Human Reproduction, Vol. 15, No. 10, 2215-2219,
October 2000
© 2000 European Society of Human Reproduction and Embryology
A longitudinal study of maternal plasma insulin-like growth factor binding protein-1 concentrations during normal pregnancy and pregnancies complicated by pre-eclampsia
1 Department of Maternal-Fetal Medicine, Division of Paediatrics Obstetrics & Gynaecology, Chelsea & Westminster Hospital, London, SW10 9NH and 2 Queen Charlotte's & Chelsea Hospital, Goldhawk Road, London, W6 OXG, UK
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Abstract |
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Insulin-like growth factor binding protein-1 (IGFBP-1) is synthesized by the decidual stroma, and is thought to act locally to inhibit IGF activity and so limit trophoblast invasion. Cross-sectional studies have reported conflicting data on maternal circulating concentrations of IGFBP-1 in early pregnancy before the development of pre-eclampsia. A longitudinal study was performed in 10 women who went on to develop pre-eclampsia and a group of 12 normal pregnant controls, chosen to be similar for maternal age, booking body mass index (BMI) and gestational age. Maternal IGFBP-1 concentrations were measured in plasma obtained at 16, 20, 24, 28, 32 and 36 weeks. Plasma IGFBP-1 concentrations were unchanged over this period in normal pregnancy. In contrast, the concentrations in women who developed pre-eclampsia increased progressively. At 16, 20, and 24 weeks the concentrations were significantly lower compared to normal pregnancy, at 28 and 32 weeks, similar, but by 36 weeks the concentrations were significantly greater than the normal controls. The data show that circulating IGFBP-1 concentrations are lower in early pregnancy before the development of pre-eclampsia. Thus, it is suggested that IGFBP-1-induced inhibition of IGF activity is unlikely to be responsible for the impaired trophoblast invasion observed in pre-eclampsia.
Key words: implantation/insulin-like growth factor binding protein-1/placentation/pre-eclampsia/trophoblast invasion
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Introduction |
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Insulin-like growth factor binding protein-1 (IGFBP-1) is produced by the decidualized endometrial stroma (Han et al., 1996
), and it is thought to play a role in implantation by reducing trophoblast invasion (Pekonen et al., 1988). Indeed, cross-sectional studies during the third trimester have reported elevated maternal circulating concentrations of IGFBP-1 in pregnancies complicated by pre-eclampsia and intrauterine growth restriction (IUGR) (Iino et al., 1986; Howell et al., 1989; Wang et al., 1996). This has led to the conclusion that IGFBP-1 inhibits fetal growth by blocking IGF-1 activity and so reducing trophoblast invasion. If IGFBP-1 were to reduce trophoblast invasion, then its effect should be earlier in pregnancy and higher concentrations should be present at this time. Two studies have investigated this with conflicting results (de Groot et al., 1996; Giudice et al., 1997). Giudice et al. observed elevated circulating IGFBP-1 concentrations at the time of placentation in pregnancies destined to develop pre-eclampsia. In contrast, de Groot et al. reported lower concentrations during the same period. Furthermore, both studies were cross-sectional as single samples were taken in different trimesters and related to the later development of pre-eclampsia. Therefore in order to test the hypothesis that IGFBP-1 concentrations are elevated at the time of placentation and remain elevated with the development of pre-eclampsia, serial samples were obtained from women who did and did not go on to develop pre-eclampsia. |
Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Subjects
Plasma IGFBP-1 concentrations were measured longitudinally in 10 women with pre-eclampsia and 12 normal pregnant controls at 16, 20, 24, 28, 32 and 36 weeks gestation. All the women were recruited from the antenatal clinic at the Chelsea and Westminster Hospital. The Riverside Research Ethics Committee approved the study. Subjects were chosen to be similar in maternal age, parity and booking body mass index (BMI). Gestational ages were determined by first trimester ultrasound examinations, and fetal growth assessed between 26 and 36 weeks gestation by serial ultrasound examinations. Pre-eclampsia was defined according to the criteria of hypertension, proteinuria and reversal of hypertension and proteinuria after the pregnancy. Hypertension was defined as an increase of 30 mmHg systolic, or a diastolic blood pressure increase of 15 mmHg, compared to values before 20 weeks of pregnancy, or an absolute blood pressure greater than 140/90 mmHg after 20 weeks gestation if the earlier values were unknown. Proteinuria was defined as >0.5 g urinary protein excretion in 24 h (Davey and MacGillivray, 1988
). All the women had normal blood glucose tolerance screening test results between 26 and 28 weeks gestation to exclude the presence of gestational diabetes. None of the patients used any medications, and women with history of metabolic or endocrine disorders that affect IGF or IGFBP-1 concentration were excluded from the study. Similarly, women with history of threatened preterm labour were excluded to avoid the possible confounding effects of uterine activity on IGFBP-1 concentrations (Hills et al., 1994). The obstetric records of all the patients were reviewed after delivery to confirm reversal of hypertension and proteinuria, and to record infant birth weights and other delivery records. Informed consent was obtained from all the women in the study.
Samples and assay
Blood samples were obtained from the antecubital fossa of the women between 10:00 and 15:00 h; the plasma was separated within 2 h and stored at –70° until assayed. IGFBP-1 was measured by radioimmunoassay as reported previously (Wang et al., 1991b). Tracer was prepared by iodination of chloramine T. A polyclonal antiserum to IGFBP-1 was used at a final dilution of 1 in 5x105 which bound ~50% of the 125I-labelled IGFBP-1. The sensitivity of the assay, defined as the smallest concentration that could be distinguished from the zero standard, was 5 µg/ml. The between-assay coefficient of variation was 6.5%. The samples were also tested for haematocrit, platelet count, creatinine, uric acid and alanine transaminase (ALT).
Statistics
Data for clinical characteristics were normally distributed and are presented, as mean ± SD. Plasma values of IGFBP-1 were not normally distributed and are expressed as the median (interquartile range). Analysis of serial measurements of plasma IGFBP-1 concentrations was by summary measures. A linear regression was fitted for each subject's data over time. The slope of the lines which represent the rate of change of the measurement, were taken as summary measures for the subjects in each group (Matthews et al., 1990). The summary measures of the two groups were compared for statistical significance using Mann–Whitney U-test. The strength of association between changes in serial changes in plasma IGFBP-1, blood pressure, duration of the disease, degree of proteinuria and plasma uric acid concentrations were tested using Spearman correlation coefficient. For all comparisons, statistical significance was defined as P < 0.05. Statistical analysis was done with the Statistical Package for Social Sciences (SPSS), Version 8.
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Results |
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The two groups were similar in maternal age, BMI and booking blood pressure (Table I
). Women with pre-eclampsia had significantly higher blood pressure (P = 0.001 and 0.0001, for systolic and diastolic blood pressures respectively), and plasma uric acid concentrations (P = 0.0001) at term. The median gestational age at diagnosis of pre-eclampsia was 34.1 (32–36) weeks. Although the haematocrit, plasma creatinine and ALT concentrations at term were higher, and platelet count lower in the pre-eclampsia group, the differences were not statistically significant (P = 0.9, 0.11, 0.3 and 0.9, for haematocrit, creatinine and ALT and platelet count (Table I). Fetal growth determined from the serial ultrasound examinations was normal in both groups, although babies born to women with pre-eclampsia had a significantly lower birth weights compared to those born to the controls (P = 0.01).
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In the controls, plasma IGFBP-1 concentrations increased slightly from 134.0 (99–175) µg/ml, median (interquartile range), at 16 weeks, reaching a peak of 155.5 (117–198) µg/ml at 24 weeks, and falling to near 16 weeks concentrations at 36 weeks. The increase in the first half of normal pregnancy was not statistically significant. In contrast IGFBP-1 concentrations increased progressively in the pre-eclampsia group from 64.0 (51.5–76.5) µg/ml, at 16 weeks to 191.5 (173–206.5) µg/ml at 36 weeks (Figures 1 and 2
). The rise in concentrations in the pre-eclampsia group was statistically significant (P = 0.009, paired t-test; Figure 3). When concentrations were compared at each gestation, plasma IGFBP-1 concentrations were significantly lower in the pre-eclampsia group at 16 weeks (P = 0.006), 20 weeks (P = 0.001), 24 weeks (P = 0.04); similar at 28 and 32 weeks gestations but higher at 36 weeks (P = 0.04). The difference between the two groups was much more striking at 16 weeks than at 36 weeks (Figure 4a,b).
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) and pre-eclampsia (•). Data points represent mean ± SD. Each subject contributed a sample at each gestational interval, for normal pregnancy (n = 12) and pre-eclampsia (n = 10).
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No significant correlation was observed between IGFBP-1 and maternal age, BMI, and blood pressure and plasma ALT concentrations. There was a significant inverse correlation between the change in IGFBP-1 concentrations and infant birth weight in normal pregnancy and pre-eclampsia, r = –0.82 (P = 0.001) and –0.87 (P = 0.002) respectively (Table II
, Figure 5). A subgroup analysis of infants delivered to the pre-eclampsia group showed that the relationship between changes in IGFBP-1 and birth weight was similar between the small and appropriate for gestation infants. The 24 h protein concentrations in urine samples from all the pre-eclamptic women were raised (1.54 ± 0.2 g/24 h) and showed a significant correlation with changes in IGFBP-1 concentrations (r = 0.84, P = 0.02). In addition, there was a strong correlation between the duration of pre-eclampsia and the concentrations of IGFBP-1 (r = 0.88, P = 0.002). A multiple regression analysis showed that IGFBP-1 was independently related to only the duration of pre-eclampsia only (P = 0.003).
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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This is the first study to investigate the serial changes in circulating IGFBP-1 concentrations in those pregnancies destined to develop pre-eclampsia. It was found that maternal circulating IGFBP-1 concentrations were lower in early pregnancy, increased progressively throughout pregnancy and exceeded normal pregnant concentrations when pre-eclampsia was established. These data are in agreement with previous studies showing elevated maternal concentrations at term in pre-eclamptic subjects. However, it was found that between 16 and 24 weeks the concentrations were significantly lower. These data do not support the hypothesis that the concentrations of IGFBP-1 acts to inhibit trophoblast invasion during placentation. Therefore, it is unlikely that increased decidual expression of IGFBP-1 is responsible for the impaired trophoblast invasion characteristic of pre-eclampsia. Maternal circulating IGFBP-1 concentrations have been measured in samples obtained before the development of pre-eclampsia by two groups previously (de Groot et al., 1996
; Giudice et al., 1997). Both obtained single samples in the different trimesters and compared the IGFBP-1 concentrations in those who did and did not develop pre-eclampsia. Despite the similarity in design between the studies, the concentrations reported were different. One study reported an increase in IGFBP-1 concentrations (Giudice et al., 1997) and the other a decrease (de Groot et al., 1996) at the time of implantation. Data reported previously (Giudice et al., 1997) are weakened by the inclusion of patients in preterm labour and women receiving corticosteriod therapy, as both uterine activity and corticosteriods are known to increase circulating concentrations of IGFBP-1 (Powell et al., 1993; Hills et al., 1994; Uchijima et al., 1999). Furthermore, the women in that study were recruited after the development of pre-eclampsia. The current data show clearly that in early pregnancy IGFBP-1 concentrations are lower in those women who go on to develop pre-eclampsia.
Many studies have reported that IGFBP-1 concentrations are elevated in pre-eclampsia (Howell et al., 1989). However, in a cross-sectional study, IGFBP-1 concentrations were found to be elevated in pre-eclampsia only when it was associated with intrauterine growth restriction (IUGR; Wang et al., 1996). The current data agree with the previous reports that IGFBP-1 concentrations are elevated with established pre-eclampsia. However, although the fetuses in the pre-eclampsia group were not thought to have IUGR on ultrasound criteria, their gestation-corrected birth weights were significantly lower. Serial data are not available for pregnancies complicated by IUGR, thus it is possible that the changes observed reflect not pre-eclampsia but the development of IUGR with pre-eclampsia superimposed. However, given that IUGR was not diagnosed by ultrasound criteria, it is felt that the changes are not likely to be due to the development of IUGR.
The origin of the lower concentrations of IGFBP-1 in early pregnancy may arise from one of several possibilities. It may simply reflect reduced decidual function, impaired trophoblast invasion resulting in a lesser decidual response and/or be a result of impaired deportation of IGFBP-1 into the maternal circulation (de Groot et al., 1996). Alternatively, the lower concentrations may be due to reduced hepatic synthesis. Whatever their origin, the lower concentrations could be of aetiological importance in the development of pre-eclampsia and/or IUGR. Indeed, IGFBP-1 has been shown to promote cell proliferation independent of IGF-1 (De Mellow and Boxter, 1988; Blum et al., 1989). Thus, IGFBP-1 may actually promote trophoblast function. However, IGFBP-1 has been suggested previously to inhibit trophoblast invasion and fetal growth by binding to and blocking IGF receptor sites (Wang et al., 1991a; Hills et al., 1996). The elucidation of the precise role played by IGFBP-1 during placentation awaits further study.
The reason for the progressive rise in IGFBP-1 concentrations in pregnancies complicated by pre-eclampsia is not clear. It is possible that the rise represents a decidual response to pre-eclampsia or placental ischaemia (Tazuke et al., 1998). No statistically significant difference was found between plasma creatinine concentrations and haematocrit between the two groups; thus, it is unlikely that the higher concentrations are due to impaired renal clearance or haemoconcentration. Furthermore, there was no significant association between plasma ALT and IGFBP-1 concentrations in either group, suggesting that the liver was not involved in the increase in IGFBP-1. The low concentrations of IGFBP-1 at 16 weeks in the group destined to develop pre-eclampsia raise the possibility that IGFBP-1 concentrations could be used as a marker for the later development of pre-eclampsia. This awaits further study (Figure 3
).
In summary, it has been demonstrated that compared to normal pregnancy, maternal circulating concentrations of IGFBP-1 in pregnancies destined to develop pre-eclampsia are lower at the time of placentation. Plasma concentrations increase progressively as the disease evolves to exceed concentrations in normal pregnancy by the third trimester. These data do not support the hypothesis that IGFBP-1 concentrations are elevated at the time of implantation in those pregnancies that develop pre-eclampsia.
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Acknowledgments |
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The Chelsea & Westminster Hospital Trustees and The Smith Charity supported this work.
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Notes |
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3 To whom correspondence should be addressed at: Department of Maternal-Fetal Medicine, Division of Paediatrics, Obstetrics & Gynaecology, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. E-mail: n.anim{at}ic.ac.uk
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Submitted on February 28, 2000; accepted on June 14, 2000.
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