The efforts to successfully manage pregnancy and delivery are traditionally evaluated in terms of the newborn's condition at birth, umbilical cord blood acid–base status, operative delivery rates, transfer to the neonatal care unit, neonatal survival, and subsequent handicap. For a meaningful international comparison of outcome variables, the variable definitions should be uniform.
To enable fair comparisons of standardized outcome variables, other factors (eg, place of birth, parity, mode of delivery, gestational age) are obvious confounders requiring stratification. In this context, term pregnancies from 37 to 42 weeks are usually regarded as a homogeneous group with stable perinatal outcome variables during the 5-week period.
Umbilical cord blood acid–base status at birth is regarded as important for evaluation of the newborn's condition. As an outcome variable, cord blood metabolic acidosis implies an increased risk of developing later motor and cognitive defects.1 However, there is no consensus on the pH definition of acidosis. In Sweden, traditionally a cord artery pH of less than 7.10 is considered indicative of fetal acidemia. This value corresponds to the mean value minus two standard deviations (SDs).2,3 Other authors have used an index value of 7.20,4 whereas a cutoff at 7.00 seems to represent a critical limit for the risk of neonatal death or neurologic handicap.1,5,6 Unless the umbilical artery pH is less than 7.00 and Apgar scores are less than 4 at both 1 and 5 minutes, newborns are at low risk of neonatal complications resulting from intrapartum asphyxia.5 The American College of Obstetricians and Gynecologists7 supports the use of an arterial pH of less than 7.00 as a clinically useful cutoff.
The aims of the present study were twofold: First, to define the reference intervals of pH in arterial cord blood as a function of gestational age in alert newborns at term. Second, to compare the association between Apgar score and pH according to a stationary definition of cord acidemia and to a gestational age–adjusted definition of a low pH, respectively.
MATERIALS AND METHODS
Data were collected from the Perinatal Revision South Registry database. The registry is a project in perinatal medicine, comprising all 11 hospitals with delivery units in the southern Swedish region and based on approximately 16,000 annual births. The project started in 1995, with the main purpose of quality assurance of perinatal care.8 Two of the delivery units are university departments with approximately 3000 deliveries a year, five are central hospitals with 1500–2000 deliveries, and four are county hospitals with less than 1000 deliveries per year. Registry-based scientific research, without identification of individuals, and rules for publication have been approved by the South Swedish Regional Board of Chairmen representing the involved departments.
The study comprised a 6-year period from 1995 to 2000. Inclusion criteria were singleton pregnancies aimed for vaginal delivery after 37 completed gestational weeks and for which information on year of birth, delivery unit, maternal age and parity, and Apgar scores was available in the database. Exclusion criteria were elective cesarean delivery, preterm delivery, multiple pregnancy, and cases without pertinent information. With the aim to define cord artery pH reference intervals of alert term newborns, 24,390 singleton infants with an Apgar score of 9 or greater at 5 minutes were included (cohort 1). This cohort was retrieved only from the two university departments, where cord blood analysis was routinely done in all newborns. At the other nine departments, cord blood gas samples were analyzed at the discretion of the obstetric staff. With the aim to investigate potential risks associated with a low pH (ie, in this study, a 5-minute Apgar score less than 7), cord blood gas status was available in 44,978 (cohort 2) of 82,386 cases (cohort 3) collected from all 11 hospitals; demographic data of the three cohorts are presented in Table 1.
Immediately after birth, and ideally before the newborn's first breath, cord blood was sampled in preheparinized syringes; arterial and venous blood gases were analyzed within 15 minutes. The analyses included pH and base excess.
A stationary cord artery acidemia was defined as a pH less than 7.10, and a gestational age–dependent acidemia as a pH less than (mean – 2 SDs). A base excess of 12 mmol/L or less was regarded indicative of metabolic acidosis in combination with an arterial pH of less than 7.10.
Term pregnancy was defined as a gestational age between 37 completed weeks (37 weeks) and 41 6/7 weeks according to routine ultrasound dating in the early second trimester.9 Postterm pregnancy was defined as a gestational age of 42 or more completed weeks, corresponding to 294 or more days.
A linear regression analysis was performed to estimate the expected pH with regard to gestational age. An analysis of variance was used to estimate the SD of umbilical artery pH. A two-tailed P of less than .05 was regarded as statistically significant. Risk assessments were expressed as odds ratio (ORs) according to the Mantel–Haenszel technique.10 Stratification was made for year of birth, delivery unit, maternal age (5-year classes), and parity (previous deliveries 0, 1, 2, and 3+, respectively). Ninety-five percent confidence intervals (CIs) were estimated using the Miettinen method.11 When comparing two stratified ORs, two-tailed z tests were carried out, using the same variance as used to estimate the 95% CI. Tests of homogeneity of the ORs across strata were based on weighed sums of the squared deviations of the stratum specific log-ORs from their weighed means (Appendix). To detect putative linear trends among a series of stratified ORs, weighed linear regression analyses were carried out (Appendix).
Table 2 shows that the mean umbilical artery pH decreased with increasing gestational age. Among all alert term newborns, the mean (± SD) cord artery pH, obtained by an introductory variance analysis, was 7.238 (± 0.081). Thus, the SD was estimated to be 1.123% of the mean.
The negative linear relationship between cord artery pH and gestational age was highly significant (P < 10−6, regression coefficient [per day of gestational age] − .00096). Based on this estimate and the SD estimated in the introductory variance analysis, the reference interval for cord artery pH with regard to gestational age was estimated according to the formula y = m + β · [x − xm], where y = pH, m = 7.238, β = − .00096, x = gestational age in days, and xm = 280.100. Under the assumption of a constant SD/mean pH ratio over gestational age strata (1 SD = 1.123% of the mean), the upper (I+) and lower (I−) 95% reference limits could be estimated by the equation I± = y ± 1.96 · SD, where SD = 0.01123 · y. The results of these estimations are displayed in Figure 1.
In Table 3 the number of newborns with low cord artery pH and low Apgar scores is shown in relation to gestational age at delivery. In 759 of 2872 newborns (26.4%) with a cord artery pH less than 7.10 the pH was within the gestational age–adjusted mean ± 2 SDs reference range. The OR trend curves for pH less than 7.10 and pH less than (mean – 2 SDs) relative to gestational age are displayed in Figure 2. The risk for pH less than 7.10 increased linearly with gestational age. This was true irrespective of whether metabolic acidosis was present (figure not shown). For example, the ORs (95% CIs) for pH less than 7.10 among infants born after 41 3/7 weeks' gestation were 1.48 (1.26, 1.72) and 1.41 (1.15, 1.73) among infants with and without metabolic acidosis, respectively. For infants born postterm, the corresponding ORs were 1.63 (1.37, 1.93) and 1.25 (0.98, 1.59), respectively, and the difference was not significant (P = .08).
The OR trend curve for low pH according to the gestational age–dependent definition of less than (mean – 2 SDs) showed no linear association with gestational age but a significant increase after 42 weeks (OR 1.24; 95% CI 1.05, 1.47) (Figure 2). Within the interval of 37–41 weeks, no association between gestational age and a low Apgar score was demonstrated, but a statistically significant positive association between a gestational age of 41 3/7 weeks or more and Apgar score less than 7 at 5 minutes was found (OR 1.85; 95% CI 1.57, 2.18) (Figure 3).
The clinical implication of a low pH was expressed as the ORs for an Apgar score less than 7 at 5 minutes among newborns with a cord artery pH less than 7.10 and less than (mean – 2 SDs), respectively. A strong positive association between low Apgar score and low pH was found. A linear decrease of the association between Apgar score less than 7 and pH less than 7.10 with increasing pregnancy duration was indicated but statistically not significant (P for linear trend = .097) (Figure 4). For pH less than (mean – 2 SDs) the results did not suggest that the association with a low Apgar score was less in the postterm period than at term (Figure 4).
Figure 5 displays the mean cord artery pH in different Apgar score cohorts as a function of gestational age. The Apgar score 9 to 10 cohort corresponds to Figure 1. The Apgar score 7 to 8 cohort showed a decreasing trend similar to the 9 to 10 cohort, with significantly lower pH at all gestational ages. The Apgar score 0–6 cohort displayed a different curve, with significantly lower pH than the other two cohorts but without any linear decrease of the mean pH during the term period.
This study showed that in term alert newborns the mean umbilical cord arterial blood pH at birth decreased linearly with gestational age. The corresponding reference interval revealed that the lower cutoff level (mean – 2 SDs) was 7.10 at 37 weeks and 7.06 at more than 42 weeks. This gestational age–dependent change was apparently a physiologic phenomenon because we in this aspect only studied alert newborns. A gestational age–dependent effect on cord blood gases and pH has been reported previously,2,12,13 and the obvious consequence of these and our findings is to question whether a stationary reference interval of cord artery pH is an accurate parameter to use for obstetric quality assurance.
For two decades we have routinely used a stationary pH cutoff value as an obstetric quality parameter at our departments. We have then regarded an arterial blood pH of less than 7.10 as an index of fetal acidemia, assuming that pH does not significantly vary with gestational age. In contrast, we found in the present study that the OR trend curve for arterial pH less than 7.10 followed an almost linearly increasing trend, from being at a significantly lower risk at 37 weeks to a significantly higher risk of acidemia at 42 weeks. This strongly suggests that arterial pH depends on gestational age.
Although pH reflects a biochemical course of events and Apgar score the newborn's vitality and alertness, the two outcome variables are expected to perform in parallel. In contrast to the pH less than 7.10 OR trend curve, the risk of having a 5-minute Apgar score less than 7 was independent of gestational age and showed no increased risk until the postterm period. At a stationary cutoff at pH less than 7.10, the Apgar score less than 7 OR trend curve showed a linear decrease with gestational age. This means that with a stationary definition of acidemia the risk of a low Apgar score in acidemic newborns should decrease with gestational age. Because this finding seemed nonphysiologic, we subsequently analyzed the same association when using a gestational age–adjusted definition of a low pH (ie, less than mean – 2 SDs) and found that during the term period the Apgar score less than 7 OR trend curve showed no association with gestational age. The gestational age–dependent pH cutoff value proved better to reflect a pathophysiologic course of event when expressed in terms of a low Apgar score.
These findings suggest that even within the narrow 5-week period of term pregnancy significant biochemical changes occur. With a stationary pH cutoff, the present study indicates that every fourth newborn with a pH less than 7.10 at term will be marked with a diagnosis of cord blood acidemia despite having a pH within the gestational age–adjusted reference range of mean ± 2 SDs. Therefore, a stationary low cord artery pH cutoff as a surrogate index of suboptimal fetal outcome should be questioned.
The physiologic mechanisms explaining the continuous decrease of cord artery pH are not known. Helwig et al2 found a higher pH in preterm newborns than in term and postterm newborns and suggested a shorter labor to be the explanation. However, Nicolaides et al12 and Weiner et al,13 in cordocentesis series starting at 18 to 19 gestational weeks, found linearly decreasing umbilical arterial and venous pH, which excludes labor as a main reason. These authors also found a linear increase of umbilical arterial and venous carbon dioxide pressure (tension) (PCO2) and of bicarbonate with gestational age. Because lactate concentration remains unchanged throughout gestation,12 we speculate that a respiratory component with a gradual rise of PCO2 parallel to the increasing body mass of the growing fetus, in combination with an impaired placental exchange of compounds across the membranes in the aging placenta, might be involved. The fetal metabolism produces organic and carbonic acids. Organic acids are eliminated mainly through the kidneys, but carbonic acid is converted to CO2 and water, whereupon CO2 is cleared through the placental circulation.
By aging of placental membranes the capacity of CO2 to cross the placenta and escape through the maternal circulation might be impaired. The placental growth and development slow down already from 36 to 37 weeks,14 as demonstrated by an increasing birth weight/placental weight ratio by gestational age.15 By an increase of CO2 and accumulation of carbonic acid the pH decreases, reflecting a trend towards respiratory acidemia. Although the present results indicate that in postterm pregnancy cord acidemia is more pronounced in the presence of metabolic acidosis, the tendency of an increased risk of low pH also in the absence of metabolic acidosis supports this theory. In postterm pregnancy a critical lower pH level might be reached, below which fetal metabolic processes are disturbed.
In summary, this study defined reference values for umbilical artery pH in 24,390 alert newborns born at term. A significant negative correlation was found between gestational age at delivery and umbilical cord artery pH: Mean pHs were 7.26 at 37 weeks and 7.22 at 42 weeks. The corresponding cutoff values for definition of cord blood acidemia, representing the mean value – 2 SDs, were 7.10 and 7.06. The OR for a pH of less than 7.10 continuously increased throughout the term period, from 0.6 at 37 weeks to 1.5 at 42 weeks. In contrast, the OR for pH less than (mean – 2 SDs) was steady until 42 weeks. To assess the risk of a suboptimal outcome relative to a low cord pH when using the two different definitions of cord blood acidemia, we calculated the OR for a 5-minute Apgar score less than 7 in 44,978 term deliveries. A linear decrease of the association between Apgar score less than 7 and pH less than 7.10 with increasing pregnancy duration was indicated (P = .097), but for pH less than (mean – 2 SDs) there was no such association. We conclude that umbilical artery pH in vigorous infants born at term decreased with gestational age and that a gestational age–adjusted lower pH cutoff level better reflected the newborns' vitality than a stationary definition of cord acidemia. A stationary pH limit for acidemia may brand a newborn as having been exposed to significant hypoxia, and a diagnosis of acidosis is settled despite a cord artery pH within physiologic limits. This should also be considered when cord pH is used as a measure of obstetric care quality.
1. Low JA, Galbraith RS, Muir DW, Killen HL, Pater EA, Karchmar EJ. Factors associated with motor and cognitive deficits in children after intrapartum fetal hypoxia. Am J Obstet Gynecol 1984;148:533–9.
2. Helwig JT, Parer JT, Kilpatrick SJ, Laros RK. Umbilical cord blood acid-base state: What is normal? Am J Obstet Gynecol 1996;174:1807–14.
3. Herbst A, Wölner-Hanssen P, Ingemarsson I. Risk factors for acidemia at birth. Obstet Gynecol 1997;90:125–30.
4. Bretscher J, Saling E. pH values in the human fetus during labor. Am J Obstet Gynecol 1967;97:906–11.
5. Gilstrap LC, Leveno JK, Burns J, Williams ML, Little BB. Diagnosis of birth asphyxia on the basis of fetal pH, Apgar score, and newborn cerebral dysfunction. Am J Obstet Gynecol 1989;161:825–30.
6. Goldaber KG, Gilstrap LC, Leveno KJ, Dags JS, McIntire DD. Pathological fetal acidemia. Obstet Gynecol 1991;78:1103–8.
7. American College of Obstetricians and Gynecologists. Umbilical artery blood acid-base analysis. Technical bulletin no. 216. Washington: American College of Obstetricians and Gynecologists, 1995.
8. Molin J. A regional perinatal database in southern Sweden—a basis for quality assurance in obstetrics and neonatology. Acta Obstet Gynecol Scand 1997;76 Suppl 164:37–9.
9. Persson P-H, Weldner B-M. Intra-uterine growth curves obtained by ultrasound. Acta Obstet Gynecol Scand 1986; 65:169–73.
10. Mantel N, Haenszel W. Statistical aspects of the analyses of data from retropsective studies of disease. J Natl Cancer Inst 1959;22:719–48.
11. Miettinen OS. Simple interval estimation of risk ratio. Am J Epidemiol 1974;100:515–25.
12. Nicolaides KH, Economides DL, Soothill PW. Blood gases, pH, and lactate in appropriate- and small-for-gestational-age fetuses. Am J Obstet Gynecol 1989;161:996–1001.
13. Weiner CP, Sipes SL, Wenstrom K. The effect of fetal age upon normal fetal laboratory values and venous pressure. Obstet Gynecol 1992;79:713–8.
14. Vorherr H. Placental insufficiency in relation to postterm pregnancy and fetal postmaturity. Evaluation of fetoplacental function: Management of the postterm gravida. Am J Obstet Gynecol 1975;123:67–103.
15. Molteni RA, Stys SJ, Battaglia FC. Relationship of fetal and placental weight in human beings: Fetal/placental weight ratios at various gestational ages and birth weight distributions. J Reprod Med 1978;21:327–34.