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Assessment of lactate production as a response to sustained intrapartum hypoxia in large‐for‐gestational‐age newborns

Abstract Introduction Lactate concentration in umbilical cord blood is an important measure of intrapartum anaerobic metabolism. The aim of the study was to compare lactate production of large‐for‐gestational‐age (LGA) fetuses against appropriate‐for‐gestational‐age (AGA) fetuses during hypoxia, in diabetic and non‐diabetic mothers. Material and methods A total of 17 358 validated paired arterial and venous umbilical cord blood samples taken at birth with a full panel of pH, glucose, and lactate were analyzed relative to LGA (n = 2789) and AGA (n = 14 569). Umbilical cord blood acidemia (pH < mean minus 2 SD) was identified in 518 cases. Results Diabetes, but not acidemia, was more common among LGA (5.4%) than AGA cases (2.9%) (respectively P < .0001 and P < .69). At normal pH, glucose was lower in non‐diabetes LGA cases, but not in diabetes LGA compared with corresponding AGA cases (respectively P < .0001 and P < .067). Glucose levels were higher in all groups during acidemia (P ≤ .0005), with lower values in non‐diabetes LGA but not in diabetes LGA compared with corresponding AGA cases (respectively P = .005 and P < .58). At normal pH, lactate was lower in non‐diabetes LGA but not in diabetes LGA compared with corresponding AGA cases (respectively P < .0001 and P < .98); during acidemia, lactate levels were higher in all groups (P < .0001), resulting in no significant difference between LGA and AGA in diabetes as well as in non‐diabetes cases (respectively P = .29 and P < .084). Conclusions Considering cord acidemia a proxy for intrapartum hypoxia, LGA fetuses showed no impaired ability to produce lactate during hypoxia. Maternal diabetes did not hamper the ability of LGA fetuses to produce lactate during hypoxia.

Based on observations made already during the 1920s, Pedersen launched his well-known hypothesis in the 1960s, highlighting the effect of maternal hyperglycemia in diabetic pregnancies leading to fetal hyperglycemia, which in turn causes fetal hyperinsulinism and subsequent "fetal gigantism" and metabolic dysfunction. 7 This correlation between maternal hyperglycemia, fetal hyperglycemia, and resultant fetal hyperinsulinism is well established 8 and is not limited to diabetes only but covers the whole range of maternal glycemia. 9 Large-for-gestational-age (LGA) fetuses in general show hyperinsulinism resulting in increased deposits of adipose tissue and overweight. [10][11][12] Chronic hyperglycemia and hyperinsulinemia independently and additively affect aerobic and anaerobic metabolism with subsequent increase in oxygen consumption, hypoxemia, acidemia, and lacticemia, as experimentally demonstrated in fetal sheep. [13][14][15] The link between hyperinsulinemia, macrosomia, and chronic hypoxemia is recognized in human fetuses as well, 8 which could explain the higher umbilical cord blood lactate found in LGA newborns. 2 However, in fetuses exposed to labor, it cannot be determined to what degree lacticemia is due to antenatal chronic hypoxemia and to intrapartumsustained oxygen deficit. Holzmann et al 16 found lower scalp blood lactate levels in LGA fetuses as compared with appropriatefor-gestational-age (AGA) fetuses in a series where non-reassuring cardiotocograms indicated fetal scalp blood sampling. This raises the question of whether LGA fetuses have an impaired ability to produce lactate when exposed to hypoxia. Holzmann and co-workers concluded that hypoxic LGA fetuses had no impaired ability to produce lactate compared with hypoxic AGA fetuses, but because they used lacticemia as a proxy for hypoxia involving comparison of fetuses with scalp lactate >4.8 mmol/L, selection bias was introduced and a difference could thus not be expected.
In this study, we addressed this issue using cord blood acidemia as a proxy for intrapartum hypoxia. We compared umbilical cord blood glucose and lactate concentrations relative to AGA and LGA birthweight cohorts in diabetic and non-diabetic pregnancies during aerobic and anaerobic conditions. We hypothesized that LGA fetuses would have higher glucose and lactate levels than AGA fetuses during non-acidemic conditions, but that during acidemia they would show lower lactate values. Since insulin inhibits glycogenolysis of glycogen to glucose, 17 endogenous glucose might be abated and we therefore also wanted to estimate the maternal glucose supply across the placenta. AGA was defined as a birthweight within the 10th to the 90th percentile interval, LGA as above the 90th percentile, and small-forgestational-age as below the 10th percentile relative to our fetal weight reference curve. 21 In Southern Sweden, a 75-g oral glucose tolerance test is routinely performed at all maternal healthcare service centers at gestational week 28 in normal pregnancies. Gestational diabetes mellitus (GDM) was defined as a 2-hour capillary blood glucose value ≥9.0 mmol/L tested with a HemoCue blood glucose analyzer (HemoCue AB, Ängelholm, Sweden) in 2 consecutive blood samples. 22 Women with a 2-hour value between 7.8 and 8.9 mmol/L were retested after 1 week.
Women diagnosed with GDM were followed at a specialist antenatal care clinic until delivery, as were women with type 1 or type 2 pregestational diabetes mellitus.

| Ethical approval
The study was approved by the Regional Research Ethics Committee

| RE SULTS
Demographic data of the study population is shown in Table 1.
Significant differences between AGA and LGA cohorts were found for nulliparity, diabetes, spontaneous vaginal delivery (SVD), and gestational age. There was a negative association between gestational age and weight deviation in percent from the gestational age-adjusted mean weight (WD%) (r 2 = .004, P < .0001) and SVD occurred less often among nulliparae (79%) than among multiparae (93%) (P < .0001). The possible influences of demographic factors on glucose and lactate values were estimated using multiple logistic regression analyses (see below).
The umbilical cord arterial plasma glucose concentration was positively associated with gestational age (r 2 = .015, P < 0.0001) and negatively associated with WD% (r 2 = .006, P < .0001), but not with birthweight (P = .89). Using multiple linear regression analysis, TA B L E 1 Demographic characteristics of the study population Statistics performed with the Mann-Whitney U test, Chi-square test or Fisher's exact test.
glucose concentration was found to be independently associated with both gestational age (P < .0001) and WD% (P < .0001).
Cord artery concentrations of glucose and lactate were linearly   F I G U R E 1 Plot of umbilical cord blood arterial glucose-tolactate values in 80 large-for-gestational-age (LGA) and 438 appropriate-for-gestational-age (AGA) acidemic newborns. Acidemia was defined as a cord artery pH below the gestational age-adjusted mean value minus 2 standard deviations Diabetes vs

Diabetes (P)
Normal pH a Normal pH was defined as cord artery pH equal to or greater than the gestational age-adjusted mean value minus 2 SD, and acidemia as pH less than the mean minus 2 SD.
or lacticemia (P = .18). Significant differences were found for LGA  Table 2 shows the umbilical artery glucose concentration relative to birthweight cohorts, diabetes, and acidemia. At normal pH, glucose was lower in LGA cases than AGA cases in both non-diabetes and diabetes cases, but the differences were significant only in the nondiabetes group. No significant differences in glucose concentration were found between non-diabetes and diabetes, either for LGA or for AGA cases with normal pH.

| Glucose concentration relative to birthweight groups, diabetes, and acidemia
At acidemia, glucose was significantly higher in all groups.
Glucose was significantly lower in non-diabetes LGA than nondiabetes AGA, but not in diabetes LGA vs diabetes AGA. In addition, significantly higher glucose levels were observed in diabetes than non-diabetes in LGA cases, but not in AGA cases.
Calculated for non-acidemic cases, including gestational age as a continuous variable and nulliparity and SVD as dichotomous variables, multiple logistic regression analysis showed that the significant differences in glucose concentration displayed in Table 2 remained for non-diabetes AGA vs non-diabetes LGA (P = .002), and the absence of significant difference remained for diabetes AGA vs diabetes LGA (P = .97).
In cases with lacticemia (n = 562), the cord arterial glucose concentration was not significantly different in LGA (n = 83) and AGA (n = 479) cases (P = .35). Table 3 shows the umbilical artery lactate concentration relative to birthweight cohorts, diabetes, and acidemia. At normal pH, lactate was lower in LGA cases than in AGA cases in non-diabetes, but in cases of diabetes there was no difference. No significant differences were observed between non-diabetes and diabetes, either for LGA or for AGA cases (Figure 2).

| Lactate concentration relative to birthweight groups, diabetes, and acidemia
In the presence of acidemia, lactate was significantly higher in all groups. However, there were no significant differences between LGA and AGA, either for non-diabetes (P = .084) or for diabetes.
Calculated for non-acidemic cases, including gestational age as a continuous variable and nulliparity and SVD as dichotomous variables, multiple logistic regression analysis showed that the significant differences in lactate concentration displayed in Table 3 remained for non-diabetes AGA vs non-diabetes LGA (P < .0001), and the absence of significant difference remained for diabetes AGA vs diabetes LGA (P = .27).
At normal pH, the lactate-to-glucose ratio was significantly higher in non-diabetes AGA cases than non-diabetes LGA cases (P < .0001), but for diabetes cases there was no difference (P = .33) (table not shown Normal pH was defined as cord artery pH greater than or equal to the gestational age-adjusted mean value minus 2 SD, and acidemia as pH less than the mean minus 2 SD.

| BD ecf and metabolic acidosis relative to birthweight groups
Arterial BD ecf could be calculated in 17 243 cases (pCO 2 values were missing in 115 cases). Metabolic acidosis status could be determined in 17 354 cases (111 of 115 cases with missing pCO 2 had a pH greater than the mean minus 2 SD, ie no metabolic acidosis by definition).
Umbilical cord artery BD ecf was significantly lower in non-diabetes LGA cases compared with non-diabetes AGA cases (P < .0001), but for diabetes LGA vs diabetes AGA there was no significant difference (P = .70) (table not shown). The prevalence of metabolic acidosis was 0.45% (65/14 566) in the AGA group and 0.25% (7/2788) in the LGA group (P = .20). There were no significant differences in glucose and lactate concentrations in comparisons between AGA and LGA groups with metabolic acidosis (P = .087 and P = .25, respectively).

| Fractional placental glucose supply
Data for FPGS calculation were available in 16 647 cases (placental weight missing in 711 cases). Among non-acidemic cases, FPGS was higher in non-diabetes AGA than non-diabetes LGA cases (P < .015); for diabetes cases, the difference was not significant (P = .58). When comparing non-acidemic and acidemic cases, FPGS decreased significantly in all groups (P ≤ .040) except among diabetes AGA cases (P = .10).
Among acidemic cases, non-diabetes LGA cases had a higher FPGS than non-diabetes AGA cases (P = .027), but there was no difference for diabetes cases (P = .61). In comparisons between diabetes and nondiabetes cases, there were no significant differences within the categories AGA and LGA, respectively, with or without acidemia (P ≥ .11).

| D ISCUSS I ON
This study showed that despite having lower cord arterial glucose levels relative to AGA fetuses during aerobic conditions, LGA fetuses had similar lactate production capabilities when exposed to sustained intrapartum hypoxia leading to acidemia. This was found in LGA fetuses of both non-diabetic and diabetic mothers. In all birthweight groups, during anaerobic metabolism, glucose was mobilized concomitantly with increased production of lactate. Furthermore, when estimating the "fractional glucose supply" by the placenta, we found that the supply in general decreased during anaerobic metabolism, but it was not impaired in LGA compared with AGA cases.
Considering the association between LGA and hyperinsulinism, a simultaneous occurrence of fetal hyperinsulinemia and hyperglycemia was not supported by this study. During both aerobic and anaerobic conditions, the cord glucose concentration was lower in non-diabetes LGA cases than non-diabetes AGA cases. This trend was similar but not significant during aerobic conditions in diabetes LGA. Furthermore, there was a weak but significant negative correlation between the cord glucose concentration and WD%, though the 0.6% impact of WD% on glucose values is negligible.
It thus appears that fetal hyperglycemia is much more a "fetal glucose hypermetabolism" rather than chronic hyperglycemia, with postprandial pulsatile hyperglycemia stimulating fetal insulin secretion. 1 Chronic hyperinsulinemia in LGA fetuses could explain the lower glucose concentration observed during aerobic conditions, enhancing glucose uptake by peripheral tissues and accelerating fetal growth; however, this did not prevent a sufficient mobilization of glucose reserves and lactate production during hypoxic stress.
A major strength of our study was that more than 17 000 complete and strictly validated paired samples of arterial and venous cord blood were analyzed. The series was unselected, meaning that all cord samples were included aside from those of suboptimal quality. However, despite the large sample size, there were only 8 LGA cases with cord blood acidemia in the group of maternal diabetes.
According to Mundry and Fisher,23 this was a large enough number to perform the non-parametric Mann-Whitney U test, but it can still be noted as a limitation when evaluating hypoxic LGA fetuses of diabetic mothers. Another strength was that we performed separate analyses for aerobic and anaerobic conditions, as designated by cord pH values, and estimated the placental glucose supply from the mother.
None of our statistical calculations indicated any impaired capacity of the LGA fetus to produce lactate during hypoxic conditions.
We merged pre-gestational and gestational diabetes in the statistical analyses, which we believe was of minor relevance to our hypothesis, since the glycemic control might vary just as much within one of the groups as between the two groups. Several GDM cases might in fact have been previously undetected pre-pregnancy type 2 diabetes. 24 We found no significant differences between the types of diabetes as regards cord glucose or lactate concentrations, or in rates of acidemia, metabolic acidosis or lacticemia.
We did not consider factors such as epidural analgesia and length of labor, which are factors that are known to influence acid-base F I G U R E 2 Umbilical cord blood lactate concentration at birth in non-acidemic and acidemic appropriate-for-gestational-age (AGA) and large-for-gestational-age (LGA) birthweight groups of newborns compared between mothers with and without diabetes. At paired comparisons, a significant difference was found only between non-acidemic non-diabetes AGA and LGA. With acidemia, lactate increased in all birthweight groups compared to normal pH (P < .0001). For details, see Table 3

AGA
LGA AGA LGA AGA LGA AGA LGA Non-diabetes Diabetes Non-diabetes Diabetes

Non-acidemia Acidemia
Lactate (mmol/L) p < 0.0001 status at birth. 25 However, using multiple logistic regression analyses, we evaluated the influence of demographic differences between the AGA and LGA cases, finding no confounding influences.
We performed numerous statistical tests, being aware of the risk of type 1 error, but all our findings were consistent and pointed to an intact lactate-producing capacity of LGA fetuses during hypoxia.

| CON CLUS ION
Considering cord blood acidemia at birth a proxy for intrapartum hypoxia, this population-based comparative study showed that, compared with AGA fetuses, LGA fetuses had an intact ability to produce lactate in response to sustained intrapartum hypoxia. Maternal diabetes did not hamper the ability of LGA fetuses to mobilize glycogen stores for the production of glucose and lactate in strenuous situations during labor.

ACK N OWLED G M ENTS
Dr. Parisa Mokarami and Dr. Fernanda Åkerman are gratefully acknowledged for assistance with conceptualizing the study.

CO N FLI C T O F I NTE R E S T
The authors have stated explicitly that they have no actual or potential conflicts of interest in connection with this article.