Timing of umbilical cord clamping: effect on iron endowment of the newborn and later iron status
CM Chaparro, FANTA-2/FHI D360, 1825 Connecticut Ave NW, Washington DC 20009-5721, USA. E-mail: email@example.com, Phone: +1-202-884-8011; Fax: +1-202-884-8432.
The optimal timing of umbilical cord clamping has been debated in the scientific literature for at least the last century, when cord clamping practices shifted from delayed towards immediate clamping. Recent research provides evidence for the beneficial effect of delayed cord clamping on infant iron status. The present review describes the physiological basis for the impact of cord clamping time on total body iron at birth and the relationship between birth body iron, as affected by cord clamping time, and iron status later in infancy. This research is discussed in the context of current clamping practices, which tend towards early cord clamping in most settings, as well as the high levels of anemia present in young infants in many countries worldwide.
Over two centuries ago, Erasmus Darwin (a respected physician, philosopher, botanist, and the grandfather of Charles Darwin) noted the importance of not clamping the umbilical cord too soon after delivery to ensure the well-being of both mother and infant: “Another thing very injurious to the child, is the tying and cutting [of] the navel-string too soon; which should always be left till the child has not only repeatedly breathed, but till all pulsation in the cord ceases. As otherwise the child is much weaker than it ought to be; a part of the blood being left in the placenta, which ought to have been in the child. . .”.1
Approximately one century later, starting in the early 1900s, obstetric practices shifted from delayed umbilical cord clamping (i.e., 2–3 min after birth or at the end of cord pulsations), which was the standard practice at the time, towards early umbilical cord clamping (i.e., 10–15 s after birth). The debate about which practice is more beneficial for the infant and, to a lesser extent, the mother has been documented in the scientific literature since at least that time. In recent years, the emphasis on “evidence-based” medicine has reinvigorated the debate and spurred new research to investigate the scientific justification for the optimal timing of umbilical cord clamping. While Darwin in 1801 most likely spoke from personal experience as a physician, increasing evidence from scientific trials conducted in the present day indicate that his advice of not “tying and cutting . . . the navel string too soon” confers beneficial effects to the newborn infant, among which improved infant iron status figures prominently. The current article reviews the importance of newborn iron endowment for later iron status, the physiology of the placental transfusion and how cord clamping time affects newborn iron endowment, the evidence-base for the effects of cord clamping time on iron status later in infancy, and current cord-clamping practices.
IMPORTANCE OF IRON ENDOWMENT AT BIRTH FOR LATER IRON STATUS
During gestation, iron is actively transported across the placenta to the fetus.2 This ensures that healthy infants born at term with adequate birth weight will generally have high total body iron (TBI) at birth, both in circulation and in stores. In healthy term infants, TBI is estimated to be approximately 75 mg/kg body weight3; for comparison, the iron content of an adult male is approximately 55 mg/kg body weight.4 Hemoglobin levels in newborns (approximately 170 g/L) are higher than at any other life stage, and hemoglobin constitutes roughly 70% of a newborn's TBI. The other significant portion (approximately 25%) is stored in ferritin, while the remaining portion (approximately 5%) is found in myoglobin in muscle and other tissues, and in iron-containing enzymes.5 After birth, the greater availability of oxygen outside of the womb makes the newborn's high hemoglobin concentration, which was important for adequate oxygen delivery in utero, unnecessary, and red blood cell production slows in response. Combined with the shorter lifespan of fetal red blood cells, these two factors result in a decrease in hemoglobin concentration during the first weeks of life. The heme iron recycled from senescent red blood cells is stored in ferritin. Thus, the iron stores present at birth, as well as the recycled heme iron added to stores during this period of redistribution, will form the main source of iron during the period of exclusive breastfeeding (from 0 to 6 months of life), as breast milk is not a rich source of iron. Factors that affect accumulation of iron during gestation (e.g., maternal iron status), or that affect the total amount of iron present in circulation as hemoglobin at birth (e.g., timing of umbilical cord clamping), will therefore have an impact on the length of time during infancy that an infant has sufficient iron for adequate growth and development, and for the prevention of iron deficiency (ID) and anemia. Under conditions in which maternal iron status, birth weight, gestational age, and umbilical cord clamping time are optimal, and exclusive breastfeeding is practiced, infants should have adequate iron stores for the first 6–8 months of life, thus preventing the onset of ID and anemia.6 From nationally representative data collected by the Demographic and Health Surveys, a high percentage of infants worldwide are anemic by 6–9 months of age (Table 1). While ID is but one of many possible causes of anemia, it is estimated to be the principal cause of anemia in this age group, contributing to roughly 50% of anemia cases.7 Anemia is the last, most severe stage of ID, and high numbers of anemia would imply an even greater prevalence of ID.
Table 1. Worldwide prevalence of anemia in children between 6 and 9 months of age.
|Sub-Saharan Africa|| |
| Angola 2006–07||74|
| Benin 2006||85|
| Burkina Faso 2003||93|
| Cameroon 2004||84|
| Congo (Brazzaville) 2005||72|
| Congo Democratic Republic 2007||83|
| Ethiopia 2005||76|
| Ghana 2008||80|
| Guinea 2005||82|
| Lesotho 2004||65|
| Liberia 2009||81|
| Madagascar 2008–09||67|
| Malawi 2004||91|
| Mali 2006||87|
| Niger 2006||88|
| Rwanda 2007–08||74|
| Senegal 2008–09||81|
| Sierra Leone 2008||82|
| Swaziland 2006–07||66|
| Tanzania 2004||83|
| Uganda 2006||92|
| Zimbabwe 2005–06||81|
|North Africa/West Africa/Europe|
| Armenia 2005||75|
| Azerbaijan 2006||57|
| Egypt 2005||60|
| Jordan 2009||50|
| Moldova 2005||45|
|Central Asia|| |
| Kazakhstan 1999||23|
| Kyrgyz Republic 1997||53|
| Turkmenistan 2000||38|
| Uzbekistan 1996||59|
|South and Southeast Asia|| |
| Cambodia 2005||85|
| India 2005–06||81|
| Nepal 2006||81|
|Latin American and the Caribbean|
| Bolivia 2003||71|
| Haiti 2005–06||75|
| Honduras 2005||63|
| Peru 2000||59|
Several studies have shown that iron status at birth is a significant predictor of infant iron status and anemia later in infancy. In a study of Zimbabwean infants, TBI at birth was calculated as a sum of hemoglobin iron and body storage iron (estimated from plasma ferritin concentrations measured at birth).8 The odds of anemia at 6, 9, and 12 months of age were three times higher among infants in the lowest versus the highest quartile of TBI at birth. In a sample of infants in Zambia, two-thirds of infants were determined to have low iron stores at birth (as measured by zinc protoporhyrin levels and mean cell hemoglobin concentration in cord blood), and 50% of infants had developed anemia by 6 months of age.9 The relationship between body iron at birth and later iron status is not limited to developing countries, however; in studies of Danish and Norwegian children followed from birth to 1 or 2 years of age, respectively, ferritin concentrations in cord blood remained a significant predictor of iron status throughout this period.10,11 In the Norwegian sample, children born with serum ferritin values in the lowest quartile had a significantly greater risk of having a low serum ferritin value at 6 months of age.11
TIMING OF CORD CLAMPING AND PHYSIOLOGY OF PLACENTAL TRANSFUSION
The timing of cord clamping is important for TBI at birth because, for a period of time after birth, circulation continues between the infant and the placenta through the umbilical vein and arteries. The time at which the cord is clamped in relation to this circulation will therefore have profound effects on infant blood volume at birth, and subsequently, the contribution of hemoglobin iron to newborn TBI. Though there are many terms and definitions used in the literature to describe the timing of cord clamping, “early” or “immediate” clamping is most commonly defined as when the cord is clamped within the first 10–15 s after delivery of the infant. “Delayed” or “late” cord clamping is most frequently defined as clamping that occurs 2 or 3 minutes after delivery of the infant, or at the point at which cord pulsations cease.
Natural closure of the umbilical vessels is thought to be dependent on many factors, some of which are hormones, prostaglandins, temperature, and oxygen saturation of cord blood. By measuring placental residual blood volume after clamping of the umbilical vein or arteries at various time points after delivery, it was shown that blood flows through the umbilical arteries (from the infant to the placenta) during the first 20–25 s after birth; in contrast, in the umbilical vein, blood flow continues from the placenta to the infant for up to 3 minutes after delivery.12 Thus, not clamping the cord immediately after delivery permits a “placental transfusion” to the infant. This placental transfusion occurs most rapidly in the first moments after birth – approximately 25% of the transfer occurs in the first 15–30 s, and between 50–78% will be completed after 1 min; it then gradually slows to completion by approximately 3 minutes.13 Not all placental blood is transferred to the infant; a small percentage remains in the placenta even after delayed cord clamping.14
Several studies conducted in the 1940s–1960s attempted to measure infant blood volume in full-term infants after different cord clamping times using a tracer-dilution technique.13,15–18 The estimated average placental blood transfer measured after delayed clamping in these studies was 18 mL of blood per kg body weight, ranging from 11 mL/kg to 26 mL/kg. However, the time at which these measurements were taken in several of the studies (more than 4 h after birth) could have affected these estimates. Because blood volume is tightly controlled, a plasma shift occurs from the intravascular to the extravascular spaces shortly after placental transfusion; thus, the timing of blood volume measurements is an important consideration. A more recent study, conducted in 1992 using a different blood volume estimation technique,19 calculated 35 mL of placental blood per kg of body weight transferred to the infant after a delay in clamping of at least 3 min. A small study conducted in 2009 of placental transfusion in 13 term infants delivered vaginally, found a median placental transfusion of 79 mL (interquartile range of 50–163 mL) as determined by weight measurements after birth.20 Assuming an average birth weight of approximately 3.2 kg, such a transfer would reflect a median placental transfusion of 25 mL/kg.
INFLUENCE OF DELAYED CORD CLAMPING ON IRON STATUS AT BIRTH AND LATER IN INFANCY
For a cord clamping delay of approximately 2–3 min in a full-term infant, about 25–35 mL blood per kg body weight is provided to the infant from the placental circulation. Assuming a hemoglobin concentration of roughly 170 g/L at birth, and an iron concentration in hemoglobin of approximately 3.4 mg/g, a roughly 3 kg infant, would receive 46–60 mg of iron as hemoglobin from this “placental transfusion.” If we estimate that a newborn infant requires approximately 0.7 mg of iron per day for growth and development, maintenance of hemoglobin levels and myoglobin and enzyme levels in muscle and other tissues,21 46–60 mg would be equivalent to roughly 1–3 months worth of infant iron requirements. Conversely, immediately clamping the umbilical cord will deprive the infant of a substantial portion of TBI at birth.
To date, 12 trials have examined the effects of cord clamping time on hematological or iron status outcomes past the neonatal period up to 6 months of age; 6 of those studies have been published in the last 5–6 years. Two recent systematic reviews have included the majority of these trials as well as others that focused on hematological and iron status outcomes in the neonatal period and later in infancy.22,23 Hutton and Hassan,22 from their review of 15 randomized controlled trials, found that a delay in clamping of the umbilical cord for a minimum of 2 min was beneficial for infant hematological and iron status through 6 months of age. The benefits of delayed cord clamping to hematological and iron status that were identified from this review included improved hematocrit (at 6 h, 24–48 h, 5 days, and 2 months of age), hemoglobin concentration (at 7 days and in one trial at 2 months of age), ferritin concentration (at 2, 3, and 6 months of age), as well as a clinically important reduction in the risk of anemia (at 24–48 h and 2–3 months of age). McDonald and Middleton23 examined both maternal and infant effects of cord clamping time and included several of the same trials reviewed by Hutton and Hassan,22 as well as unpublished data from the first author. Similar results were shown, i.e., improved newborn hemoglobin and improved ferritin levels through 6 months of life.23 The trial included in both previously mentioned reviews with the longest follow-up showed that infants whose cords were clamped at approximately 1½ min after birth had significantly higher iron status at 6 months of age than infants whose umbilical cords were clamped immediately (approximately 17 s after birth).24 At 6 months of age, in comparison to early-clamped infants, body storage iron was greater in delayed-clamped infants by approximately 27 mg of iron (the equivalent of 1¼ months of infant iron requirements). Infants who were at higher risk of developing ID during infancy, because of smaller size at birth (birth weight between 2,500 and 3,000 g) or because they were born to mothers with ID, derived a significantly greater benefit from a delay in cord clamping than infants born with birth weight > 3,000 g or to iron-replete mothers. Furthermore, infants who received delayed cord clamping had lower blood levels of lead, an effect due, in part, to improved iron status during infancy.25
Since the publication of these reviews, two additional studies have been published that examined the impact of cord clamping time on iron status during the first 6 months of life, and they conform with the results of previous trials.26,27 One randomized controlled trial in Brazil showed that infants who received delayed cord clamping at 1 min after delivery had significantly higher ferritin levels at 3 months of age in comparison to infants with immediate cord clamping.26 In Argentina, Ceriani-Cernadas et al.27 found that a delay in clamping of 3 min significantly increased infant ferritin values at 6 months of age in comparison to infants whose cords were clamped within the first 15 s after delivery. However, in contrast to the results from Brazil, where a 1-min delay was sufficient to increase ferritin values through 3 months of age, a third treatment group in the study from Argentina, whose cords were clamped at 1 min after delivery, did not have significantly different ferritin levels at 6 months of age compared with those who received immediate cord clamping. The authors speculate that this result could indicate that a delay longer than 1 min may be needed to derive maximum benefit for infant iron status; the authors also acknowledge that the study was not originally designed to examine outcomes at 6 months of age, and thus may not have been adequately powered to examine this outcome. In this same trial from Argentina, the group of infants with cord clamping at 3 min after delivery, were also three times less likely to have iron-deficiency anemia as compared to the infants with immediate clamping, though this difference did not reach significance (7.0% versus 2.4%).
While the previous discussion focused on term infants, the effect of cord clamping time on premature and low-birth-weight infants is an area of active research. Two recent systematic reviews28,29 have examined the evidence base for the impact of delayed cord clamping on multiple outcomes in the neonatal period, including hematological status, respiratory function, intraventricular hemorrhage, and sepsis. Both systematic reviews showed that premature infants (<37 weeks gestation) who received delayed cord clamping had greater hematocrit after birth, fewer transfusions for anemia or low blood pressure, greater circulating blood volume, and reduced incidence of intraventricular hemorrhage. Few studies have examined longer-term outcomes with regards to hematological or iron status in preterm/low-birth-weight infants. In one study of 37 infants of gestational age between 34 and 36 weeks, infants randomly assigned to receive clamping at 3 min after birth had significantly higher hemoglobin concentrations at 10 weeks of age, compared to the early-clamped group (mean of 13 s after birth).30 Though additional research is needed to fully examine the longer-term effects of clamping time in preterm infants, it is likely that these infants could receive significant long-term benefit from delayed cord clamping because of their increased risk of developing ID and anemia later in life due to their smaller iron reserves at birth (due to smaller birth size and premature birth) as well as their faster rate of growth during infancy.
It is important to mention that negative effects due to cord clamping (e.g., increased risk of polycythemia or jaundice in the infant, and increased maternal bleeding) are negligible for both the mother and the infant.22,23 Hutton and Hassan23 found that although delayed-clamped infants did have significantly higher hematocrit levels through the first 48 h following delivery, no clinical signs of polycythemia were reported. Clinical symptoms of polycythemia are generally required to warrant treatment, which may, in itself, have adverse risks.31 The same meta-analysis showed that delayed clamping did not significantly increase mean serum bilirubin, the incidence of clinical jaundice, or the number of infants requiring phototherapy. McDonald and Middleton23 found that significantly more delayed-clamped infants required phototherapy for jaundice than early-clamped infants; however, the criteria for the application of phototherapy in the included studies was not provided, nor was it clear whether it was standard across trials.
Because of the past inclusion of early cord clamping as part of the protocol for active management of the third stage of labor to prevent postpartum hemorrhage – a set of procedures promoted during the last two decades for the prevention of maternal postpartum hemorrhage32– a belief commonly exists among practitioners that delayed cord clamping will increase maternal bleeding. However, there is no evidence to support a relationship between cord clamping time (independent of other active management techniques) and postpartum hemorrhage. McDonald and Middleton's review of the cord clamping literature showed that the timing of cord clamping was not associated with blood loss at delivery, length of third stage of labor, or need for manual removal of the placenta.23
CURRENT CORD CLAMPING PRACTICES
As mentioned in the introduction, early cord clamping is believed to be the standard practice in many delivery settings, reflecting a change in practice that occurred early in the last century. Multiple factors contributed to this shift from delayed to early umbilical cord clamping. Some of these factors were associated with an overall progression of obstetrics towards more “interventionist” techniques and the movement of more births from the home into the hospital setting where “ligation of the cord makes it possible to get babies and mothers out of the delivery room more rapidly.”33 Other reasons that have been suggested for early clamping include the following: the fear of increasing hyperbilirubinemia and/or polycythemia in the late-clamped infant, the presence of a neonatologist or pediatrician in the delivery room anxious to attend to the infant, the rush to measure cord blood pH and gases, and the desire to place the infant in skin-to-skin contact with the mother as soon as possible.34 Previous protocols for active management of the third stage of labor included early cord clamping,32 which may have contributed to the transition to and maintenance of early cord clamping as a standard practice in many settings, including in developing countries.
Regardless of the particular reasons for the change in practices, several recent surveys (conducted between 1999 and 2008) of delivery care practices during the third stage of labor in healthcare facilities have revealed that in both developed and developing countries, early umbilical cord clamping tends to be the standard practice (Table 2). Though data are limited, these surveys also show that practices are not consistent within or between countries, nor even between practitioners in the same country. There appear to be no published studies on cord clamping time in home deliveries.
Table 2. Cord clamping practices in facility-based deliveries worldwide.
|Albania (Tirana)||27||Self-completed questionnaire||2008||<20 s||22||Bimbashi et al. (2010)39|
|Albania (Tirana)||156||Observation||2008||<20 s||85||Bimbashi et al. (2010)39|
|Bangladesh (multiple sites)||447||Observation||2008||<1 min||95||POPPHI/PATH (2006)40|
|China (Chengdu)||30||Observation||1999||“Immediately”||100||Festin et al. (2003)41|
|Colombia (Bogotá)||56||Observation||1999||“Immediately”||30||Festin et al. (2003)41|
|Egypt (Cairo)||176||Observation||2001||Not defined||93||Cherine et al. (2004)42|
|El Salvador (multiple sites)||190||Observation||2006||<1 min||71||POPPHI/PATH (2006)40|
|Ethiopia (multiple sites)||286||Observation||2006||<1 min||93||POPPHI/PATH (2006)40|
|Ghana (multiple sites)||322||Observation||2007||<1 min||67||POPPHI/PATH (2006)40|
|Guatemala (multiple sites)||172||Observation||2006||<1 min||90||POPPHI/PATH (2006)40|
|Honduras (multiple sites)||221||Observation||2006||<1 min||88||POPPHI/PATH (2006)40|
|India (Nagpur, Trivandrum, Vellore, New Delhi)||111||Observation||1999||“Immediately”||91||Festin et al. (2003)41|
|Indonesia (multiple sites)||408||Observation||2006||<1 min||81||POPPHI/PATH (2006)40|
|Indonesia (Semarang)||30||Observation||1999||“Immediately”||100||Festin et al. (2003)41|
|Nicaragua (multiple sites)||180||Observation||2006||<1 min||94||POPPHI/PATH (2006)40|
|Philippines (Manila)||30||Observation||1999||“Immediately”||87||Festin et al. (2003)41|
|Tanzania (multiple sites)||251||Observation||2006||<1 min||75||POPPHI/PATH (2006)40|
|Thailand (Khon Kaen, Bangkok)||60||Observation||1999||“Immediately”||88||Festin et al. (2003)41|
|UK (Dublin)||30||Observation||1999||“Immediately”||100||Festin et al. (2003)41|
|UK (national, obstetricians)||926||Self-completed questionnaire||2008||<20 s||74||Farrar et al. (2010)37|
|UK (national, midwives)||1,297||Self-completed questionnaire||2008||<20 s||41||Farrar et al. (2010)37|
|USA (national, midwives)||157||Self-completed questionnaire||1998||“Immediately”||26||Mercer et al. (2000)43|
|USA (Philadelphia)||30||Observation||1999||“Immediately”||97||Festin et al. (2003)41|
|Zimbabwe (Harare)||44||Observation||1999||“Immediately”||89||Festin et al. (2003)41|
In 2007, the World Health Organization modified their recommendations for active management of the third stage of labor for the prevention of postpartum hemorrhage and removed early cord clamping.35 The International Federation of Obstetricians and Gynecologists and the International Confederation of Midwives published a joint statement in 2006 for active management that no longer include early cord clamping.36 However, the most recent survey on cord clamping practices, conducted among midwives and obstetricians in the United Kingdom in 2008, showed that the most frequent request for additional evidence to guide third-stage management was in regards to the timing of cord clamping.37 Another survey of practitioners found that among those who continued to practice early cord clamping (preterm birth specifically), lack of knowledge of the benefits of delayed cord clamping was the most frequent justification for their practice.38
Infant TBI at birth – composed primarily of circulating hemoglobin iron and iron in stores – forms the main source of iron for infants during the first half of infancy. The timing of umbilical cord clamping has a profound effect on the amount of blood that remains in the infant's circulation at birth, and thus the amount of iron in hemoglobin. The importance of delayed cord clamping for iron status in the first 2–3 months through 6 months of age has been demonstrated in several randomized controlled trials; two recent systematic reviews concluded that delayed cord clamping is warranted in term infants due to the beneficial effects on infant iron status and the negligible negative effects on mothers or infants. However, recent surveys indicate that early cord clamping remains the standard of care in many delivery settings, in both developed and developing countries. Because infant iron status is most likely not the first outcome that comes to mind by a practitioner deciding when to clamp the cord, education and advocacy efforts on the part of the nutrition community are needed, so that appropriate cord clamping practices are adopted.
Declaration of interest. The author has no relevant interests to declare.