Fetal umbilical cord oxygen values and birth to placental weight ratio in relation to size at birth

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1 Fetal umbilical cord oxygen values and birth to placental weight ratio in relation to size at birth Felice Lackman, MD, Vivian Capewell, DVM, MSc, Robert Gagnon, MD, and Bryan Richardson, MD* London, Ontario, Canada OBJECTIVE: Our purpose was to examine regulatory linkages between fetal oxygenation and fetal and placental growth. We determined umbilical cord PO 2 and oxygen saturation, fractional oxygen extraction, and birth to placental weight ratio values in relation to size at birth for a large tertiary hospital population delivering at term. STUDY DESIGN: The computerized perinatal database of St Joseph s Health Care London, London, Ontario, was used to obtain the umbilical cord gases, ph, birth weight, placental weight, and other selected information for all term, singleton, liveborn infants between January 1990 and December 1999 (N = 27,043). Oxygen saturation values were calculated from the umbilical cord PO 2 and ph data with a previously derived empirical equation; fractional oxygen extraction values were calculated from the umbilical cord oxygen saturation data. Size at birth was divided into the following 5 birth weight categories using neonatal growth standards: fetal growth restriction, <3%; borderline fetal growth restriction, 3% and <10%; appropriate for gestational age, 10% and 90%; borderline large for gestational age, >90% and 97%; large for gestational age, >97%. RESULTS: Infants in the borderline fetal growth restriction and fetal growth restriction groups had umbilical vein and artery PO 2 and oxygen saturation values that were stepwise lower than respective values for infants in the appropriate for gestational age group. Conversely, infants in the borderline large for gestational age and large for gestational age groups had umbilical vein PO 2 and oxygen saturation values that were stepwise higher than respective appropriate for gestational age group values; infants in these groups showed no change in arterial PO 2 and oxygen saturation values. Therefore infants in the borderline fetal growth restriction and fetal growth restriction groups had fractional oxygen extraction values that were stepwise higher than the appropriate for gestational age group value, whereas values for infants in the borderline large for gestational age and large for gestational age groups remained unchanged. Birth weight was disproportional to placental weight for infants in the borderline fetal growth restriction and fetal growth restriction groups when compared with that of the infants in the appropriate for gestational age group, with the birth to placental weight ratio values stepwise decreased. Conversely, birth weight was proportional to placental weight for infants in the borderline large for gestational age and large for gestational age groups with the birth to placental weight ratio values thus unchanged when compared with that of the infants in the appropriate for gestational age group. CONCLUSION: We conclude that fetal oxygenation is related to size at birth across the entire range of birth weights as studied at term from macrosomic to growth-restricted infants; this conclusion supports oxygen as a primary determinant of fetal growth. However, there are differences in the linkage between fetal oxygenation and metabolic rate or growth for these cohort groups that may relate to underlying etiologic processes. ( 2001;185: ) Key words: Fetal growth restriction, umbilical cord blood gases, fetal growth From the Departments of Obstetrics and Gynaecology, Physiology, and Paediatrics, the Canadian Institutes of Health Research Group in Fetal and Neonatal Health and Development, University of Western Ontario. Received for publication December 7, 2000; revised March 22, 2001; accepted April 24, *B. Richardson, MD, is the recipient of the Wyeth-Ayerst/Canadian Institute of Health Research Chair in Women s Health for Perinatology. Reprint requests: Bryan S. Richardson, MD, FRCSC, Department of Obstetrics and Gynaecology, St Joseph s Health Care London, 268 Grosvenor St, Room B325, London, Ontario N6A 4V2. brichar1@julian.uwo.ca. Copyright 2001 by Mosby, Inc /2001 $ /1/ doi: /mob Fetal growth and thus size attained for a given gestational age are intricately linked to oxygen availability and placental development. Animal studies with chronic reduction in fetal oxygenation in different species and with different techniques indicate a positive correlation between the degree to which oxygenation is reduced and resultant growth restriction. 1-4 These studies in the ovine fetus, in which in utero catheterization has additionally been used, generally indicate related degrees of fetal hypoxemia as oxygen delivery decreases in relation to oxygen consumption, with a resulting increase in fractional oxy- 674

2 Volume 185, Number 3 Lackman et al 675 gen extraction. 1, 4 However, with prolonged restriction of uterine blood flow and resultant growth restriction in the ovine fetus, there is no related hypoxemia or change in fractional oxygen extraction as the decrease in growth and in oxygen consumption becomes proportional to the decrease in oxygen delivery. 5 Placental growth and development in these studies with chronic reduction in fetal oxygenation are variably affected depending on the species studied and on the mode of oxygen reduction. Although the relationship between fetal oxygenation and induced growth restriction has been well studied in animal models, the relationship between fetal oxygenation and macrosomia has been little studied, with the exception of glucose and insulin alterations and diabetesrelated studies. Human studies of growth-restricted fetuses with cordocentesis indicate variable degrees of hypoxemia, although in many instances blood gas values are within the normal range, which suggests a degree of normalization with the decrease in growth. 6, 7 Cohort population analysis with the study of umbilical cord gases at birth in growth-restricted fetuses likewise indicates variable degrees of hypoxemia and associated acidemia. 8, 9 However, these studies involve small numbers of patients with variable definitions of fetal growth restriction and, for the most part, are not targeted at fetal oxygenation per se but rather at associated phenomena such as behavioral or cardiovascular responses. Placental growth and development in the human fetus with growth restriction are variably affected depending on the underlying clinical condition. 10 The relationship between fetal oxygenation and macrosomia in the human fetus has not undergone extensive study. Although it is recognized that the study of umbilical cord blood at the time of delivery has limitations as a measure of longer-term oxygenation in the fetus, 11, 12 when it is collected routinely such study has the advantage of providing information on large patient numbers and therefore of detecting small differences between patient groups that may be of biologic if not clinical importance. Likewise, the study of placental weight at the time of delivery is a crude measure of placental growth and development; however, when it is collected in a routine manner and related to birth weight, it may provide information of biological importance. To further examine regulatory linkages between fetal oxygenation and fetal and placental growth, we have determined umbilical vein PO 2 and oxygen saturation as measures of umbilical oxygen delivery, umbilical artery PO 2 and oxygen saturation as measures of systemic oxygen levels, fractional oxygen extraction as a measure of oxygen consumed by the fetus as a fraction of that delivered, and the birth to placental weight ratio as a measure of placental development in relation to size at birth for a large tertiary hospital population. Patients have been studied at term to limit the effects of varying gestational age and the use of neonatal versus fetal growth standards, 13 controlling for those variables within our database known to affect either cord gases, size at birth, or both. Material and methods The computerized perinatal database of St Joseph s Health Care London, London, Ontario, provides targeted information on all births occurring at the hospital, with data prospectively entered from the medical chart, delivery records, and neonatal records by a dedicated research assistant. The hospital is the tertiary care facility for southwestern Ontario and serves a predominantly Caucasian population of approximately 1.5 million. Information collected includes maternal medical problems, pregnancy complications, obstetric history, and perinatal outcome. The study population was formed on the basis of the following inclusion criteria: date of birth between January 1, 1990, and December 31, 1999; singleton; liveborn; gestational age at birth between 37 and 41 weeks; and no major anomalies present. The database was used to obtain the following variables for this study population: gestational age at delivery rounded to completed weeks; birth weight; placental weight; gender; umbilical cord gases and ph; maternal age; parity; Apgar scores at 1 and 5 minutes; mode of delivery; presence or absence of a nuchal cord; presence or absence of maternal hypertensive disorder; and presence or absence of maternal gestational or insulin-dependent diabetes. According to clinical practice, gestational-age estimation throughout the study was derived from the last menstrual period if either first trimester ultrasonography was within ± 4 days of the estimated date of confinement or second trimester ultrasonography was within ± 10 days of the estimated date of confinement. Otherwise, gestational age was corrected on the basis of ultrasonographic measurements that are routinely obtained for all pregnant women in the province of Ontario for pregnancy dating. At St Joseph s Health Care London, an electronic weight scale (Scale Tronex 4800, Ingram and Bell Ltd; Don Mills, Ontario) was used by nursing personnel to weigh infants immediately after delivery. Placentas were weighed by nursing assistants with an electronic weight scale that has been used since November 1991; before November 1991 a balance weight scale was used. Placentas were weighed with membranes and umbilical cord, including that segment of cord used for cord blood sampling. No attempt was made to remove placental blood before weighing. Umbilical cord blood was routinely sampled by nursing personnel immediately after delivery for all infants deemed to be viable. Blood was taken first from the artery and then from the vein with 3-mL preheparinized plastic syringes. Sampling was almost always performed within 10 minutes of birth; cord bloods were

3 676 Lackman et al September 2001 Table I. Population characteristics by birth weight category from Arbuckle neonatal growth standards FGR (n = 581) bfgr (n = 1519) AGA (n = 21,588) blga (n = 2206) LGA (n = 1149) Gestational age at delivery (wk) 38.9 ± ± ± ± ± 0.9 Maternal age (y) 28.2 ± ± 5.6* 28.6 ± ± 4.9* 29.8 ± 4.9* Parity 0.8 ± 1.1* 0.8 ± 1.0* 0.9 ± ± 1.1* 1.3 ± 1.2* 1-min Apgar score 7.8 ± 1.9* 8.1 ± ± ± 1.6* 7.7 ± 1.9* 5-min Apgar score 8.9 ± 0.8* 9.0 ± ± ± ± 0.9* Cesarean (%) 19.6* * 25.9* Nuchal cord (%) * * 17.9* Maternal hypertension (%) 17.2* * Maternal diabetes (%) * 14.2* Data presented as mean ± SD; n = 27,043. *P <.001 versus AGA group. P <.05. placed on ice after sampling. Subsequent analysis was usually achieved within 30 minutes of delivery and in no case longer than 60 minutes after delivery. An ABL-500 Blood Gas Analyzer (Radiometer, Copenhagen, Denmark) was used throughout the study. Oxygen saturation values were calculated from the umbilical cord PO 2 and ph data obtained from the computerized database with a previously derived empirical equation relating oxygen tension, percentage saturation, and ph in fetal blood, whereby log PO 2 = ph log S/100 - S in which S indicates oxygen saturation. 14 Fractional oxygen extraction values were calculated as: (Umbilical Vein Oxygen Saturation Umbilical Artery Oxygen Saturation) / Umbilical Vein Oxygen Saturation Size at birth was divided into the following 5 birth weight categories determined on the basis of birth weight percentile in relation to weeks of gestation attained at the time of delivery as previously reported 13 : (1) fetal growth restriction (FGR) birth weight <3rd percentile, (2) borderline fetal growth restriction (bfgr) birth weight 3rd percentile and <10th percentile, (3) appropriate for gestational age (AGA) birth weight 10th percentile and 90th percentile, (4) borderline large for gestational age (blga) birth weight >90th percentile and 97th percentile, and (5) large for gestational age (LGA) birth weight >97th percentile. Neonatal growth standards corrected for gender have been determined on the basis of 1,119,440 births that occurred in Canada and were published by Arbuckle, Wilkins, and Sherman 15 ; these growth standards were used for the birth weight categorization. The birth weight cutoffs at each gestational week used in the present study from these neonatal growth standards have previously been published. 13 Data analysis. The effect of birth weight category on umbilical cord gases, oxygen saturation, fractional oxygen extraction, and the birth to placental weight ratio was examined, along with the relationship to maternal age, parity, Apgar scores, cesarean rate, nuchal cord incidence, incidence of maternal hypertensive disorder, and incidence of maternal gestational or insulin-dependent diabetes. Data are presented as grouped mean ± SD; statistical significance between groups was determined by analysis of variance with post hoc Dunnett s test for continuous variables or χ 2 analysis with a Bonferonni adjustment for dichotomous variables. Adjustments to the statistical significance between groups for potentially confounding variables were made by means of analysis of covariance. The AGA group was used as reference against the other 4 groups (FGR, bfgr, blga, and LGA). Results Characteristics of the study population. Between January 1990 and December 1999, there were 27,043 term, singleton, liveborn infants delivered at St Joseph s Health Care London, London, Ontario, excluding those with major anomalies. The study population characteristics are shown by birth weight categories in Table I. The distribution of the number of neonates in each of the birth weight categories was 2.2%, 5.6%, 79.8%, 8.2%, and 4.2% for the FGR, bfgr, AGA, blga, and LGA groups, respectively. Mothers of infants in the FGR and bfgr groups were younger and of lower parity, whereas mothers of infants in the blga and LGA groups were older and of higher parity when compared with mothers of infants in the AGA group. Infants in the FGR, bfgr, blga, and LGA groups had lower Apgar scores and were more likely to be delivered by cesarean when compared with infants in the AGA group. When compared with infants in the AGA group, infants in the FGR and bfgr groups were also more likely to have a nuchal cord noted at the time of delivery, whereas infants in the blga and LGA groups were less likely. Whereas mothers of infants in the FGR group were more likely to have hypertension, mothers of infants in the blga and LGA groups were more likely to have gestational or insulin-dependent diabetes

4 Volume 185, Number 3 Lackman et al 677 Table II. Umbilical cord blood gas, ph, oxygen saturation, and fractional oxygen extraction values by birth weight category FGR bfgr AGA blga LGA (n = 495 and 464) (n = 1333 and 1253) (n = 19,253 and 18,376) (n = 2019 and 1959) (n = 1062 and 1043) Umbilical vein PO 2 (mm Hg) 25.6 ± 8.0* 26.7 ± 6.6* 28.3 ± ± ± 7.2* PCO 2 (mm Hg) 41.9 ± 7.2* 40.7 ± 7.4* 39.0 ± ± ± 6.6* ph 7.32 ± 0.06* 7.33 ± 0.06* 7.35 ± ± ± 0.06 Base excess (mmol/l) 4.6 ± 2.5* 4.3 ± 2.4* 3.9 ± ± 2.2* 3.8 ± 2.3 Oxygen saturation (%) 56.2 ± 17.1* 59.9 ± 16.5* 64.4 ± ± 14.1* 65.7 ± 14.8 Umbilical artery PO 2 (mm Hg) 13.8 ± 4.9* 14.8 ± 5.3* 15.7 ± ± ± 5.4 PCO 2 (mm Hg) 55.4 ± 9.6* 54.3 ± ± ± ± 9.3* ph 7.24 ± 0.07* 7.25 ± ± ± ± 0.06 Base excess (mmol/l) 5.3 ± 3.1* 5.0 ± ± ± ± 2.8* Oxygen saturation (%) 19.9 ± 13.6* 23.1 ± 14.9* 25.8 ± ± ± 15.0 Fractional oxygen 0.65 ± 0.19* 0.62 ± ± ± ± 0.19 extraction Data presented as mean ± SD; n values shown for vein and then for artery. *P <.001 versus AGA group adjusting for the confounding effects of mode of delivery, nuchal cord status, maternal hypertension, and maternal diabetes. P <.05. P <.01. when compared with mothers of infants in the AGA group. Umbilical cord blood gas, ph, and oxygen saturation values. Umbilical cord blood gas results were available in the computerized database for 26,116 of these deliveries (96.6%), with staff either forgetting to obtain or unable to obtain samples in the remaining cases. To obtain validated umbilical vein and artery blood gas and ph data as discussed by Westgate Garibaldi, and Greene, 16 patient data were excluded when an unreliable ph, PCO 2, or PO 2 (as indicated by the blood gas analyzer) was obtained from one or both vessels, when either the umbilical vein PO 2 was less than that of the artery or the umbilical vein PCO 2 was greater than that of the artery and thus deemed unphysiologic, and when either the umbilical venousarterial ph difference was less than 0.02 or the PCO 2 difference was less than 3.8 mm Hg, thus removing results that demonstrated a high probability that the same vessel was sampled twice. Patient data were not excluded when only a single cord blood sample was obtained, as long as this was noted to be the venous cord sample, recognizing the ease of sampling the vein compared with the artery. After these patient data exclusions, there were 24,162 and 23,095 validated umbilical vein and artery blood gas and ph results, respectively. The umbilical cord blood gas, ph, oxygen saturation, and fractional oxygen extraction values are shown by birth weight categories in Table II and in Figs 1, 2, and 3. Significant effects as shown have been adjusted for the confounding effects of mode of delivery, nuchal cord status, maternal hypertension, and maternal diabetes. Infants in the bfgr and FGR groups had umbilical vein and artery PO 2 values that were stepwise lower than the respective AGA group values (Fig 1). Infants in the blga and LGA groups had umbilical vein PO 2 values that were stepwise higher than respective AGA group values but without any change in arterial PO 2 values. Infants in the FGR, bfgr, blga, and LGA groups had umbilical vein and artery PCO 2 values that were variably higher than respective AGA group values. Infants in the bfgr and FGR groups had umbilical vein and artery base excess values that were stepwise lower than respective AGA group values, whereas corresponding values for infants in the blga and LGA groups were variably higher (Fig 2). Infants in the bfgr and FGR groups also had umbilical vein and artery ph values that were stepwise lower than respective AGA group values, reflecting both the higher PCO 2 and lower base excess values. Infants in the bfgr and FGR groups had umbilical vein and artery oxygen saturation values that were stepwise lower, whereas infants in the blga and LGA groups had umbilical vein oxygen saturation values that were higher than respective AGA group values (Fig 3), with these changes similar to those noted for the PO 2 values. Therefore infants in the bfgr and FGR groups had fractional oxygen extraction values that were stepwise higher than the AGA group values, whereas values for infants in the blga and LGA groups remained unchanged (Fig 3). Birth weight, placental weight, and birth weight to placental weight ratio values. Although birth weights were available for all 27,043 infants in the study population, placental weights were only available in the computerized database for 25,202 of these deliveries (93.2%). To avoid including data from incomplete placental material at the time of delivery (eg, piecemeal manual extraction of placenta), placental weights <3 SD below the mean for each of the 5 birth weight categories were excluded. Therefore there were 25,020 placental weight results.

5 678 Lackman et al September 2001 Fig 1. Umbilical vein (closed triangle) and artery (open triangle) PO 2 and PCO 2 values for the birth weight categories as indicated. Statistical significance between groups was determined with the AGA group as reference against the other 4 groups and adjusting for the confounding effects of mode of delivery, nuchal cord status, maternal hypertension, and maternal diabetes. Fig 2. Umbilical vein (closed triangle) and artery (open triangle) ph and base excess values for the birth weight categories as indicated. Statistical significance between groups was determined with the AGA group as reference against the other 4 groups and adjusting for the confounding effects of mode of delivery, nuchal cord status, maternal hypertension, and maternal diabetes. The birth weight, placental weight, and birth to placental weight ratio values are shown by birth weight categories in Table III. The significant effects shown have been adjusted for the confounding effects of maternal age, parity, nuchal cord status, maternal hypertension, and maternal diabetes. With the increase in birth weight values through the 5 birth weight categories, there was an associated increase in placental weight values. Birth weight was proportional to placental weight for the infants in the blga and LGA groups when compared with infants in the AGA group, with the birth to placental weight ratio values unchanged. However, birth weight was disproportional to placental weight for the infants in the bfgr and FGR groups, with the birth to placental weight ratio values stepwise decreased. Comments In this large-population study of infants born at term and using information prospectively entered into our perinatal database, several variables were found to inter-

6 Volume 185, Number 3 Lackman et al 679 Fig 3. Umbilical vein (closed triangle) and artery (open triangle) calculated oxygen saturation and fractional oxygen extraction values for the birth weight categories as indicated. Statistical significance between groups was determined with the AGA group as reference against the other 4 groups and adjusting for the confounding effects of mode of delivery, nuchal cord status, maternal hypertension, and maternal diabetes. P <.05 vs AGA; +P <.01 vs AGA; *P <.001 vs AGA. Table III. Birth weight, placental weight, and birth to placental weight ratio values by birth weight category FGR bfgr AGA blga LGA (n = 581 and 539) (n = 1519 and 1427) (n = 21,588 and 20,037) (n = 2206 and 2027) (n = 1149 and 990) Birth weight (g) 2373 ± 276* 2710 ± 184* 3403 ± ± 183* 4484 ± 281* Placental weight (g) 485 ± 105* 538 ± 103* 662 ± ± 125* 856 ± 120* Birth to placental 5.08 ± 1.05* 5.20 ± ± ± ± 0.80 weight ratio Data presented as mean ± SD; n values shown for birth weight and then for placental weight. *P <.001 versus AGA group adjusting for the confounding effects of maternal age, parity, nuchal cord status, maternal hypertension, and maternal diabetes. P <.05. act with birth weight categorization in keeping with a causal effect on size at birth as previously reported. 17 Infants in the FGR and bfgr groups were born to mothers of lower age and parity and with an increased incidence of hypertension; these infants were also more likely to have a nuchal cord. Conversely, infants in the LGA and blga groups were born to mothers of higher age and parity and with an increased incidence of diabetes and were less likely to have a nuchal cord. Moreover, all 4 of these groups were more likely to be delivered by cesarean when compared with infants in the AGA group; this may, in turn, have an impact on cord gases and ph at delivery. 18 Therefore the confounding effects of these variables were adjusted for when determining the interactive effect of birth weight category on umbilical cord gas and birth to placental weight ratio values. To our knowledge, this is the first large-population study demonstrating the association between birth weight categories and umbilical cord gas and ph values studied at term. These values obtained at birth from the umbilical vein and artery can be affected by the events of labor 11 ; additionally, values for the umbilical artery can be affected by alterations in cord blood flow with the delivery process. 12 However, to the extent that such effects are similar across the 5 birth weight categories or are adjusted for by mode of delivery, these values should also be reflective of longer-term metabolic status. Oxygen saturation values were calculated from the umbilical cord PO 2 and ph data with a previously derived empirical equation and, although highly accurate for values above 20%, will serve to underestimate lower values. 14, 18 Therefore mean oxygen saturation values reported herein will also be underestimated; this is especially true for the umbilical artery. However, although the degree of any effect on values from the umbilical artery will tend to be exaggerated, this should not negate the significant effect of birth weight categorization on these values and on fractional oxygen extraction. Fetal oxygen extraction is the ratio between fetal

7 680 Lackman et al September 2001 oxygen consumption and oxygen delivery and thus is a measure of the amount of oxygen consumed by the fetus as a fraction of that delivered; it can be calculated as the difference between umbilical venous and arterial blood oxygen contents divided by umbilical venous oxygen content. Because oxygen content is directly proportional to the oxygen saturation of blood and because hemoglobin values remain unchanged across the umbilical circulation, 19 oxygen saturation can be used in place of oxygen content in this calculation. Umbilical vein PO 2 and oxygen saturation values studied were stepwise lower for the infants in the bfgr and FGR groups and higher for infants in the blga and LGA groups when compared with respective values for the infants in the AGA group. These values are directly related to uterine oxygen delivery and to the diffusion and transport properties of the placenta 20 and indicate a graded reduction in these aspects of oxygen transport to the fetus in relation to size at birth. Although oxygen delivery to the fetus is also dependent on hemoglobin values and umbilical blood flow, it is likely that this is similarly reduced to the extent that increases in hemoglobin reported for the growth-restricted fetus 6, 7 are offset by decreases in umbilical blood flow with the reported increase in Doppler-measured resistance indices. 21 Size at birth across the entire range of birth weights studied at term can thus be seen as a continuum in relation to fetal oxygenation; this supports the concept that the maternal and uterine environment and placental development normally determine and limit fetal growth. 17 Umbilical artery PO 2 and oxygen saturation values were also stepwise lower for the infants in the bfgr and FGR groups, indicating a corresponding lowering of systemic oxygen levels. These values are directly related to fetal oxygen delivery and inversely related to fetal oxygen consumption; thus umbilical artery PO 2 and oxygen saturation values are also inversely related to fetal oxygen consumption relative to oxygen delivery, that is, to fractional oxygen extraction. 20 Therefore these values indicate a graded increase in fractional oxygen extraction as measured in relation to size at birth for growthrestricted fetuses. As such, growth restriction in the human fetus and the corresponding reduction in metabolic consumptive needs in response to reductions in either oxygenation, other nutrients, or both can be seen as insufficient to result in normalization of systemic oxygen levels. The increased fractional oxygen extraction noted for infants in the FGR group at term is similar to the value we have previously reported for infants born post term 18 ; this indicates a lowered oxygen margin of safety as a measure of the oxygen reserve available and thus a lower tolerance for hypoxia-related events. It should be noted that umbilical artery PO 2 and oxygen saturation values were unchanged for infants in the blga and LGA groups when compared with respective values for infants in the AGA group, indicating similar systemic oxygen levels and fractional oxygen extraction values as measured in these infant groups. Therefore macrosomia in the human fetus and the corresponding increase in metabolic consumptive needs in response to increases in either oxygenation, other nutrients, or both can be seen as sufficient to result in a normalization of systemic oxygen levels. Infants in the FGR, bfgr, blga, and LGA groups had umbilical vein and artery PCO 2 values that were variably higher than respective AGA values, indicating an increase in fetal production of carbon dioxide and thus in placental carbon dioxide delivery relative to placental clearance. Infants in the bfgr and FGR groups had umbilical vein and artery base excess values that were stepwise lower than respective AGA values, suggesting an increase in fetal production of lactate relative to placental clearance as the principal fixed acid contributing to metabolic acidosis in the fetus. 22 Conversely, infants in the blga and LGA groups had umbilical vein and artery base excess values that were higher than respective AGA values, suggesting a decrease in fetal production of lactate relative to placental clearance. Infants in the bfgr and FGR groups also had umbilical vein and artery ph values that were stepwise lower than respective AGA values, reflecting both the higher PCO 2 and lower base excess values. Although the level of significance for the effects of birth weight categorization on these cord measurements has been adjusted for presence of labor and mode of delivery, it is well known that carbon dioxide values normally increase during labor, whereas base excess values normally decrease. 22 Although not specifically studied, these labor-related effects are likely to be greater in the growth-restricted fetus with poor placental function. In the present study we have determined birth to placental weight ratio values as a crude measure of placental development in relation to size at birth for a large tertiary hospital population delivering at term. Values reported are similar to those we 23 have previously reported for patients at term but are considerably lower than those in which the placenta has been trimmed and drained of blood before weighing. 24, 25 In the largest study to date relating birth to placental weight ratio to size at birth, Molteni, Stys, and Battaglia 25 found no significant differences among infants in the FGR, AGA, and LGA groups. However, fewer patients were studied, with only 91 term, small for gestational age infants and birth to placental weight ratio values were, in fact, slightly lower for these infants. In a recent study of term infants with normal birth weights, low birth to placental weight ratios were associated with increased rates of low birth weight to head circumference ratio and low ponderal index as markers for asymmetric growth. 26 Infants in the

8 Volume 185, Number 3 Lackman et al 681 bfgr and FGR groups here studied had birth to placental weight ratios that were stepwise lower than respective AGA values, whereas values for infants in the blga and LGA groups were unchanged. Therefore the growth-restricted fetus can be seen as undergrown in relation to placental size, suggesting functional rather than size constraints for the placenta; the macrosomic fetus can be seen as proportionally grown in relation to placental size, suggesting normal placental function. These findings, which were determined on the basis of cohort population analysis, are consistent with the views of Kingdom and Kaufmann, 10 in which preplacental or uteroplacental hypoxia with adaptive placental growth is a primary cause for growth restriction at term. However, the nonplacental chorion and amnion also contribute to overall placental weight, and more so for the smaller gestational age infant 24 ; this may also account, at least in part, for the lower birth to placental weight ratio of infants in the FGR and bfgr groups. In this large tertiary hospital population delivering at term, we have demonstrated a significant relationship between birth weight categorization and thus size at birth, and umbilical cord PO 2, umbilical cord oxygen saturation, fractional oxygen extraction, and birth to placental weight ratio values. These findings provide insight to the regulatory linkages between fetal oxygenation and fetal and placental growth to the extent that these measurements are reflective of longer-term oxygenation and metabolic and developmental processes. The findings support fetal oxygenation as a primary determinant of fetal growth and thus size at birth for the human infant, given the graded reduction in umbilical vein oxygen values across the entire range of birth weights as studied from macrosomic to growth-restricted infants. However, the decrease in growth and therefore in size at birth for growth-restricted infants can be seen as insufficient to result in normalization of umbilical artery oxygen values as a measure of systemic oxygen levels when compared with that of appropriately grown infants. Conversely, the increase in growth and in size at birth for macrosomic infants can be seen as sufficient to result in normalization of umbilical artery oxygen values and thus systemic oxygen levels. These findings suggest a difference in the linkage between fetal oxygenation and metabolic rate or growth for these cohort groups that may relate to underlying causes. Therefore a mechanistic model is proposed in which most growth-restricted infants as studied at term can be seen as having constraints in their oxygenation that are likely to be extrinsic and maternal, or uterine in origin, resulting in an adaptive increase in placental size in relation to birth weight. Conversely, most macrosomic infants can be seen as having increases in their oxygenation that may be intrinsically determined through placentation and thus with proportional placental size in relation to birth weight. We thank Mr Larry Stitt for his expertise in statistical analysis and Mr Russell Wilkins from Statistics Canada for providing Canadian birth weight percentile cut-off values. REFERENCES 1. Clapp JF, Szeto HH, Larrow R, Hewitt J, Mann LI. Fetal metabolic response to experimental placental vascular damage. Am J Obstet Gynecol 1981;140: van Geijn HP, Kaylor WM, Nicola KR, Zuspan FP. Intrauterine growth retardation by lowered ambient oxygen concentration. 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