Biol. Neonate 26: 129-145 (1975)
Influence on Fetal Carbohydrate and Fat Metabolism and on Acid-Base Balance of Glucose Administration to the Mother during Labour S. G ä r d m a r k , G. G ennser , L. J acobso n , G. R ooth and J. T horell Department of Obstetrics and Gynaecology, Isotope Laboratory, General Hospital, Malmö, and Research Department I, E-blocket, University Hospital, Lund
Key Words. Glucose • Insulin • Lactate • Pyruvate • ¡5-Hydroxy butyrate • Glycerol • Acid-base status • Sodium Abstract. Parturients during normal labour were given glucose. The maternal-fetal dif ference of glucose increased with increasing maternal glucose level. Glucose load caused a rapid early response of maternal insulin release. A parallel rise in plasma lactate and pyru vate occurred in both fetus and mother. The basal maternal hydroxybutyrate and glycerol concentrations decreased significantly during glucose load. The study demonstrated that at term, components of lipid metabolism in fetal and maternal plasma - in contrast to glucose - vary independently. No major disturbances of the fetal acid-base balance were found.
Glucose administration to women in labour is used in many places in ord er to augment the fetal chances of survival where there is asphyxia during birth [R om ney and G abel , 1966; P aterson et al., 1967a; P r Fbylova and Z nam en a cek , 1970; H u t e r , 1972; S abata et al., 1973]. The metabolic conse quences for the human fetus of such a treatment are not fully known, having been studied mainly by single-point determinations of biochemical param eters in fetal blood [P aterson et al., 1967a; A n d erson et al., 1970], The opin ion has recently been expressed that glucose load to parturients may adverse ly increase the acidosis in the oxygen-deprived fetus owing to a rise of plasma lactate [S helley , 1973]. Furthermore, the role of glucose as the predominant source of energy for fetal metabolism [S abata et al., 1968; A lexander et al., 1969] has recently been challenged [S etchell et al., 1972; B attaglia and M eschia , 1973] but the alternatives of metabolic fuel are not yet completely defined. The metabolic effects of glucose administration prenatally are thus
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Introduction
130
G ardmark/G ennser/J acobson/R ooth /T horell
of great physiological and clinical importance. By applying ultramicro-analytical methods on fetal scalp blood samples, it is possible to follow several si multaneous metabolic events during labour. The present investigation was performed with such a technique on normal parturients in order to analyse whether glucose load influenced the fetal acid-base balance by affecting the carbohydrate and fat metabolism and to elucidate the maternal-fetal interre lationship of the metabolic responses.
Material and Methods
Clinical Procedure The study began in the first stage of labour as soon as the position of the fetal head and the cervical dilatation permitted fetal scalp blood sampling. None of the patients experi enced severe labour pains during the studied period. Two patients received 50-75 mg pethi dine: one just before the beginning of the glucose administration and the other just after the end. No other analgetic drug was given during the study. In accordance with the pre vailing dietary scheme of the labour ward, were the patients allowed an unrestricted liquid diet consisting of sugar-sweetened juice and soup, before and during the study. The caloric intake was not measured, but was generally fairly low. The patients remained in the recum bent position during the study. The glucose infusion was intended to give a stable elevated maternal plasma glucose concentration for 1 h. To achieve a rapid plasma glucose rise, 100 ml 25-percent or 120 ml 20-percent glucose solution was infused into an antecubital vein as rapidly as possible. A 20-percent glucose solution was then continuously infused intravenously by means of an Ivac 501 infusion pump. The maternal plasma glucose concentration was monitored by fre-
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 10:24:28 PM
Material The material comprises 13 healthy women, aged 18-31 (mean 23.7), with uncomplicat ed term pregnancies and normal spontaneous labour. All except one were primiparac; the birth weights of their infants ranged from 2,980 to 4,850 g (mean 3,680 g). The normality of the group of patients was shown by the uneventful history of the present pregnancy, the clinical course of the delivery before and during the study, and the absence of any signs of fetal asphyxia. The newborns subsequently appeared mature with appropriate birth weights and an Apgar score of 8-10. The nature and purpose of the investigation were ex plained to the patients; all gave their consent. 15 primiparae with normal labour before and during the study served as controls. These patients, for other purposes, were subjected to blood sampling and determination of the same parameters as in the present investigation. In this series, fetal and maternal blood were obtained on two occasions at 60-min intervals. The blood sampling started somewhat later in the first stage (at a cervical dilatation of 3-5 cm) and the parturients had a more painful labour than those in the series receiving glucose. Details of the control cases are re ported elsewhere [G ardmark et at., 1974a], The results of the analyses in the control series are expressed as means and are only reported in figures 1-9 to demonstrate the numerical levels and changes normally occurring during the period of labour studied.
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quent blood-sugar determinations with Dextrostix® test tape and Ames Reflectance Meter®, and the level was kept as constant as possible at 180-240 mg% by adjustment of the in fusion speed. The maternal blood glucose level was also measured by a standard laboratory glucose oxidase method (‘Analytical Methods’) 30 min after reaching a steady state and at the end of the infusion, the mean values being 237 ±32 and 239 ±31 mg%, respectively. The total infusion time ranged from 60 to 120 min (mean 88) and the total amount of glu cose given from 54 to 120 g (mean 80). Sample Collection Fetal and maternal capillary blood were sampled simultaneously on three occasions in each of 13 patients, i.e. (1) before beginning, (2) at the end of, and (3) 30 min after the end
Sampling moment
Fig. 1. Glucose concentrations in maternal ( • ) and fetal (O ) plasma before (A), during (A,), at the end of (B), and 30 min after (C), intravenous glucose infusion to the mother. Mean values and upper/lower 95% confidence limits of the means. Symbols connected by the dotted lines represent mean values in an untreated control series at two instances with a 60-min interval during the first stage of labour (‘Material’).
Fig. 2. Maternal and fetal plasma lactate concentrations in relation to glucose infusion to the mother. Symbols as in figure 1.
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G ardmark/G ennser/J acobson/R ooth/T horell
Fig. 3. Maternal and fetal plasma pyruvate concentrations in relation to glucose infu sion to the mother. Symbols as in figure I.
Sampling moment
Fig. 4. Maternal and fetal L/P ratio in relation to glucose infusion to the mother. Sym bols as in figure 1.
Fig. 5. Maternal and fetal plasma (3-HB concentrations in relation to glucose infusion to the mother. Symbols as in figure 1.
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Sampling moment
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Fig. 6. Maternal and fetal plasma glycerol concentrations in relation to glucose infusion to the mother. Symbols as in figure 1.
Fig. 7. Maternal and fetal pH in relation to glucose infusion to the mother. Symbols as in figure 1.
Fig. 8. Maternal and fetal Pco2 in relation to glucose infusion to the mother. Symbols as in figure 1.
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Fig. 9. Maternal and fetal BD ecf in relation to glucose infusion to the mother. Sym bols as in figure 1.
of the glucose administration. Maternal capillary blood samples were also taken for glu cose determination 30 min after reaching steady state of maternal plasma glucose concen tration. Maternal venous blood for insulin measurements was obtained from 8 women be fore and at 3, 5, 7, 10, 15, 30, 45, and 60 min after beginning the infusion, and 15 and 30 min after the end. The fetal scalp blood was collected anaerobically in heparinized glass capillaries ap proximately 20 cm in length and connected in their outer end to a polyethylene catheter. Approximately 0.8 ml fetal capillary blood was obtained at each sampling. For insulin determination in the mother, blood was aspirated from an antecubital vein contralaterally to the infusion arm through an indwelling catheter, and collected in EDTAcontaining test tubes. For all other purposes, arterialized maternal capillary blood was sampled from a finger-tip and into short heparinized glass capillary tubes (for pH, Pco, and haemoglobin measurements) and in small plastic tubes for a Beckman high speed mi cro-centrifuge (for plasma glucose, lactate, pyruvate, (3-hydroxybutyrate, glycerol, and so dium determinations). The acid-base parameters were determined within a few minutes. For the other bio chemical analyses, the samples were kept cool before centrifuging within 10 min, and plasma was separated and stored in a deep-freeze for a maximum of 1 month before further proc essing.
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 10:24:28 PM
A nalyHeal M ethods
pH was measured by means of the Radiometer glass micro-electrode unit 5021 and pH meter PHM 27. P co2 was determined with the Eshweiler micro-CO .-electrode assembly. Base deficit was calculated for the entire extracellular fluid compartment (BD ecf ) from the Siggaard-Andersen [1963] alignment nomogram. Haemoglobin (Hb) concentration was determined with a Vitatron Photometer. Glucose was determined by the glucose oxidase method described by M arks [1959], Lactate was determined with an ultramicro-adaptation of the slightly modified Boehringer enzymatic method (Boehringer Bulletin T C-B 972) [R ooth , unpublished, 1967]. {j-hydroxybutyrate (¡3-HB) was determined by the 3-HB dehydrogenase method of Wil liamson et at. [1962] modified according to P ersson [1970].
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Pyruvate was determined fluorimetrically by an ultramicro-adaptation of the Boehringer enzymatic method using for the final stage a spectrofluorometer (Boehringer Bulletin T C-B 972) [R ooth , unpublished, 1967]. Glycerol was determined by an enzymatic fluorometric micro-method described by L aurell and T ibblin [1966]. Sodium was determined according to the method of K aplan and del C armen [1956], Insulin was determined by radio-immunoassay with ethanol precipitation of antibodies [H eding, 1966]. The insulin response to an intravenous glucose load in 8 women during the first 10 min (Early Insulin Response) was quantified according to T horell el at. [1973], by the equation response = It + K • areat, where I is the plasma insulin concentration; area refers to the area under the insulin curve for 0-t min, and K is the elimination constant of 0.1 min-1. The plasma insulin values (¡iU/ml) upon intravenous glucose infusion were 45± 22, aft er 5 min, 118 ±34, after 7 min, 110±34, after 10 min, 120±29. The Early Insulin Response was 138±43 pU/ml. Results are means ±95% confidence limits of the means. The proba bilities are derived from statistical analyses of paired samples.
Results Glucose (fig. 1). The glucose infusion increased the maternal plasma glu cose concentration from 97 before to 239 mg% at the end of the glucose ad ministration. 30 min after the glucose infusion ended, the level was still ele vated at 137 mg% (p
Influence on Fetal Carbohydrate and Fat Metabolism and on Acid-Base Balance of Glucose Administration to the Mother during Labour S. G ä r d m a r k , G. G ennser , L. J acobso n , G. R ooth and J. T horell Department of Obstetrics and Gynaecology, Isotope Laboratory, General Hospital, Malmö, and Research Department I, E-blocket, University Hospital, Lund
Key Words. Glucose • Insulin • Lactate • Pyruvate • ¡5-Hydroxy butyrate • Glycerol • Acid-base status • Sodium Abstract. Parturients during normal labour were given glucose. The maternal-fetal dif ference of glucose increased with increasing maternal glucose level. Glucose load caused a rapid early response of maternal insulin release. A parallel rise in plasma lactate and pyru vate occurred in both fetus and mother. The basal maternal hydroxybutyrate and glycerol concentrations decreased significantly during glucose load. The study demonstrated that at term, components of lipid metabolism in fetal and maternal plasma - in contrast to glucose - vary independently. No major disturbances of the fetal acid-base balance were found.
Glucose administration to women in labour is used in many places in ord er to augment the fetal chances of survival where there is asphyxia during birth [R om ney and G abel , 1966; P aterson et al., 1967a; P r Fbylova and Z nam en a cek , 1970; H u t e r , 1972; S abata et al., 1973]. The metabolic conse quences for the human fetus of such a treatment are not fully known, having been studied mainly by single-point determinations of biochemical param eters in fetal blood [P aterson et al., 1967a; A n d erson et al., 1970], The opin ion has recently been expressed that glucose load to parturients may adverse ly increase the acidosis in the oxygen-deprived fetus owing to a rise of plasma lactate [S helley , 1973]. Furthermore, the role of glucose as the predominant source of energy for fetal metabolism [S abata et al., 1968; A lexander et al., 1969] has recently been challenged [S etchell et al., 1972; B attaglia and M eschia , 1973] but the alternatives of metabolic fuel are not yet completely defined. The metabolic effects of glucose administration prenatally are thus
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 10:24:28 PM
Introduction
130
G ardmark/G ennser/J acobson/R ooth /T horell
of great physiological and clinical importance. By applying ultramicro-analytical methods on fetal scalp blood samples, it is possible to follow several si multaneous metabolic events during labour. The present investigation was performed with such a technique on normal parturients in order to analyse whether glucose load influenced the fetal acid-base balance by affecting the carbohydrate and fat metabolism and to elucidate the maternal-fetal interre lationship of the metabolic responses.
Material and Methods
Clinical Procedure The study began in the first stage of labour as soon as the position of the fetal head and the cervical dilatation permitted fetal scalp blood sampling. None of the patients experi enced severe labour pains during the studied period. Two patients received 50-75 mg pethi dine: one just before the beginning of the glucose administration and the other just after the end. No other analgetic drug was given during the study. In accordance with the pre vailing dietary scheme of the labour ward, were the patients allowed an unrestricted liquid diet consisting of sugar-sweetened juice and soup, before and during the study. The caloric intake was not measured, but was generally fairly low. The patients remained in the recum bent position during the study. The glucose infusion was intended to give a stable elevated maternal plasma glucose concentration for 1 h. To achieve a rapid plasma glucose rise, 100 ml 25-percent or 120 ml 20-percent glucose solution was infused into an antecubital vein as rapidly as possible. A 20-percent glucose solution was then continuously infused intravenously by means of an Ivac 501 infusion pump. The maternal plasma glucose concentration was monitored by fre-
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 10:24:28 PM
Material The material comprises 13 healthy women, aged 18-31 (mean 23.7), with uncomplicat ed term pregnancies and normal spontaneous labour. All except one were primiparac; the birth weights of their infants ranged from 2,980 to 4,850 g (mean 3,680 g). The normality of the group of patients was shown by the uneventful history of the present pregnancy, the clinical course of the delivery before and during the study, and the absence of any signs of fetal asphyxia. The newborns subsequently appeared mature with appropriate birth weights and an Apgar score of 8-10. The nature and purpose of the investigation were ex plained to the patients; all gave their consent. 15 primiparae with normal labour before and during the study served as controls. These patients, for other purposes, were subjected to blood sampling and determination of the same parameters as in the present investigation. In this series, fetal and maternal blood were obtained on two occasions at 60-min intervals. The blood sampling started somewhat later in the first stage (at a cervical dilatation of 3-5 cm) and the parturients had a more painful labour than those in the series receiving glucose. Details of the control cases are re ported elsewhere [G ardmark et at., 1974a], The results of the analyses in the control series are expressed as means and are only reported in figures 1-9 to demonstrate the numerical levels and changes normally occurring during the period of labour studied.
Fetal Carbohydrate and Fat Metabolism
131
quent blood-sugar determinations with Dextrostix® test tape and Ames Reflectance Meter®, and the level was kept as constant as possible at 180-240 mg% by adjustment of the in fusion speed. The maternal blood glucose level was also measured by a standard laboratory glucose oxidase method (‘Analytical Methods’) 30 min after reaching a steady state and at the end of the infusion, the mean values being 237 ±32 and 239 ±31 mg%, respectively. The total infusion time ranged from 60 to 120 min (mean 88) and the total amount of glu cose given from 54 to 120 g (mean 80). Sample Collection Fetal and maternal capillary blood were sampled simultaneously on three occasions in each of 13 patients, i.e. (1) before beginning, (2) at the end of, and (3) 30 min after the end
Sampling moment
Fig. 1. Glucose concentrations in maternal ( • ) and fetal (O ) plasma before (A), during (A,), at the end of (B), and 30 min after (C), intravenous glucose infusion to the mother. Mean values and upper/lower 95% confidence limits of the means. Symbols connected by the dotted lines represent mean values in an untreated control series at two instances with a 60-min interval during the first stage of labour (‘Material’).
Fig. 2. Maternal and fetal plasma lactate concentrations in relation to glucose infusion to the mother. Symbols as in figure 1.
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Sampling moment
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G ardmark/G ennser/J acobson/R ooth/T horell
Fig. 3. Maternal and fetal plasma pyruvate concentrations in relation to glucose infu sion to the mother. Symbols as in figure I.
Sampling moment
Fig. 4. Maternal and fetal L/P ratio in relation to glucose infusion to the mother. Sym bols as in figure 1.
Fig. 5. Maternal and fetal plasma (3-HB concentrations in relation to glucose infusion to the mother. Symbols as in figure 1.
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Sampling moment
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Fig. 6. Maternal and fetal plasma glycerol concentrations in relation to glucose infusion to the mother. Symbols as in figure 1.
Fig. 7. Maternal and fetal pH in relation to glucose infusion to the mother. Symbols as in figure 1.
Fig. 8. Maternal and fetal Pco2 in relation to glucose infusion to the mother. Symbols as in figure 1.
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G ardmark/G ennser/J acobson/R ooth/T horell
Fig. 9. Maternal and fetal BD ecf in relation to glucose infusion to the mother. Sym bols as in figure 1.
of the glucose administration. Maternal capillary blood samples were also taken for glu cose determination 30 min after reaching steady state of maternal plasma glucose concen tration. Maternal venous blood for insulin measurements was obtained from 8 women be fore and at 3, 5, 7, 10, 15, 30, 45, and 60 min after beginning the infusion, and 15 and 30 min after the end. The fetal scalp blood was collected anaerobically in heparinized glass capillaries ap proximately 20 cm in length and connected in their outer end to a polyethylene catheter. Approximately 0.8 ml fetal capillary blood was obtained at each sampling. For insulin determination in the mother, blood was aspirated from an antecubital vein contralaterally to the infusion arm through an indwelling catheter, and collected in EDTAcontaining test tubes. For all other purposes, arterialized maternal capillary blood was sampled from a finger-tip and into short heparinized glass capillary tubes (for pH, Pco, and haemoglobin measurements) and in small plastic tubes for a Beckman high speed mi cro-centrifuge (for plasma glucose, lactate, pyruvate, (3-hydroxybutyrate, glycerol, and so dium determinations). The acid-base parameters were determined within a few minutes. For the other bio chemical analyses, the samples were kept cool before centrifuging within 10 min, and plasma was separated and stored in a deep-freeze for a maximum of 1 month before further proc essing.
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 10:24:28 PM
A nalyHeal M ethods
pH was measured by means of the Radiometer glass micro-electrode unit 5021 and pH meter PHM 27. P co2 was determined with the Eshweiler micro-CO .-electrode assembly. Base deficit was calculated for the entire extracellular fluid compartment (BD ecf ) from the Siggaard-Andersen [1963] alignment nomogram. Haemoglobin (Hb) concentration was determined with a Vitatron Photometer. Glucose was determined by the glucose oxidase method described by M arks [1959], Lactate was determined with an ultramicro-adaptation of the slightly modified Boehringer enzymatic method (Boehringer Bulletin T C-B 972) [R ooth , unpublished, 1967]. {j-hydroxybutyrate (¡3-HB) was determined by the 3-HB dehydrogenase method of Wil liamson et at. [1962] modified according to P ersson [1970].
Fetal Carbohydrate and Fat Metabolism
135
Pyruvate was determined fluorimetrically by an ultramicro-adaptation of the Boehringer enzymatic method using for the final stage a spectrofluorometer (Boehringer Bulletin T C-B 972) [R ooth , unpublished, 1967]. Glycerol was determined by an enzymatic fluorometric micro-method described by L aurell and T ibblin [1966]. Sodium was determined according to the method of K aplan and del C armen [1956], Insulin was determined by radio-immunoassay with ethanol precipitation of antibodies [H eding, 1966]. The insulin response to an intravenous glucose load in 8 women during the first 10 min (Early Insulin Response) was quantified according to T horell el at. [1973], by the equation response = It + K • areat, where I is the plasma insulin concentration; area refers to the area under the insulin curve for 0-t min, and K is the elimination constant of 0.1 min-1. The plasma insulin values (¡iU/ml) upon intravenous glucose infusion were 45± 22, aft er 5 min, 118 ±34, after 7 min, 110±34, after 10 min, 120±29. The Early Insulin Response was 138±43 pU/ml. Results are means ±95% confidence limits of the means. The proba bilities are derived from statistical analyses of paired samples.
Results Glucose (fig. 1). The glucose infusion increased the maternal plasma glu cose concentration from 97 before to 239 mg% at the end of the glucose ad ministration. 30 min after the glucose infusion ended, the level was still ele vated at 137 mg% (p
