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Gynecological/Obstetrical Research Department Y, Aarhus University Hospital (J.F., P.O.), Skejby Sygehus, DK-8200 Aarhus N, Denmark; Department of Obstetrics and Gynecology, Holstebro Centralsygehus (F.L.), DK-7500 Holstebro, Denmark; and Medical Research Laboratories, Aarhus University Hospital, Aarhus Kommunehospital (A.F.), DK-8000 Aarhus C, Denmark
Address all correspondence and requests for reprints to: Jens Fuglsang, M.D., Gynecological/Obstetrical Research Department Y, Aarhus University Hospital, Skejby Hospital, DK-8200 Aarhus N, Denmark. E-mail address: jens_fuglsang{at}hotmail.com.
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Abstract |
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0.021). Serum hPGH correlated to serum IGF-I from wk 24- 35, and changes in IGF-I followed the increase in hPGH between wk 26–35 (rs = 0.53; P < 0.001), as did IGF-II (rs = 0.37; P = 0.008). Changes in IGF-I and IGF-II between wk 26–35 also correlated to the birth weight z-score (P 0.020), but only hPGH remained significant in multiple regression analysis. Similar results were found in the subgroup delivering at term. Interestingly, the increase in hPGH was not correlated to the increase in insulin requirements, nor was any consistent relationship revealed during each gestational period. In conclusion, our study suggests a role for hPGH in the regulation of both IGFs and fetal growth in type 1 diabetes. In contrast, the increase in insulin requirements during pregnancy in type 1 diabetic subjects could not be related to hPGH levels. |
Introduction |
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Pregnancy is known to be followed by a certain degree of insulin resistance. It is well known that in type 1 diabetes insulin requirements increase during the third trimester (9). A recent study in nonpregnant transgenic mice revealed that hPGH causes insulin resistance at levels somewhat above human third trimester levels (10). Diabetes in pregnancy may lead to macrosomia in the newborn, but the impact of hPGH on birth weight in diabetes, especially type 1 diabetes, has only been sparsely investigated. In contrast, both IGF-I and IGF-II have been found to be correlated to birth weight in diabetic, as well as in normal, pregnancies (5, 6, 11, 12), although not consistently (5, 13). Thus, as hPGH may theoretically influence both fetal growth and maternal insulin requirements in type 1 diabetes, this study was undertaken with the aim of examining the relationship between hPGH and IGF-I and -II in a cohort of type 1 diabetic subjects and to examine the impact of hPGH and IGFs on birth weight and placental weight. Furthermore, the extent to which insulin requirements in pregnancy were related to hPGH levels was examined.
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Materials and Methods |
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Type 1 diabetic women were seen every second week from late first trimester and weekly from wk 30–32 depending on individual needs. The women were recruited consecutively, and blood samples were drawn at maternity ward visits. Women with pregestational macroalbuminuria (urinary albumin excretion, >300 mg/24 h) were not included. Nonfasting blood samples were obtained after informed consent was given, blood was centrifuged, and serum was pipetted off and frozen at -20 C for later analysis. The study was approved by the regional ethical committee for Aarhus County, Denmark.
Blood samples were obtained from 55 subjects, 2 of whom had twin pregnancies, 1 had a stillbirth, and 1 had insufficient blood samples drawn. In this way, 51 women were included in the study. A total of 717 blood samples were obtained, with a median of 14 blood samples (range, 8–26)/woman during pregnancy.
Gestational age was determined from the last menstrual cycle and was verified with ultrasound scan measurements; alternatively, gestational age was determined by ultrasound scan measurements alone when appropriate. Insulin dose was recorded at each visit and is given as the number of international units per 24 h. Measurement of hemoglobin A1c (HbA1c) was performed according to individual requirements, thus usually a lower number of HbA1c values than insulin doses were available. HbA1c values are given as a fraction of total hemoglobin, and the normal range is 0.044–0.064. Patient and newborn characteristics were retrieved from patients’ and newborns’ records after delivery.
One patient was receiving thyroid substitution therapy, and two patients were prescribed an angiotensin-converting enzyme inhibitor in advance of pregnancy. No other systemic medication was recorded. Microalbuminuria was defined as urinary excretion of 30–300 mg protein/24 h and was noted in five women. Two had known microalbuminuria before pregnancy. Three women presented with microalbuminuria at first visit before wk 9 and were classified as having microalbuminuria.
Preeclampsia was defined as two or more of the following: proteinuria of 0.3 g/liter or less, blood pressure greater than 140/90 mm Hg, peripheral edema and subjective symptoms (visual disturbances, retrosternal pain, and headache).
Birth weights were compared with birth weights from a cohort of 12,644 live-born babies from singleton pregnancies in nondiabetic mothers, who delivered in the same period at the Obstetrical Department Y, Aarhus University Hospital. When comparing birth weights over a range of gestational ages, birth weight was expressed as the birth weight z-score [z-score = (birth weight - mean birth weight)/SD of birth weights]. The z-scores were calculated for each gestational week and corrected for gender. Data from this normal cohort did not allow for construction of a similar placental weight z-score.
Hormone assays
All hormone analyses were performed in duplicate, and all samples from the same subject were analyzed within the same run of a hormone assay. Serum hPGH was determined using a commercially available, solid phase, immunoradiometric assay (hPGH IRMA, BC1017, Biocode, Liege, Belgium). In our hands the intra- and interassay coefficients of variation (CV) were less than 4% and less than 6%, respectively. Serum total IGF-I was determined using an in-house, time-resolved, immunofluorometric assay after acid-ethanol extraction (14). The detection limit is 2.7 µg/liter, and the intra- and interassay CVs are less than 5% and less than 10%, respectively. Serum total IGF-II was determined using an in-house, time-resolved, immunofluorometric assay after acid-ethanol extraction (14). The detection limit averages 10.7 µg/liter, and intra- and interassay CVs are less than 4% and less than 7%, respectively.
Statistics
Gestational age is given in weeks, and each time point reflects the number of completed weeks, e.g. wk 16/17 corresponds to a gestational age of 112–125 d, and wk 37 corresponds to 259–265 d. Results were pooled in 2-wk periods until gestational wk 30; thereafter, weekly data are given. In any case of more than one measurement at a time point, the mean value of measurements was used.
Results are given as the mean ± SEM for data with a normal distribution, whereas nonparametric data are given as the median (range). Serum hPGH values did not follow Gaussian distribution after logarithmic transformation. Differences between gestational weeks were investigated with paired t tests for parametric data; otherwise, Wilcoxon’s signed ranks test was applied to the data. Correlation analyses were performed using Spearman’s rank order coefficient, denoted rs. The changes in hormone levels over several time periods were investigated with analyses of slopes, and slopes were derived from linear regression analysis in the time period. Multiple linear regression analysis was used to investigate the relationship between the birth weight z-score and changes in hormone levels. P < 0.05 was considered significant.
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Results |
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. Of the 51 patients, 2 patients delivered in wk 32, 2 in wk 33, 3 in wk 34, and 7 in wk 35. Six patients had spontaneous labor (wk 33, 35, 35, 36, 37, and 38). Preeclampsia was suspected in 7 patients (delivery in gestational wk 32, 33, 34, 35, 35, 36, and 37).
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The time course of serum hPGH is shown in Fig. 1A. In all subjects a rise in serum hPGH was noted during pregnancy. Placental GH was detected in some women as early as wk 6. Maximum serum hPGH levels were observed in wk 35 (median, 23.1 µg/liter; range, 6.7–157 µg/liter), but with individual variations. Overall, the steepest rise in hPGH concentrations was noted after wk 26 (Fig. 1A), and the increase in hPGH between wk 16 and 25 correlated significantly to the increase in hPGH between wk 26 and 35 (rs = 0.58; P < 0.001). A slight decrease after wk 35 did not reach statistical significance. As expected, serum hPGH levels decreased to undetectable levels after birth (n = 5; data not shown).
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A significant decrease was observed in serum IGF-I values from the first trimester to the second trimester [wk 8–11 (96.8 ± 4.7 µg/liter) vs. wk 12–16 (88.7 ± 4.2 µg/liter), P = 0.021; vs. wk 16–19 (87.0 ± 4.0 µg/liter), P = 0.006; Fig. 1B
). Serum IGF-I reached a trough from wk 12–21, with IGF-I at 85.6 ± 3.9 µg/liter. Maximum IGF-I values were reached in the third trimester, in many subjects in the last blood sample obtained.
From wk 24–35, serum hPGH significantly correlated to serum IGF-I at each time point (Table 2). The increase in hPGH from wk 26–35 was significantly correlated to the change in IGF-I in the same period (rs = 0.53; P < 0.001; Fig. 2), whereas this correlation only showed a trend in the period from wk 16–25 (rs = 0.27; P = 0.058).
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In the late first trimester, IGF-II values averaged 800 µg/liter (806 ± 32 µg/liter). In the second half of pregnancy, IGF-II values increased nearly one third to 1063 µg/liter (range, 541-1704) in wk 34, but in several subjects the maximum IGF-II value was observed in the last sample available (Fig. 1C).
Serum IGF-II levels correlated to serum hPGH levels in wk 31, 33, 34, and 35 (Table 2). Also, significant correlations were noted between alterations in serum hPGH and serum IGF-II from wk 16–25 (rs = 0.33; P = 0.020) and from wk 26–35 (rs = 0.37; P = 0.008). Serum IGF-II values correlated to serum IGF-I values in wk 16/17 and 18/19 and from wk 24/25 onward (0.36 < rs < 0.74; 0.001 < P 0.032), with the strongest correlations from wk 32 onward. Furthermore, the increases in serum IGF-I and -II correlated significantly in both the periods from wk 16–25 (rs = 0.44; P = 0.014) and from wk 26–35 (rs = 0.37; P = 0.004).
Insulin and HbA1c
Insulin requirements are shown in Fig. 1D. Until midgestation a slight decrease was observed from 43.0 ± 2.7 U in wk 8–11 to a slightly lower level of 40.3 ± 2.2 U in wk 12–16 (P = 0.040), followed by an increase in the third trimester to a level of 67.0 ± 3.4 in the period from wk 32–35 (P < 0.001). After wk 35 decreasing insulin requirements were observed. This decrease was statistically significant only in the minor proportion of subjects delivering late in pregnancy (n = 8; P = 0.024).
The third trimester increase paralleled the increase in hPGH values. However, no statistically significant correlations were detected between alterations in insulin requirements and increases in hPGH in the period from wk 16–25 or from wk 26–35. Insulin requirements generally were not correlated to hPGH values, except for a single gestational age (wk 28/29: rs = 0.39; P = 0.017). No trend was observed in adjacent periods (data not shown), nor were any correlations between insulin requirements and IGF-I values detected. Investigating relative differences in insulin requirements between the lowest level in the second trimester and the maximum level in the third trimester did not reveal any correlation between third trimester hPGH values and insulin.
HbA1c values slowly decreased throughout pregnancy, with values averaging 0.073 ± 0.002 in the end of the first trimester to an average of 0.067 ± 0.002 around wk 34 (data not shown). No significant correlations were noted between hPGH or IGF-I and HbA1c. No consistent correlations were noted for IGF-II. Changes in HbA1c and insulin requirements, hPGH, IGF-I, or IGF-II were not associated in the period from wk 16–25 or from wk 26–35.
Correlations to birth characteristics
As expected, birth weight and placental weight were correlated (rs = 0.78; P < 0.001), partly reflecting the different gestational ages at delivery for the cohort. As a placental weight z-score could not be constructed, comparisons of birth weight and placental weight for the entire cohort were not possible.
Serum hPGH correlated to birth weight z-scores from the mid end of the second trimester (Table 2), with examples from wk 28/29 and wk 35 shown in Fig. 3. Around middle of the third trimester, hPGH correlated to the birth length as well (Table 2). The increase in hPGH in both the period from wk 16- 25 and that from wk 26–35 correlated to the birth weight z-score; however, only the latter reached statistical significance (rs = 0.26; P = 0.064 and rs = 0.54; P < 0.001, respectively). An estimate of the association between serum hPGH and placental weight was obtained by comparing hPGH values in each gestational period with placental weight. This revealed positive correlations from wk 30–36 (0.44 < rs < 0.68; P < 0.014).
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Multiple linear regression analysis with z-score as the dependent variable disclosed a significant relationship for the increase in hPGH from wk 26–35 (P = 0.005), but not for the IGF-I and IGF-II increases.
Term deliveries
The subgroup with delivery at term (wk 37 onward; n = 26) is characterized in Table 1. In this group, birth weight did not correlate with gestational age. Birth weight and placental weight correlated well (rs = 0.74; P < 0.001).
The maximum hPGH concentration was reached around wk 34 (23.9 µg/liter; range, 8.3–6.0 µg/liter). In this group, hPGH concentrations were correlated to the birth weight z-scores in wk 32, 33, 35, and 36 (0.52 < rs < 0.68; P 0.014), and a trend was observed in wk 34 (rs = 0.37; P = 0.084). The correlation between hPGH levels and birth weight z-scores was also present when expressing hPGH as the maximum hPGH concentration (27.4 µg/liter; range, 10.6–86.2; rs = 0.56; P = 0.003), the mean hPGH concentration during the last 4 wk of gestation (23.3 µg/liter; range, 7.8–73.2; rs = 0.50; P = 0.011), or the hPGH concentration in the last sample (25.2 µg/liter; range, 8.5–83.1; rs = 0.56; P = 0.003). The placental weight was significantly correlated to hPGH values from wk 30–36 (Table 2), although a trend was seen only in wk 31 (P = 0.074).
In this subgroup, IGF-I and IGF-II values did not show any consistent pattern between z-score and hormone values at each gestational period, and only nonsignificant trends were observed when comparing z-score with the maximum IGF-I value, the last obtained IGF-I value, or the mean IGF-I value from the last 4 wk of pregnancy. With respect to IGF-II, the z-score correlated to the last and the mean IGF-II value 4 wk before delivery (rs = 0.40 and 0.40, respectively; P < 0.05). The increase in IGF-I in wk 26–35 correlated to the birth weight z-score (rs = 0.51; P = 0.010), whereas a trend was only observed for IGF-II (rs = 0.38; P = 0.064).
Multiple linear regression with birth weight z-score as the dependent variable detected the wk 26–35 increase in hPGH as a significant predictor (P = 0.020), not the IGF-I or -II increases.
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Discussion |
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The physiological impact of hPGH is still largely unknown. The putative effects of hPGH in pregnancy have mostly been derived from its structural homology with pituitary GH, but growing evidence indicates that hPGH may be involved in the supply of nutrients to the fetus via the placenta (3). Placental GH is found only in the maternal circulation (2) and may exert its effects either directly or indirectly via IGF-I. Serum hPGH is correlated to serum IGF-I in normal pregnancies and in pregnancies with intrauterine growth retardation (1, 4, 5, 15), and the present results confirm that this is also the case in type 1 diabetes. Furthermore, hPGH was found to be related to birth weight and placental weight, as in nondiabetic pregnancies (7), and this association was noted from as early as the beginning of the third trimester, as recently shown in normal pregnancies (6, 8). Essentially similar results were found for both the entire cohort and the subgroup delivering at term.
An issue that needs to be addressed in future studies is the amount of hPGH in diabetic pregnancies compared with nondiabetic pregnancies. Despite the high incidence of macrosomic fetuses in diabetic pregnancies, no studies have hitherto demonstrated higher levels of serum hPGH. In one study nonsignificantly higher hPGH levels were noted in wk 28, but not in wk 36, but at both gestational ages the percentage of free hPGH was higher in the type 1 diabetic group (6). In that study the type 1 diabetic cohort comprised 13 individuals, and given the large interpersonal variation in hPGH values, larger cohorts will be needed to solve this issue. In neither pregnancies with type 2 nor gestational diabetes has any significant difference in hPGH levels compared with nondiabetic individuals been demonstrated (5).
The newer hPGH immunoassays allow detection of hPGH at a much earlier gestational age than the methods formerly used, and hPGH has been detected as early as gestational wk 7–8 (16, 17). In our setting, hPGH was detected from gestational wk 6, thus confirming early onset of the synthesis of the placental variant of GH.
The second trimester is characterized by a low, but increasing, production of hPGH and, at the same time, a continuously waning pituitary GH production (4, 5). Interestingly, serum IGF-I values significantly decreased in the period from first to second trimester in type 1 diabetic subjects, confirming a previous report in normal and diabetic pregnancies (18). One could speculate that the additive influence of pituitary GH and hPGH on peripheral metabolism is at its lowest in the beginning of the second trimester. This might, in turn, lead to decreased IGF-I secretion until the steeper rise in hPGH occurs. However, only hPGH concentrations have been determined in the present study, as the pulsatile secretion of GH precluded its analysis.
The diabetogenic effect of pituitary GH is well known, and a recent paper describes insulin resistance in genetically modified mice overexpressing the hPGH gene (10), although the levels of hPGH were well above the levels reported here and by other groups using the same hPGH detection assay (7, 16). McIntyre et al. (6) found a positive association between hPGH and postprandial glucose levels using mean values obtained from wk 20–30 in a mixed group of type 1 and type 2 diabetics and hypothesized that hPGH might be the driving factor in increased glycemia. In the second trimester, lower total GH levels might exert lesser diabetogenic effects, and in support of this theory, insulin requirements were at their lowest in the second trimester in our study. A decrease in insulin requirements in the second half of the first trimester independent of glycemic control has been reported recently in a cohort comprising 281 subjects (19). However, altered insulin requirements in the first half of pregnancy may be obscured by the effect of more frequent visits to the out-patient clinic in pregnancy, probably increasing awareness of the optimal diabetic regulation. In type 1 diabetic women, insulin requirements increase to a maximum in the third trimester, as evidenced here and by others (9). Assuming a straightforward diabetogenic effect of hPGH, either insulin requirements or HbA1c values should be expected to be elevated in pregnant individuals with high values of hPGH. In the present study the increase in serum hPGH coincided with the increased insulin demands, but no consistent correlations were detected between serum hPGH and insulin requirements in the third trimester, and increases in hPGH were not correlated to increases in insulin requirements. Considering the tightness of regulation of diabetes in the cohort, an association of HbA1c and hPGH could not be demonstrated. In line with the present results, two recent studies in nondiabetic individuals did not find any correlation of postprandial glucose levels and hPGH after an oral glucose tolerance test in wk 24–30 (15, 20), whereas a decrease in hPGH concentrations has been reported in gestational diabetes after an oral glucose load (21). A possible confounder in relation to the glycemic status is the potential ability of the pituitary gland to reactivate compensatory GH secretion under hypoglycemic circumstances in pregnant type 1 diabetics, as evidenced in one study using a hyperinsulinemic, hypoglycemic clamp (22). The reactivated GH secretion was noted at a blood glucose level of 2.2 mmol/liter in an acute setting. Whether this capability is acute only is unknown. Theoretically, an acute effect could be seen in diabetes with poor glycemic control with large fluctuations in blood glucose values, thus increasing the total levels of GHs. The theory of hPGH as a mediator of the diabetogenic effect of pregnancy (10) awaits further elucidation, and the possibility exists that the physiological impact of hPGH on glycemia, or vice versa, may be different in diabetes.
Serum IGF-I and -II levels increase during the second and third trimesters (4, 5, 12, 13, 23, 24, 25, 26), and both IGF-I and IGF-II appear to be involved in fetal growth. Published data regarding the influence of serum IGF-I on birth weight and placental weight are not uniform, but several papers report positive correlations in both diabetic and nondiabetic pregnancies when focusing on third trimester IGF-I values (5, 6, 11, 12, 25, 27). IGF-II has been found to be correlated to fetal weight (6, 12). In the present study a crude analysis revealed that increases in IGF-I and IGF-II correlated to birth weight. This effect might at least in part mirror the level of hPGH, as hPGH seems to regulate IGF-I in nondiabetic pregnancies and pregnancies with gestational or type 2 diabetes (1, 4, 5). Using multiple linear regression, only increases in hPGH, and not IGFs, remained significant, and the present findings thus corroborate an influential role of hPGH on IGF-I levels in type 1 diabetes as well. Besides the regulatory influence of hPGH, IGF-I values may be influenced by diabetic control, IGF-binding proteins, and the amount of circulating insulin, all of which may affect the association of interest (12, 25, 28). Serum IGF-I and IGF-II values were in our study were not related to either insulin requirements or HbA1c values.
As evidenced by the present data, maximum hPGH and IGF-I values did not coincide, and other regulatory mechanisms may prevail in the last weeks of pregnancy. The short half-life of hPGH (16) makesa long-lasting influence of hPGH on IGF-I unlikely. However, it must be remembered that as the majority of the type 1 diabetic women in this study did not deliver spontaneously, available blood samples yield incomplete datasets for the last weeks of pregnancy, potentially masking valuable information about hormones and their interrelationships.
In conclusion, this study points toward an effect of hPGH on fetal growth in pregnancies in type 1 diabetic subjects. Furthermore, effects of GHs on IGF-I are suggested both during the shift from pituitary to placental GH and during the hPGH-dominated third trimester of pregnancy. In contrast, a direct diabetogenic effect of hPGH was not supported by the present findings. Further studies are warranted to resolve the diabetogenic potency of hPGH.
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Acknowledgments |
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Footnotes |
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Abbreviations: CV, Coefficient of variation; HbA1c, hemoglobin A1c; hPGH, human placental GH.
Received April 24, 2003.
Accepted June 10, 2003.
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, women giving birth before gestational wk 37. Both correlations remained significant when excluding the outlier (A: rs = 0.37; P = 0.019; B: rs = 0.58; P < 0.001).