Refeeding Syndrome in Very-Low-Birth-Weight Intrauterine Growth-Restricted Neonates

ORIGINAL ARTICLE Refeeding syndrome in very-low-birth-weight intrauterine growth-restricted neonates

JR Ross, C Finch, M Ebeling and SN Taylor

OBJECTIVE: Determine the incidence of refeeding syndrome, defined by the presence of hypophosphatemia in very-low- birth-weight (VLBW) infants with intrauterine growth restriction (IUGR) compared with those without IUGR. STUDY DESIGN: In this retrospective cohort study, VLBW infants admitted over a 10-year period (271 IUGR and 1982 non-IUGR) were evaluated for specific electrolyte abnormalities in the first postnatal week. RESULT: IUGR infants were significantly more likely to have hypophosphatemia (41% vs 8.9%, relative risk (95% confidence interval: 7.25 (5.45, 9.65)) and severe hypophosphatemia (11.4% vs 1%, 12.06 (6.82, 21.33)) in the first postnatal week. The incidence of hypophosphatemia was significantly associated with the presence of maternal preeclampsia in all VLBW infants (odds ratio (OR): 2.58 (1.96, 3.40)) when controlling for birth weight and gestational age. CONCLUSION: Refeeding syndrome occurs in VLBW infants with IUGR and born to mothers with preeclampsia. Close monitoring of electrolytes, especially phosphorus, is warranted in this population.

Journal of Perinatology (2013) 33, 717–720; doi:10.1038/jp.2013.28; published online 28 March 2013 Keywords: hypophosphatemia; intrauterine growth retardation; fetal growth retardation; premature infant

INTRODUCTION that IUGR neonates experience a similar ‘refeeding’ syndrome Intrauterine growth restriction (IUGR) or fetal growth restriction is following the initiation of nutrition support after birth. The intent defined as growth that deviates from the expected fetal growth of this study was to evaluate the incidence of the characteristic pattern. It is related to significant physiologic impact on the electrolyte dyscrasias in IUGR vs non-IUGR very-low-birth-weight growing fetus and is the second leading cause of perinatal (VLBW) infants. morbidity and mortality. IUGR infants are at higher risk of neonatal complications and have been linked to increased risk of disease later in adulthood.1 Placental insufficiency leads to a state of METHODS chronic malnourishment, which poses significant risk for the fetus. We performed a retrospective cohort study based on the information Refeeding syndrome is a constellation of fluid and electrolyte extracted from a perinatal database containing 41000 data points and dysregulation that occurs upon initiation of enteral or parenteral inpatient medical records. All VLBW patients (o1500 gm) admitted to the 2 Neonatal Intensive Care Unit at the Medical University of South Carolina nutrition following a period of malnutrition or starvation. In within the first 24 postnatal hours from 2001–2010 were included in the chronic malnutrition, glucose and glycogen stores are depleted, study. There were no additional exclusion criteria. The variables extracted followed by an adaptation in metabolism where energy is then included gestational age, birth weight, incidence of IUGR, small for derived from lipolysis and ketone production. Following initiation gestational age (SGA) status, multiple gestation and days of mechanical of feeding, glucose metabolism results in increased phosphate ventilation. The occurrence of electrolyte abnormalities, including phos- usage for ATP production. This increased demand depletes serum phorus, potassium, glucose and magnesium, occurring in first 7 postnatal stores of phosphorus and magnesium.2 Hypophosphatemia days were collected on each patient. Incidence of maternal preeclampsia, is often accompanied by hypokalemia from intracellular shifts maternal diabetes mellitus and neonatal complications, including bronch- secondary to increased insulin, hyperglycemia secondary to excess opulmonary dysplasia (BPD), late-onset sepsis, necrotizing enterocolitis, patent ductus arteriosus and grade 3/4 intraventricular hemorrhage, glucose delivery in a system now adapted to fat metabolism, 2 were also collected for comparison between groups and association and significant vitamin deficiencies, thiamine in particular. The with electrolyte dyscrasias. This study was approved by the institutional physiologic disturbances, if untreated, can lead to life-threatening review board. complications, including heart failure, arrhythmias, respiratory and An infant was classified as IUGR based on the presence of obstetrical neuromuscular compromise.3,4 This phenomenon has been diagnosis at the time of delivery. SGA was defined as birth weight less extensively described in the anorexic, intensive care unit, and than the 10th percentile on the Fenton growth curve.7 The following post-surgical adult and pediatric population but to date has not cutoffs were used to define the collected electrolyte dyscrasias— 5,6 hypophosphatemia (phosphorus o4mgdlÀ 1), severe hypophosphatemia been reported in the neonatal population. À 1 À 1 In the neonatal population, IUGR secondary to placental (phosphorus o2.5 mg dl ), hypokalemia (potassium p3.0 mg dl ), hypomagnesemia (magnesium o1.5 mg dl À 1) and hyperglycemia insufficiency and altered oxygen delivery, results in a state of (glucose4180 mg dl À 1). chronic, prolonged malnourishment that can be compared with Over the 10-year period of the review, it was a standard practice for that of the anorexic or critical surgical patient. It is hypothesized dextrose-containing intravenous fluids (2001–2005) or dextrose- and

Division of Neonatology, Department of Pediatrics, Medical University of South Carolina Children’s Hospital, Charleston, SC, USA. Correspondence: Dr JR Ross, Division of Neonatology, Department of Pediatrics, Medical University of South Carolina Children’s Hospital, 165 Ashley Avenue, MSC 917, Charleston, SC 29425, USA. E-mail: [email protected] Received 21 August 2012; revised 3 February 2013; accepted 15 February 2013; published online 28 March 2013 Refeeding syndrome in growth-restricted neonates JR Ross et al 718 protein-containing parenteral nutrition (2005–2010) to be initiated respectively). In addition, the following relationships also immediately following the establishment of intravenous access. Through- remained significant: IUGR and hypomagnesemia (OR: 8.94; 95% out the study period, the standard practice included initiation of parenteral CI: 3.00, 26.65; Po0.0001); IUGR and hypophosphatemia þ nutrition in all VLBW patients within the first 24––36 h of life. Standard À 1 hypomagnesemia (OR: 23.05; 95% CI: 5.05, 105.26; Po0.0001); concentrations of electrolytes, phosphorus (0.5–1 mM/dl ), potassium IUGR and hypophosphatemia þ hypokalemia (OR: 7.14; 95% CI: (1.3–1.4 mEq dl À 1) and magnesium (0.3 mEq dl À 1) typically were added to parenteral nutrition by postnatal day 3. Enteral feeding practices, including 4.26, 11.96; Po0.0001); and IUGR and hypophosphatemia þ timing of initiation and advancement of feeds, varied during the 10-year hypokalemia þ hypomagnesemia þ hyperglycemia (OR: 7.46; 95% period. Standardized enteral feeding guidelines were developed, including CI: 3.19, 17.44; Po0.0001). trophic feeding schedule based on birth weight, initiation of enteral feeds As shown in Figure 1, the prevalence of hypophosphatemia was within first 6 h of life and fortification of human milk at 100 ml kg À 1 per higher in infants born to mothers with preeclampsia in both IUGR day, which occurs between postnatal day 7 and 12. Major changes and non-IUGR infants. This difference was significant for the in parenteral and enteral feeding practices were completed by 2006. non-IUGR (17% vs 6.2%, RR: 3.26 (95% CI: 2.38, 4.47)) but not for Significant process changes in mechanical ventilation occurred over the the IUGR infants (46% vs 38%, RR: 1.39 (95% CI: 0.86, 2.27)). 10-year study period. All major changes were completed in 2006, including However, when controlling for birth weight and gestational age, a a standardized ventilator management protocol, thus days of mechanical ventilation were evaluated for years 2007–2010. significant association was noted between IUGR infants with hypophosphatemia and the incidence of maternal preeclampsia (OR: 1.84; 95% CI: 1.19, 2.81; P ¼ 0.005). In addition, when Statistical analysis controlling for birth weight and gestational age, all infants born This study was conducted to compare incidence of electrolyte dyscrasias to mothers with preeclampsia were significantly more likely to between IUGR and non-IUGR VLBW infants. Statistical analysis was 2 exhibit hypophosphatemia than those born to mothers without performed via w test for non-continuous variables, Student’s t-test for preeclampsia (OR: 2.58; 95% CI: 1.96, 3.40; P 0.0001). When continuous variables and relative risk (RR). Ordinal values were compared o by nonparametric Kruskal–Wallis test. Logistic regression was performed to controlling for birth weight, gestational age and IUGR status, there evaluate clinical outcomes while controlling for certain clinical factors with was no significant relationship between maternal diabetes resulting odds ratios (OR). A two-sided P-value of o0.05 was defined mellitus and hypophosphatemia (OR: 1.34; 95% CI: 0.806, 2.23; a priori as statistically significant. P ¼ 0.25). Owing to the significant changes in parenteral and enteral feeding methods that occurred over the 10-year period, the data RESULTS were analyzed with a logistic regression model controlling for time A total of 2253 VLBW infants (271 IUGR and 1982 non-IUGR) were period. Time period 2 (2006–2010) was significantly associated admitted to the Neonatal Intensive Care Unit within the first 24 with increased risk of hypophosphatemia (OR: 3.13; 95% CI: 2.33, postnatal hours during study period and were included in the 4.21; Po0.0001) and severe hypophosphatemia (OR: 2.59; 95% CI: analysis. Patient characteristics can be seen in Table 1. The groups 1.34, 4.97; P ¼ 0.004) when controlling for birth weight, gestational were significantly different for median gestational age, birth age and IUGR status. weight, sex, 5 min Apgar score and SGA status. Significantly more When controlling for birth gestational age, weight and IUGR IUGR patients were born to mothers with preeclampsia as well. status, hypophosphatemia was significantly associated with the Overall morbidity and mortality in the first postnatal week did not incidence of BPD (OR: 2.38; 95% CI: 1.73, 3.28; Po0.0001) and differ between groups. patent ductus arteriosus (OR: 1.68; 95% CI: 1.24, 2.27; P ¼ 0.0004). As shown in Table 2, the incidence of hypophosphatemia and The relationship between hypophosphatemia and BPD also severe hypophosphatemia was significantly greater in the IUGR remained significant when adding maternal preeclampsia patients. The combination of hypophosphatemia and hypokale- into the regression (OR: 2.52, 95% CI: 1.82, 3.48). No association mia, as well as the combination of hypophosphatemia, hypoka- between hypophosphatemia and necrotizing enterocolitis (OR: lemia and hyperglycemia were also significantly greater in the 1.32; 95% CI: 0.83, 2.12; P ¼ 0.24), severe intraventricular hemor- IUGR group. In addition, the diagnoses of hypomagnesemia alone rhage (OR: 1.30; 95% CI: 0.86, 1.97; P ¼ 0.21) or late-onset bacterial and with other dyscrasias were significantly more likely in IUGR sepsis (OR: 0.78; 95% CI: 0.59, 1.07; P ¼ 0.12) was noted. From subjects. 2007–2010, the median number of days of mechanical ventilation Owing to the differences in mean birth gestational age and differed between VLBW infants with hypophosphatemia and those weight between the groups, logistic regression analysis was without hypophosphatemia (median (interquartile range): 5 (1–23) performed controlling for birth gestational age and weight. In and 2 (1–7); Po0.0001, respectively). However, these differences these analyses, the associations between IUGR and hypopho- did not remain significant when controlling for birth weight and sphatemia, and IUGR and severe hypophosphatemia remained gestational age. VLBW infants with hypophosphatemia were significant (OR: 6.25; 95% confidence interval (CI): 4.31, 9.08; significantly more likely to require mechanical ventilation X3 Po0.0001 and OR: 8.54; 95% CI: 4.28, 17.01; Po0.0001, days when compared with those without hypophosphatemia

Table 1. Demographic and clinical characteristics

Variables IUGR, n ¼ 271 Non-IUGR, n ¼ 1982 P-value

Gestational age (weeks) median (25–75%tile) 31.0 (29–33) 28.0 (26–30) o0.0001 Birth weight (g) median (25–75%tile) 1050 (755–1310) 1080 (835–1300) 0.02 Male, n (%) 107 (39) 989 (49) 0.001 Apgar score at 5 min median (25–75%tile) 8 (7–9) 8 (6–9) o0.0001 SGA, n (%) 219 (81) 304 (15) o0.0001 Maternal preeclampsia, n (%) 119 (44) 480 (24) o0.0001 Maternal diabetes mellitus, n (%) 22 (1) 131 (6) 0.35 Mortality, n (%) 24 (8.9) 230 (5.4) NS Mortality ﬁrst week of life, n (%) 11 (3.9) 108 (5) NS Abbreviations: IUGR, intrauterine growth restriction; NS, not signiﬁcant; SGA, small for gestational age.

Journal of Perinatology (2013), 717 – 720 & 2013 Nature America, Inc. Refeeding syndrome in growth-restricted neonates JR Ross et al 719 Table 2. Rate of electrolyte dyscrasias

Incidence in ﬁrst postnatal week IUGR, non-IUGR, Relative risk n ¼ 271 n ¼ 1982 (95% conﬁdence interval)

Hypophosphatemia, n (%) 113 (41.2) 178 (8.9) 7.25 (5.45, 9.65) Severe hypophosphatemia, n (%) 31 (11.4) 21 (1) 12.06 (6.82, 21.33) Hypophosphatemia þ hypokalemia, n (%) 54 (20) 53 (2.7) 9.06 (6.05, 13.57) Hypophosphatemia þ hypokalemia þ hyperglycemia, n (%) 19 (7) 16 (0.8) 9.26 (4.7, 18.25) Hypomagnesemia 13 (4.8) 10 (0.5) 9.94 (4.31, 22.89) Hypophosphatemia þ hypomagnesemia 12 (4.43) 3 (0.15) 30.56 (8.57, 109.03) Hypophosphatemia þ hypokalemia þ hyperglycemia þ hypomagnesemia, n (%) 6 (2.2) 1 (0.05) 44.85 (5.38, 374.02) Abbreviations: IUGR, intrauterine growth restriction.

inadequate ATP is thought to be the primary mechanism for the observed respiratory failure.14 In this study, although the incidence of hypophosphatemia was not associated with a significantly increased median ventilator days when controlling for gestational age and birth weight, it was associated with the requirement of mechanical ventilation for three or more days. The marker of 3 days was chosen based on our experience that most infants with uncomplicated respiratory distress syndrome require less than 24–48 h of mechanical ventilation post surfactant administration. Hypophosphatemia in refeeding syndrome typically becomes apparent around 3 days following refeeding2,15 and may contribute to at least short-term prolonged ventilation. As mechanical ventilation leads to volutrauma and barotrauma, thus increasing damage to the lungs; the length of mechanical ventilation days and the associated trauma and inflammation in these patients may lead to the increased incidence of BPD found in VLBW infants with hypophosphatemia. In addition, many maternal and neonatal factors have been linked to an increased incidence in BPD including maternal preeclampsia16 and IUGR.17–19 In this study, the relationship between BPD and Figure 1. Prevalence of hypophosphatemia and association with hypophosphatemia remained when controlling for the presence preeclampsia and intrauterine growth restriction (IUGR) status, of IUGR and maternal preeclampsia. No other studies have *Po0.05. reported such a link between hypophosphatemia and BPD and additional study is needed to evaluate this relationship. (Po0.0001) and these differences remained significant when In addition to hypophosphatemia, IUGR infants were also at controlling for gestational age and birth weight (OR: 1.76, 95% significantly increased risk of hypokalemia, hypomagnesemia and CI: 1.1, 2.70, P ¼ 0.0096). hypoglycemia. The full impact of these electrolyte disturbances were not completely evaluated in the scope of this study. Hypokalemia is known to cause decreased gut motility or ileus20 DISCUSSION and it could be hypothesized that the IUGR infants with refeeding In a cohort of 2253 VLBW infants, IUGR was associated with syndrome have delayed achievement of full enteral feedings. hypophosphatemia, hypokalemia, hyperglycemia and hypomag- Investigation into time to achieve full enteral nutrition and length nesemia, which are laboratory markers of refeeding syndrome. of parenteral nutrition in this population is needed to further These associations with IUGR status support the hypothesis of a evaluate the clinical impact of refeeding syndrome. The finding of refeeding syndrome in this population. Clinical manifestations of hypomagnesemia was surprising in this study and gives additional refeeding syndrome were originally described by Keys and Brozek evidence to the constellation of findings associated with refeeding in the 1940s during intentional experiments of the effects of syndrome in this population. Standard therapy during labor with starvation8 and by Schnitker when malnourished prisoners of war maternal preeclampsia is intravenous magnesium as seizure died following reinitiation of regular nutrition.9 Although clinically prophylaxis. Despite a high occurrence of preeclampsia in the observed for years in the chronically malnourished patients, it was IUGR population, the incidence of hypomagnesemia was not officially reported and referenced as ‘Refeeding Syndrome’ significant. Maternal preeclampsia is identified as an until 1981.10 The only additional study linking hypophosphatemia independent risk factor for hypophosphatemia in this study. The to growth restriction found that IUGR piglets fed high-protein increased risk of hypophosphatemia in non-IUGR infants, born to formula had poor growth and hypotonia, with associated mothers with preeclampsia, raises concern that the risk refeeding hypophosphatemia and hypokalemia.11 This study is the first syndrome is highest in infants subjected to states of malnutrition clinical evidence supporting the incidence of refeeding syndrome in utero even in the absence of growth restriction. Further in the neonatal population and has important implications for the evaluation of states of placental insufficiency and neonatal identification and management of those infants. hypophosphatemia in the absence of overt growth restriction is Phosphorus is essential for generation of ATP and its depletion warranted. has detrimental effects on cellular metabolism. Many studies have Refeeding syndrome and the associated electrolyte dyscrasias reported respiratory and neuromuscular failure as a result require the initiation of either enteral or parenteral nutrition. In of hypophosphatemia secondary to refeeding syndrome.4,12,13 A this study, a significantly increased risk of hypophosphatemia and decrease in effective diaphragmatic contractility secondary to severe hypophosphatemia in IUGR patients was found in the

& 2013 Nature America, Inc. Journal of Perinatology (2013), 717 – 720 Refeeding syndrome in growth-restricted neonates JR Ross et al 720 2006–2010 time period following many major changes in enteral Finch: aided in design of the study, reviewed and revised the manuscript and and parenteral nutrition in this population. The combination of approved the final manuscript as submitted. Ms Myla Ebeling: contributed to earlier parenteral nutrition with increased protein delivery, acquisition and statistical analysis of data and approved the final manuscript as increased dextrose concentration due to earlier central line submitted. Dr Sarah Taylor: mentored Julie Ross in study conception, supervised placement and early initiation of enteral nutrition without data collection and interpretation, critically reviewed the manuscript and alteration in parenteral electrolyte management may contribute approved the final manuscript as submitted. to the increased risk of electrolyte dyscrasias in this high-risk population. Limitations of this study include the retrospective design. No standard protocol for monitoring of phosphorus existed REFERENCES during the study time. Thus, not all patients in the study 1 Barker DJ. The developmental origins of adult disease. J Am Coll Nutr 2004; 23: had a phosphorus level measured in the first postnatal week of 588S–595SS. life. All patients were included in the data analysis and patients 2 Boateng AA, Sriram K, Meguid MM, Crook M. Refeeding syndrome: treatment considerations based on collective analysis of literature case reports. Nutrition without phosphorus levels in the first postnatal week were 2010; 26: 156–167. analyzed as normal phosphorus. The study may also be limited by 3 Skipper A. Refeeding syndrome or refeeding hypophosphatemia: a systematic the definition of IUGR utilized to define cohort. The comparison review of cases. Nutr Clin Pract 2012; 27: 34–40. based on obstetrical diagnosis of IUGR was chosen over SGA as a 4 Patel U, Sriram K. Acute respiratory failure due to refeeding syndrome and standard birth weight percentile measurement in order to better hypophosphatemia induced by hypocaloric enteral nutrition. Nutrition 2009; 25: select those patients with pathologic growth restriction as 364–367. opposed to constitutional small size. The IUGR condition is always 5 Byrnes MC, Stangenes J. Refeeding in the ICU: an adult and pediatric problem. pathologic and complicates as many as 7% of all pregnancies and Curr Opin Clin Nutr Metab Care 2011; 14: 186–192. up to 28% of pregnancies complicated by hypertension or 6 Dunn RL, Stettler N, Mascarenhas MR. Refeeding syndrome in hospitalized 21 pediatric patients. Nutr Clin Pract 2003; 18: 327–332. preeclampsia. It must be differentiated from SGA, which is 7 Fenton TR. A new growth chart for preterm babies: Babson and Benda’s chart defined as weight for gestation below a given threshold, updated with recent data and a new format. BMC Pediatr 2003; 3:13. commonly the 10th percentile, and is secondary to 8 Keys AB, Brozek J, Henschel A. The biology of human starvation. University of 22 constitutional or physiological causes. Thus, an infant may be Minnesota Press: Minneapolis, 1950. IUGR without being SGA and an infant with SGA status may 9 Schnitker MA, Mattman PE, Bliss TL. A clinical study of malnutrition in Japanese not be IUGR. Oxygen delivery is a primary determinant of fetal prisoners of war. Ann Intern Med 1951; 35: 69–96. growth and thus IUGR is most commonly secondary to placental 10 Weinsier RL, Krumdieck CL. Death resulting from overzealous total insufficiency.23 Utilizing an obstetrical diagnosis of IUGR does have parenteral nutrition: the refeeding syndrome revisited. Am J Clin Nutr 1981; 34: limitations as a lack of effective customized growth assessment 393–399. 11 Jamin A, D’Inca R, Le Floc’h N, Kuster A, Orsonneau JL, Darmaun D et al. has resulted in difficulty delineating between pathologic growth Fatal effects of a neonatal high-protein diet in low-birth-weight piglets used as a restriction and constitutional small growth, which is critical model of intrauterine growth restriction. Neonatology 2010; 97: 321–328. for risk assessment of the fetus. However, we feel as though this 12 Vignaud M, Constantin JM, Ruivard M, Villemeyre-Plane M, Futier E, Bazin JE et al. is an acceptable limitation in this study and best identifies the Refeeding syndrome influences outcome of anorexia nervosa patients in chronically malnourished population at risk for refeeding intensive care unit: an observational study. Crit Care 2010; 14: R172. syndrome. 13 Oud L. Transient hypoxic respiratory failure in a patient with severe hypophosphatemia. Med Sci Monit 2009; 15: CS49–CS53. 14 Aubier M, Murciano D, Lecocguic Y, Viires N, Jacquens Y, Squara P et al. CONCLUSIONS Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure. N Engl J Med 1985; 313: 420–424. Hypophosphatemia poses significant risk to IUGR VLBW neonates. 15 Hayek ME, Eisenberg PG. Severe hypophosphatemia following the institution of Its occurrence, in addition to associated hypokalemia, hypomag- enteral feedings. Arch Surg 1989; 124: 1325–1328. nesemia and hyperglycemia in IUGR VLBW infants is consistent 16 Hansen AR, Barnes CM, Folkman J, McElrath TF. Maternal preeclampsia with refeeding syndrome. Based on the results of this study, close predicts the development of bronchopulmonary dysplasia. J Pediatr 2010; 156: monitoring of electrolytes, especially phosphorus, is warranted 532–536. following initiation of parenteral or enteral nutrition in this patient 17 Bose C, Van Marter LJ, Laughon M, O’Shea TM, Allred EN, Karna P et al. Fetal population. Additional prospective studies evaluating trends in growth restriction and chronic lung disease among infants born before the 28th phosphorus levels over the first postnatal week of life in IUGR week of gestation. Pediatrics 2009; 124: e450–e458. VLBW neonates are needed to better identify of those patients at 18 Reiss I, Landmann E, Heckmann M, Misselwitz B, Gortner L. Increased risk of bronchopulmonary dysplasia and increased mortality in very highest risk for refeeding syndrome. Alterations in parenteral preterm infants being small for gestational age. Arch Gynecol Obstet 2003; 269: nutrition administration, including earlier administration of higher 40–44. phosphorus and potassium, may decrease the incidence of 19 Lal MK, Manktelow BN, Draper ES, Field DJ. Chronic lung disease of prematurity electrolyte abnormalities and improve clinical outcomes, primarily and intrauterine growth retardation: a population-based study. Pediatrics 2003; the need for mechanical ventilation. 111: 483–487. 20 Gleason CA, Devaskar SU, Avery ME. Avery’s diseases of the newborn. 9th ed. Elsevier/Saunders: Philadelphia, PA, 2012. CONFLICT OF INTEREST 21 Romo A, Carceller R, Tobajas J. Intrauterine growth retardation (IUGR): epide- miology and etiology. Pediatr Endocrinol Rev 2009; 6(Suppl 3): 332–336. The authors declare no conflict of interest. 22 Figueras F, Gardosi J. Intrauterine growth restriction: new concepts in antenatal surveillance, diagnosis, and management. Am J Obstet Gynecol 2011; AUTHOR CONTRIBUTIONS 204: 288–300. 23 Lackman F, Capewell V, Gagnon R, Richardson B. Fetal umbilical cord oxygen Dr Julie Ross: conceptualized and designed the study, drafted the initial values and birth to placental weight ratio in relation to size at birth. Am J Obstet manuscript and approved the final manuscript as submitted. Ms Carolyn Gynecol 2001; 185: 674–682.

Journal of Perinatology (2013), 717 – 720 & 2013 Nature America, Inc.