helpful Q&A style format that consumers and professionals can use to discuss this important topic.

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photo credit pattiramos.com

Many maternity care providers continue to clamp the umbilical cord immediately after an uncomplicated vaginal birth, even though the significant neonatal benefits of delayed cord clamping (usually defined as 2 to 3 minutes after birth) are now well known.

In some cases this continued practice is due to a misunderstanding of placental physiology in the first few minutes after birth. In others, human nature plays a role: We are often reluctant to change the way we were taught to do things, even in the face of clear evidence that contradicts that teaching.

Though there is no strong scientific support for immediate cord clamping (ICC), entrenched medical habits can be glacially slow in changing. Here are some often-heard objections to delayed cord clamping (DCC), and how an advocate for delayed clamping might respond to them:

1) I have a very busy practice. DCC takes too much time!

Not really, especially when you consider the benefits. Nearly one-third of a baby’s total blood volume resides in the placenta at birth. Half of that blood is transfused into the baby by 1 minute of age. By 3 minutes, more than 90% of the transfusion is complete. (1)

 2) Immediate clamping helps prevent severe postpartum hemorrhage.

There is no convincing evidence to support this view. Several large studies, including a 2009 Cochrane review of 5 trials involving more than 2,200 women, have found no significant difference between ICC and DCC in terms of postpartum hemorrhage or severe postpartum hemorrhage. (2-6, 10)

 3) A healthy, term baby doesn’t get much benefit from delayed clamping.

Though this is a commonly held belief, it’s definitely untrue.

Whether a fetus is premature or full term, approximately one-third of its total blood volume resides in the placenta. This is equal to the volume of blood that will be needed to fully perfuse the fetal lungs, liver, and kidneys at birth.

In addition to the benefits that come with adequate iron stores (see below), babies whose cords are clamped at 2 to 3 minutes—and thus, who have an increased total blood volume compared with their immediately-clamped peers—have a smoother cardiopulmonary transition at birth.

A third benefit: stem cells, which play an essential role in the development of the immune, respiratory, cardiovascular, and central nervous systems, among many other functions. The concentration of stem cells in fetal blood is higher than at any other time of life. ICC leaves nearly one-third of these critical cells in the placenta. (1,3,4,6-10)

Unclamped cord over the course of 15 minutes.
photo nurturingheartsbirthservices.com

 4) Okay, so delayed clamping means a baby gets more blood and more iron. But iron deficiency isn’t really a problem in first-world countries, right?

Wrong. At least 10% of the general U.S. toddler population (1-3 years of age) is iron deficient, with the prevalence rising well above 20% in selected ethnic and socioeconomic populations.

Immediate cord clamping is only one of many factors that contribute to iron deficiency in early childhood. But babies who start out life low on iron have a very difficult time catching up. Delayed cord clamping provides a baby with as much as a 4- to 6-month supply of iron. (1,3,6-10)

 5) Doesn’t iron deficiency just make kids tired?

Iron deficiency does much more damage than that. Early infancy is a time of rapid brain growth and development, and iron is essential to that process. Studies of infants with iron deficiency have found specific deficits in cognitive processing (including attention and memory) which may lead to permanently decreased intellectual functioning. Making matters even worse, children with severe iron deficiency often exhibit “emotional dulling”—difficulty engaging with caretakers and their environment—which can lead to long-lasting social-emotional deficits. For many reasons, early infancy is a particularly bad time to be low on iron. (1,11)

 6) Don’t babies get plenty of iron from breast milk? 

Unfortunately, no. While breast milk contains a remarkable array of healthful components, a high concentration of iron isn’t one of them. This most likely has to do with maternal recovery from childbirth. A recuperating mother has her own urgent iron needs; replacing the blood typically lost in childbirth takes a lot of it. Nature intends babies to get most of the iron they’ll need for their early development from the placental blood reservoir, rather than from mother, and so comparatively little iron goes into breast milk.  (3,7)

 7) But the baby can lose significant blood volume back into the placenta (aka “backflow bleeding”) if clamping is delayed.

This is extremely unlikely in an uncomplicated birth. With some brief exceptions (e.g., between uterine contractions, or when a baby bears down during crying), blood flow immediately after birth is primarily one-way, from placenta to baby. Here’s a brief explanation of why this is true:

In a process that begins during labor and accelerates as the newborn begins to cry, the pulmonary blood vessels, which receive very little blood flow during pregnancy, open and fill. This relatively sudden change causes the newborn’s blood pressure to fall below the pressure in the placenta. Placental blood, driven by strong uterine contractions, follows the pressure gradient and flows through the umbilical vein into the baby.

As the newborn’s oxygen saturation increases, the umbilical arteries close, which stops nearly all blood flow from baby to placenta. The umbilical vein, which isn’t sensitive to oxygen, remains open somewhat longer, allowing a final bit of blood to flow from placenta to baby before it, too, closes.

The lack of significant “backflow bleeding” is confirmed by the fact that DCC results in ~ 30% greater neonatal blood volume than does ICC.  (1,12)

8) DCC can lead to dangerously high levels of neonatal jaundice.

Since bilirubin, the source of neonatal jaundice, originates in red blood cells, it seems logical that the increased blood volume associated with delayed clamping could lead to severe hyperbilirubinemia.

Yet while some studies have demonstrated mildly increased bilirubin levels in DCC babies in the first few days postpartum, most have found no significant difference between DCC and ICC.

This seeming paradox—relatively stable bilirubin levels in the face of substantially increased blood volume—may have to do with increased blood flow to the neonatal liver that comes with the higher total blood volume associated with DCC. Yes, more blood means more bilirubin, which in turn could mean more jaundice, but better blood flow allows the liver to process bilirubin more efficiently.  (3,4,6,7,9,10)

 9) Delayed clamping can lead to neonatal hyperviscocity—“thick blood” that can cause kidney damage and strokes.

DCC can lead to a somewhat higher neonatal hematocrit than ICC, which isn’t surprising given the additional blood volume. Yet, despite fears of thicker blood “sludging” in organs like the brain and kidneys, no studies have demonstrated this to be the case from DCC alone. (4,6,9,10)

 10) You can’t have both the benefits of DCC and immediate skin-to-skin contact. If you place a newborn on his mother’s abdomen (i.e., above the level of the placenta), gravity will reduce the flow of blood from placenta to baby.

Gravity does matter, but mainly in terms of the speed of the placental transfusion. A baby held below the level of the placenta will receive a full transfusion in about 3 minutes; one held above the placenta (e.g., a baby in immediate skin-to-skin contact) will also receive a full transfusion—it just takes a little longer (about 5 minutes). (1,13)

 11) But what if the baby needs resuscitation? Isn’t it best to hand her over to the pediatrician immediately?

One of the first things a truly sick baby in the NICU is going to receive is fluid support—often as a 20 to 40 ml/kg bolus of normal saline or blood. Yet that is exactly what’s left behind in the placenta with ICC—about 30 ml/kg of whole blood. There is considerable evidence that sick babies, both term and preterm, have better outcomes with DCC. It’s better to let nature do its own transfusing. (14-16)

Summary: 

Delayed cord clamping promotes a healthy neonatal cardiopulmonary transition, prevents iron deficiency at a critical time in brain development, provides the newborn with a rich supply of stem cells, and helps sick neonates achieve better outcomes—all with little apparent risk to mother or baby. The evidence of benefit from DCC is so compelling that the burden of proof must now lie with those who wish to continue the practice of immediate clamping, rather than with those who prefer—as nature intended—to wait.

What do you tell your patients, students and clients about delayed cord clamping?  Do you have a favorite resource or two that you like to share?  What are the community standards around delayed cord clamping in your community?  Are health care providers discussing this with their patients?  Do they have recommendations one way or another that you are hearing?  Please join in the discussion.- SM

References

1) Mercer JS, Erickson-Owens DA. Rethinking placental transfusion and cord clamping issues. Journal of Perinatal & Neonatal Nursing. July/September 2012 26:3; 202–217 doi: 10.1097/JPN.0b013e31825d2d9a

2) Andersson O, Hellstrom-Westas L, Andersson D, et al. Effects of delayed compared with early umbilical cord clamping on maternal postpartum hemorrhage and cord blood gas sampling: a randomized trial. Acta Obstetricia et Gynecologica Scandinavica. Article first published online: 17 Oct, 2012. DOI: 10.1111/j.1600-0412.2012.01530.x

3) Chaparro, CM. Timing of umbilical cord clamping: effect on iron endowment of the newborn and later iron status. Nutrition Reviews. Volume 69, Issue Supplement s1, pages S30–S36, November 2011.

4) Ceriani Cernadas JM, Carroli G, Pellegrini L, et.al. The Effect of Timing of Cord Clamping on Neonatal Venous Hematocrit Values and Clinical Outcome at Term: A Randomized, Controlled Trial. Pediatrics. Vol. 117 No. 4 April 1, 2006 pp. e779 -e786 (2,3 8,9(doi: 10.1542/peds.2005-1156). Published online March 27, 2006.

5) WHO. Department of Making Pregnancy Safer. WHO recommendations for the prevention of postpartum haemorrhage. Geneva: World Health Organization, 2007.

6) McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD004074. DOI:10.1002/14651858.CD004074.pub2.

7) Andersson O, Hellstrom-Westas L, Andersson D, Domellof M. Effect of delayed versus early umbilical cord clamping on neonatal outcomes and iron status at 4 months: a randomised controlled trial. British Medical Journal. 2011; 343: d7157. Published online 2011 November 15. doi:  10.1136/bmj.d7157

8) Ceriani Cernadas JM, Carroli G, Pellegrini L, et.al. The effect of early and delayed umbilical cord clamping on ferritin levels in term infants at six months of life: a randomized, control trial. Arch Argent Pediatr. 2010; 108:201-208.

9) Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007 Mar 21;297(11):1241-52.

10) McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD004074. DOI:10.1002/14651858.CD004074.pub2.

11) Carter RC, Jacobson JL, Burden MJ, et al. Iron deficiency anemia and cognitive function in infancy. Pediatrics. 2010; 126:2 pp e427-e434 (doi: 10.1542/peds.2009-2097).

12) Mercer JS, Skovgaard R. Neonatal Transitional Physiology: A New Paradigm. J Perinat Neonat Nursing 2002; 15(4) 56-75

13) Yao AC, Lind J. Effect of gravity on placental transfusion. Lancet. 1969; 2:505-508.

14) Mercer JS, Vohr BR, Erickson-Owens DA, et al. Seven-month developmental outcomes of very low-birth-weight infants enrolled in a randomized controlled trial of delayed versus immediate cord clamping. J Perinatol. 2010; 30:11-16.

15) Kinmond S, Aitchison TC, Holland BM, et al. Umbilical cord clamping and preterm infants: a randomized trial. British Medical Journal. 1993; 306:172-175.

16) Rabe H, Wacker, A, Hulskamp G, et al. A randomized controlled trial of delayed cord-clamping in very low-birth-weight preterm infants Eur J Pediatr. 2000; 159:775-777.

About Mark Sloan, M.D.

Mark Sloan has been a pediatrician and a Fellow of the American Academy of Pediatrics for more than 25 years. Since 1982, he has practiced with the Permanente Medical Group in Sacramento and Santa Rosa, California, where he was Chief of Pediatrics from 1997 to 2002. He is an Assistant Clinical Professor in the Department of Community and Family Medicine at the University of California, San Francisco. Dr. Sloan’s first book, Birth Day: A Pediatrician Explores the Science, the History and the Wonder of Childbirth was published in 2009 by Ballantine BooksHis writing has appeared in the Chicago Tribune, the San Francisco Chronicle, the San Francisco Examiner, and Notre Dame Magazine, among other publications.  Dr. Sloan can be reached through his blog.

 

American Academy of Pediatrics, Delayed Cord Clamping, Do No Harm, Evidence Based Medicine, Healthy Birth Practices, Healthy Care Practices, informed Consent, Medical Interventions, Newborns, Research, Third Stage, Uncategorized , , , , , , , , , ,

Consider the Source: An interview with Cord Clamping Researcher, Judith Mercer

November 17th, 2009 by avatar

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.

2ndLeveldo_badge1Dr. Mercer graciously agreed to be the first to participate in our Consider the Source series, answering questions about her research in honor of National Prematurity Awareness Month and 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, DNSc, CNM

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.

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