An estimated 140 million neonates are born worldwide every year1, contributing to our planet's growing population, which is currently over 8 billion people. With every birth, the umbilical cord needs to be managed. Several different strategies can be used to manage the umbilical cord at birth, including early cord clamping (or immediate cord clamping), delayed cord clamping (or deferred cord clamping) and umbilical cord milking. Early cord clamping (ECC) prevents the normal flow of oxygen-rich blood between the placenta and the newborn. Delayed cord clamping (DCC) typically involves waiting at least 30–60 seconds after the baby is born to clamp and cut the cord, which allows more blood to flow from the placenta to the baby. Umbilical cord milking (UCM), which can be performed through a cut or intact umbilical cord, is a technique that involves manually expressing umbilical cord blood from the umbilical cord by milking it 3-4 times along a 20-30 cm segment of the cord at a rate of 10 cm/second.

Worldwide, multiple governing bodies recommend DCC in preterm and term infants2, 3, 4, 5, 6, 7. The World Health Organization (WHO) advocates for DCC (not earlier than 1 min after birth) to improve maternal and infant health and nutrition outcomes4. For pregnant mothers worldwide, DCC is one of the actions included in a package for reduction of the risk of postpartum hemorrhage, which includes both vaginal and caesarean births. After birth, the practice of DCC appears to be associated with reduced in-hospital mortality in preterm infants8, 9, 10, 11, 12. Given 15.22 million infants were born premature in 201913, DCC may play an important role globally for improving neonatal outcomes. Between 2019–2030, 483 million births are projected to occur in sub-Saharan Africa, a region where child mortality rates are the highest in the world, which translates into approximately 58 million preterm births, assuming a 12% prematurity rate14. DCC has been shown to reduce all-cause mortality before discharge from hospital, with a number needed to benefit of 33 (95% confidence interval, 20-100)9. Extrapolating this benefit to only hospital-based births (an estimated 42% of births in sub-Saharan Africa)15, performing DCC could potentially reduce hospital mortality, resulting in 243,600 to 1,218,000 additional survivors between 2019–2030 in sub-Saharan Africa, based on a risk difference of -0.03 and 95% confidence interval (CI) of -0.05 to -0.01.

Globally, children have the highest risk of death in their first month, mainly due to preterm births, asphyxia, infections, and congenital anomalies16. At a global rate of 18 deaths per 1,000 live births, an estimated 2.5 million infants died in the first month after birth in 2018, which is approximately 7,000 daily17. Most neonatal deaths occur in low- and middle-income countries (LMICs), with rates that are often tenfold the rates in high-income countries (HICs), with many low-income countries having current mortality rates on par with rates in HICs from the early 1900’s18. Despite numerous randomized controlled trials (RCTs) involving thousands of infants, research on placental transfusion strategies in LMICs, the regions of the world where most births occur, remains limited. This article addresses outcomes associated with DCC from LMICs, discusses prevalent conditions that may be impacted by DCC, and identifies knowledge gaps that offer future research opportunities.

The focus of this article is to provide a global perspective on DCC, centered mainly on LMICs, a topic with limited research despite most of the world's annual births occurring in countries with this classification. In 2023 fiscal year, 136 countries were categorized as LMIC categories, representing ∼70% of countries in the world19. The World Bank assigns income classifications based on the countries’ Gross National Income (i.e., the dollar value of a country's final income in a year, divided by its population) with low-income countries ranging from US$1,085 or less in 2021 and upper-middle-income countries ranging from US$4,256–US$13,20519. Classifying countries as LMIC can be a useful way to group countries based on their level of economic development and to provide a general sense of the challenges and opportunities that these countries face in terms of healthcare. However, when considering the generalizability of DCC risks and benefits from existing studies, it is important to recognize that this classification is an imperfect measure with several limitations.

The term ‘LMIC’ as a category has numerous shortcomings and risks perpetuating and naturalizing differences between countries based solely on income classification while failing to recognize meaningful similarities and variations between countries and regions20. Some LMICs, such as China and India, have advanced medical facilities that surpass those in some high-income countries, while some high-income countries have less efficient healthcare systems. Healthcare metrics based on broad income classifications may obscure disparities, a point illustrated by considering differences in infant mortality rate (IMR), which is the number of infant deaths for every 1,000 live births. Worldwide, IMR ranges from 1.5 in Iceland to 80.1 in Sierra Leone21, The United States, which is the richest country in the world and has the highest per capita healthcare spending22 has an IMR of 5.423. However, state-level data in the United States demonstrates that some states have IMRs higher than some LMICs. IMRs in Mississippi (8.3), Louisiana (7.5), West Virginia (7.5), Arkansas (7.3), Alabama (7.2) are higher than IMRs in Cuba (4.1), Bosnia and Herzegovina (4.9), Serbia (4.9), Maldives (5.5), Costa Rica (6.7), Ukraine (6.9)21,23. Like IMR, DCC rates may vary between and within countries, likely due to factors other than national income. Limited global data on placental transfusion practices in specific regions or centers hinders the understanding of the impact of cord management strategies on infant outcomes.

A 2022 systematic review and network meta-analysis (NMA) on placental transfusion strategies in preterm infants in LMICs by Ramaswamy et al24. included 27 RCTs involving 3,136 infants with certainty of evidence assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE)25. Most of the studies (67%; 2098/3136) in this systematic review were conducted in India and China, with only 3 from sub-Saharan Africa (Kenya, 1 study; South Africa, 2 studies). While China (1.41 billion people) and India (1.39 billion people) are the most populous countries in the world, sub-Saharan Africa has population of 1.7 billion people, highlighting the paucity of evidenced-based data on placental transfusion strategies that affect a significant proportion of the world, especially considering that collectively, sub-Saharan Africa countries have the highest average fertility rate in the world26. In infants <34 weeks of gestation who received DCC for 30–60 seconds compared to ECC, key finding in this review included no clear benefit or harm in survival to hospital discharge (NMA of 9 RCTs, 1,164 newborns; risk ratio 0.96, 95% credible interval: 0.78–1.12, moderate certainty GRADE ranking) and a higher peak hematocrit after DCC for 120 seconds (NMA of 23 RCTs, 2,386 newborns; mean difference 8.63, 95% credible interval: 2.69–14.68, very low certainty GRADE ranking). When comparing DCC versus ECC in newborns <34 weeks of gestation, benefit versus harm could not be ruled out with the following outcomes: intraventricular hemorrhage Grade > II, bronchopulmonary dysplasia, sepsis, necrotizing enterocolitis stage ≥ II, duration of hospital stay, and retinopathy of prematurity requiring intervention. Newborns who received DCC for 45 seconds had a decreased the risk of inotropic support (NMA of 10 RCTs, 1,250 newborns; risk ratio 0.29, 95% credible interval: 0.07–0.95, low certainty GRADE ranking), but no difference was detected when this intervention was grouped with other interval of DCC (i.e., 30–60 seconds).

Numerous systematic reviews and meta-analyses, which included studies from both HICs and LMICs, have assessed the impact of DCC versus ECC in preterm neonates9, 10, 11, 12,27. Overall, compared with ECC, in preterm infants, DCC appears to be associated with reduced in-hospital mortality, increased hemoglobin or hematocrit shortly after birth, a decreased need for packed red blood cell transfusions while in the hospital, increased blood pressure and decreased need for inotropes (in the first 24 hours) and hyperbilirubinemia without an increased need for phototherapy8. Generalizing the results of these studies to different setting globally is challenging, due to differences in healthcare systems, economic conditions, and cultural practices. While these systematic reviews included HICs and LMICs, the number of LMICs was limited to seven different countries (China, India, Iran, Pakistan, South Africa, Thailand, and Turkey). For all these reviews, a minority of the total infants studied came from LMICs (Figure 1). Of the total number of infants included in each review, infants from LMICs represented 26.2% (1578/5772) in the Seidler et al. review27, 38.29% (1464/3823) in the Jasani et al. review10, 13.91% (523/3759) in the Persad et al. review11, 41.6% (1290/3100) in the Rabe et al. review12, and 15.81% (448/2834) in the Fogarty et al review9.

Globally, because DCC has the potential to save a consequential number of lives by decreasing in-hospital mortality, DCC should be routinely practiced, especially in setting with high prematurity rates. Prematurity is a major contributor to infant mortality, and the rate of prematurity varies widely among countries (see Figure 2), ranging from 3.97% in Saudi Arabia to 19.15% in Bangladesh28 and within the United States, ranging from 8% in Vermont to 15% in Mississippi23, a rate higher than most countries in the world. Global data is lacking on placental transfusion strategies, such as implementation rates of DCC, which hinders insight into the association of DCC with morbidities and mortality in most LMICs. A small online survey that included responses from 70 maternity workers across 10 LMICs suggests that there is inconsistent timing of cord clamping in preterm infants in LMICs due to lack of guideline awareness29. More information on placental transfusion strategies in LMICs is desirable recognizing that survival rates of extremely low birth weight neonates (birth weight <1000 grams) and extremely low gestational age neonates (born <28 weeks’ gestation) born in LMICs are variable, but are significantly lower than the survival rates reported from high income countries30.

Insufficient iron for metabolic needs may occur due to inadequate dietary iron intake, excessive iron loss (i.e., uncompensated blood loss), or increased utilization (e.g., during rapid growth and development). Depleted iron stores can lead to iron deficiency and iron deficiency anemia, a common type of anemia that occurs when the body lacks enough iron for proper red blood cell production. Iron deficiency and iron deficiency anemia are most common in preschool-age children and women of reproductive age, especially in in low-income settings where dietary iron content and availability are low and parasitic infections are highly prevalent31. Iron deficiency affects 43% of children, 38% of pregnant women, and, 29% of non-pregnant women worldwide32. Iron-deficiency anemia was reported in 1.24 billion people in 201633. Preterm, small for their gestational age, and low birthweight infants are at increased risk of iron deficiency due decreased iron stores34. Since iron is essential for all cell function and is critical for brain development, iron deficiency can result in irreversible long-term cognitive, motor, and behavioral deficits35.

The first 1000 days after birth have been identified as the period of life with the highest risk of iron deficiency36. The first three minutes after birth may arguably be the period of life with the greatest opportunity to reduce the risk of iron deficiency by performing DCC to increase the infant's iron endowment at birth. Unfortunately, interpretation of outcomes from studies on DCC looking at anemia beyond the neonatal period is hindered by study participants who were lost to follow-up, inconsistent criteria for diagnosing anemia, heterogeneity of reported outcomes, variable durations of delayed cord clamping, uncertainty about iron supplementation and feeding practices, and lack of data on intercurrent diseases. The following RCTs from LMICs assessed iron stores beyond the neonatal period.

A RCT from New Delhi, India that included 102 term infants compared effects of DCC (the moment when the placenta appeared in the vagina) to ECC on iron stores of infants at 3 months of age who were born to anemic mothers37 At 3 months of age, the proportion of infants who had Hb <10 g/dL were significantly less in the DCC (44%) than in the ECC (86%; odds ratio 7.7, 95% CI, 1.84-34.9) group and the proportion of infants who had low iron stores (serum ferritin <50 μg/L) were significantly less in the DCC (3%) compared to the ECC (27%; odds ratio 10.67, 95% CI 1.1-249.5) group.

A RCT from northern India that included 113 small for gestational age infants born at ≥35 weeks’ gestational age compared effects of DCC (mean 62.6 ± 6.5 seconds) to ECC (mean 12.05 ± 3.7 seconds) on serum ferritin levels at 3 months of age38. The median (interquartile range) serum ferritin levels were significantly higher in the DCC group (86 μg/ml, 43.35–134.75) compared to the ECC group (50.5 μg/ml, 29.5–83.5) and fewer infants had iron deficiency (serum ferritin < 50 μg/ml) in the DCC group (9/38, 23.6%) compared to ECC group (21/44, 47.7%) (p = 0.03, number needed to treat, 4; 95% CI 2–25). There were no significant between group differences regarding infants with symptomatic polycythemia or receiving partial exchange transfusions.

A RCT from Mexico City, Mexico that included 378 appropriate for gestation age term infants compared effects of DCC (mean 93.8 ± 44.2 seconds) to ECC (16.5 ± 6.4 seconds) on iron and hematological status at up to 6 months of age39. Compared to infants who received ECC, infants who received DCC had significantly increased iron status as 6 months of age based on a higher ferritin, mean corpuscular volume, transferrin receptor to ferritin ratio, estimated total body iron, and storage iron. Iron status was improved in infants with birth weights between 2500 and 3000 grams, born to iron-deficient mothers, and who did not receive infant formulas or iron-fortified milk. These findings suggest that DCC may help promote enhanced iron stores in infants the first six months after birth in populations where iron-deficiency is prevalent in pregnant women and infants receive exclusive human breastmilk.

A RCT conducted in Kathmandu, Nepal that included 540 term infants at high risk for iron deficiency anemia investigated the effects of DCC (≥180 seconds), compared with ECC (≤60 seconds) on hemoglobin and ferritin levels at 8 and 12 months of age40. At 8 months, the prevalence of anemia (hemoglobin level <11.0 g/dL) was lower in infants who received DCC (197/270, 73.0%) compared to infants who received ECC (222/270, 82.2%) (relative risk, 0.89; 95%CI, 0.81-0.98; number needed to treat, 11; 95%CI, 6-54). The risk for iron deficiency (ferritin level <12 μg/L) was decreased in infants who received DCC (60/270, 22.2%) compared to infants who received ECC (103/270, 38.1%) (relative risk, 0.58; 95%CI, 0.44-0.77; number needed to treat, 6; 95%CI, 4-13). The risk for iron deficiency anemia (hemoglobin level <11.0 g/dL and ferritin level <12 μg/L) was also decreased in infants who received DCC (52/270, 19.3%) compared to infants who received ECC (90/270, 33.3%) (relative risk, 0.58; 95%CI, 0.42-0.78; number needed to treat, 7; 95%CI, 5-16).

While the long-term impact of DCC on iron deficiency and iron deficiency anemia in children remains understudied, findings from RCTs conducted in LMICs suggest that DCC leads to improved iron stores for up to 8 months of age. This simple, cost-free opportunity to augment iron stores in the first few minutes after birth may be especially important in setting with a high prevalence of anemia, challenges with iron supplementation, and limited blood supplies to meet transfusion needs.

In malaria-endemic settings such sub-Saharan Africa, iron deficiency anemia may protect against falciparum malaria and iron supplementation may increase susceptibility to clinically significant malaria41. WHO recommends that iron supplementation for anemia should only be given in endemic settings in conjunction with public health measures to prevent, diagnose and treat malaria42. How DCC, which may increase iron stores after birth and decrease iron deficiency anemia, reduces the need for iron supplementation and alters the risk of malaria is unclear.

The impact of DCC in non-hospital settings (e.g., home births) on maternal and infant outcomes and safety is unclear. Understanding placental transfusion strategy practices in home deliveries may be important when considering infant outcome data. In low-risk pregnancies in HICs, planned place of birth (e.g., home versus hospital) appears to have little significant impact on adverse perinatal outcomes43. In LMICs, infant outcomes related to home births may be influenced by lack of skilled birth attendants, limited resources, and challenges with timely access to health facilities in case of complications. A 2021 meta-analysis of demographic and health surveys that included 67 LMICs, estimated a 28% (95% CI: 0.24–0.33) global prevalence of home births, with a higher proportion of home births noted in sub-Saharan African countries (e.g., 78% in Chad, 73% in Ethiopia, and 70% in Niger)44. Studies are needed to determine short- and long-term outcomes related to placental transfusion practices in home births in LMICs, especially in settings with increased risks of anemia like sub-Saharan African.

For infants who are pale, limp, and have minimal or no breathing at birth and need resuscitation, neither DCC nor UCM are recommended. These nonvigorous infants may include preterm infants or those with neonatal encephalopathy, a condition that causes over half a million newborn deaths worldwide annually45. A prospective cohort study done in 11 community-based research sites in south Asia and sub-Saharan Africa that included 263,563 births demonstrated that perinatal asphyxia was one of the most common causes of neonatal deaths (40%, 95% CI 39–42, in south Asia; 34%, 95% CI 32–36, in sub-Saharan Africa)46. In this study, neonatal mortality was 43 per 1000 livebirths (95% CI 39–47.3) in south Asia and 20.1 per 1000 livebirths (95% CI 14·6–27.6) in sub-Saharan Africa. Although this article focuses on DCC, it's worth noting that UCM, while not currently recommended, can be a quicker alternative and may improve cardiopulmonary transition and reduce morbidity for these nonvigorous infants who require resuscitation. A few studies have assessed the safety and potential benefit of UCM in nonvigorous neonates.

A quasi-randomized, non-blinded, controlled trial conducted at two centers in Nagpur, India that included 101 neonates (≥35 weeks’ gestation) who were depressed at birth evaluated the feasibility and safety of UCM (x3; n=50) versus ECC (n=51)47. There were no significant differences in short-term outcomes between the two groups including the duration of respiratory support, diagnosis of neonatal encephalopathy, duration of hospitalization, an abnormal neurological examination at discharge, and death.

A single center RCT conducted in Bangalore, India that included 60 preterm neonates (median 33 weeks’ gestation) requiring resuscitation demonstrated UCM (x3; n=30) resulted in a significantly higher hemoglobin and serum ferritin at 6 weeks of age compared to no cord milking (n=30)48. There were no significant between-group differences in neonatal morbidities or mortality.

A multicenter pragmatic cluster-randomized crossover trial that included nonvigorous infants born at 35 to 42 weeks’ gestation from 10 medical centers in 3 countries (7 in the United States, 2 in Canada, and 1 in Poland) assessed the safety and efficacy of UCM (872 infants) compared to ECC (858 infants) at birth49. While admission to the neonatal intensive care unit was not reduced in infants who received UCM compared to ECC, infants who received UCM had higher hemoglobin levels (modeled mean difference between UCM and ECC groups was 0.68 g/dL, 95% CI 0.31-1.05), decreased cardiorespiratory support at delivery (61% vs 71%, modeled odds ratio, 0.57; 95% confidence interval, 0.33-0.99), less moderate-to-severe neonatal encephalopathy (1% vs 3%, crude odds ratio, 0.48; 95% CI, 0.24-0.96), and less therapeutic hypothermia (3% vs 4%, crude odds ratio, 0.57; 95% CI, 0.33-0.99) without significant differences regarding normal saline boluses, phototherapy, or a serious adverse event composite of death before discharge. Importantly, infants from this study will be followed for 2-year neurodevelopmental outcomes (NCT03621943). These results may not be generalizable to LMICs, especially to non-hospital births; however, given the high incidence of neonatal encephalopathy in low resource settings, further studies on UCM in LMICs are warranted to find strategies to reduce infant morbidity and mortality. A randomized, crossover study conducted in India of term and late preterm infants who were non-vigorous at birth and received UCM or ECC, the Comparative Outcomes Related to Delivery-room Cord Milking In Low-resourced Kountries trial (CORDMILK trial: NCT03657394), will have a follow-up trial (NCT03682042) that will evaluate the difference in survival and neurodevelopmental outcomes at 22-26 months age.

Many centers worldwide practice UCM, which has been demonstrated to increase hemoglobin, increase blood pressure, and reduce need for transfusions in preterm and term infants50. However, the International Liaison Committee on Resuscitation recommends against UCM for preterm neonates born before 29 weeks’ gestation2. A randomized trial by Katheria et al. compared UCM to DCC in preterm neonates born before 32 weeks and found that the rate of death or severe brain bleeding was similar between groups, 12% and 8% respectively (p=0.16)51. However, UCM was associated with an increased risk of severe brain bleeding in extremely preterm neonates born between 23-27 weeks, and death or severe brain bleeding in preterm neonates born vaginally. These findings, from a multicenter study conducted in HICs, raise concern for similar adverse outcomes in extremely preterm neonates born in LMICs.

Globally, the prevalence of anemia is increased in HIV-positive patients and those with AIDS52. Since antiretroviral drugs for mothers living with HIV and postnatal prophylaxis in newborns can result in neonatal anemia, DCC at birth may reduce the risk for anemia by enhancing iron stores. WHO guidelines recommend DCC for at least 1–3 minutes among women living with HIV4. Antiretroviral therapy should be given to women living with HIV and their newborns to prevent the transmission of HIV from the mother to the child.

Limited research is available regarding DCC and the risk of vertical transmission from mothers with HIV to their newborns. A randomized study conducted at the University of Milan, Italy, which included 64 mother–newborn dyads, assessed the safety of DCC (120 seconds) versus ECC (<30 seconds) in term infants delivered by planned cesarean to mothers on stable antiretroviral therapy53. In this study, none of the infants had positive HIV–polymerase chain reaction from birth through 18 months of age. While infants who received DCC had significantly higher mean hemoglobin concentrations at 24 hours and 1 month of age, no long-term outcomes were reported.

More research is needed to better assess the long-term impact of DCC on children born to mothers with HIV residing in LMICs, especially considering sub-Saharan Africa bears a disproportionate burden of the global HIV epidemic, including new infections and deaths54.

Limited information is available on the effect of DCC long-term neurodevelopmental outcomes, especially in LMICs. A systematic review and meta-analysis that included 4 articles from 3 single blinded RCTs conducted in Sweden, Iran, and Nepal assessed neurodevelopmental outcomes in infants who received DCC (>90 or >180 s) compared with ECC55. A total of 765 infants had four-month follow-up and 672 had 12 months follow-up with neurodevelopmental outcomes assessed using the Ages and Stages Questionnaire (ASQ), a parent-completed child developmental-behavioral screening tool. Based on this review, DCC significantly improves the infants’ domains of communication (mean difference 0.6; 95% CI: 0.1-1.1) and personal-social (mean difference 1.0; 95% CI: 0.3-1.6) assessed through ASQ at 12 months of age, but DCC has no impact on ASQ total score at 12-month follow-up (mean difference 1.1; 95% CI: −5.1-7.3). The low number of clinical trials on this topic means that definitive conclusions cannot be drawn, and more clinical trials are needed to strengthen the current findings. Results from different populations are similar, suggesting a potential benefit of the DCC, but generalizability is impaired by lack of standardization in timing of cord clamping in routine clinical practice and variable adherence to DCC recommendations among healthcare workers.

More research is needed to determine the effect of DCC on neurodevelopment in both preterm and full-term infants at school age, in both HICs and LMICs. Neurodevelopmental impairment in infancy is only a weak predictor of impairment in middle childhood. The importance of long-term follow-up into childhood is highlighted by data from the Extremely Low Gestational Age Newborn Study, a cohort of children from the United States who were born extremely preterm (<28 weeks’ gestation), which showed that many infants with moderate to severe impairment improved by age 10, compared to age two56.