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ORIGINAL RESEARCH |
From the Department of Community Medicine and General Practice, Department of Cancer Research and Molecular Biology, and Department of Obstetrics and Gynecology, Norwegian University of Science and Technology, Trondheim, Norway; and Department of Obstetrics and Gynecology, Rogaland Central Hospital, Stavanger, Norway.
Address reprint requests to: Lars J. Vatten, MD, PhD, Norwegian University of Science and Technology, University Medical Centre, N-7489 Trondheim, Norway; E-mail: lars.vatten{at}medisin.ntnu.no.
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ABSTRACT |
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METHODS: Cord blood was collected in 12,804 consecutive deliveries. We identified 258 preeclamptic pregnancies that were subclassified as mild or severe and early or late. For comparison, 609 control pregnancies were selected. Fetal growth was expressed as the ratio between observed and expected birth weight, with adjustment for gestational age at birth. IGF-I, IGFBP-1, and IGFBP-3 were measured in umbilical plasma. The contribution of preeclampsia and birth weight to each measured factor was assessed by multiple linear regression analyses.
RESULTS: Between mild preeclampsia and controls, there were no differences in IGF-I, IGFBP-1, and IGFBP-3. In severe and early onset preeclampsia, umbilical cord plasma IGF-I was approximately 50% lower, and IGFBP-1 was more than twice as high as in controls (both P < .01). At each birth weight level, IGF-I was lower and IGFBP-1 was higher in severe or early preeclampsia than among controls of similar weight. Birth weight and preeclampsia were, independent of each other, associated with IGF-I, whereas birth weight, but not preeclampsia, was associated with IGFBP-1, after adjustment for gestational age.
CONCLUSION: Fetal growth restriction caused by severe or early preeclampsia is associated with lower umbilical levels of IGF-I than low birth weight caused by other conditions. Preeclampsia may contribute to the observed IGF-I reduction, either as part of the underlying causes of preeclampsia, or as a consequence of the disease.
Insulin-like growth factor-I (IGF-I) is a mitogenic polypeptide that stimulates cellular proliferation and differentiation.1 The strong positive correlation between umbilical cord IGF-I and birth weight indicates its importance for fetal growth.1–4 Thus, IGF-I is expressed by fetal organs,5 membranes,6 and by the placenta.6–9 The function of IGF-I is modulated by six binding proteins with high affinity (IGFBPs). The smaller, such as IG-FBP-1, may be responsible for the transfer of IGF-I from the circulation to the extracellular space, whereas the larger IGFBP-3 binds 95% of IGF-I and provides a reservoir for IGF-I in the circulation.1,9 IGFBP-1 usually inhibits the effects of IGF-I at the cellular level,9 but is also related to cell growth independent of IGF-I.9 In pregnancy, the production of IGFBP-1 is strongly increased,9 and abnormally high levels of IGFBP-1 have been found in umbilical10–16 blood in conjunction with fetal growth restriction, whereas umbilical IGFBP-3 may be lower in infants born small for their gestational age.17 It has been hypothesized that inadequate nutrition of the fetus will stimulate production of IGFBP-1 and inhibit the effect of IGF-I.18 A combination of high umbilical levels of IGFBP-1 and low IGF-I could, therefore, reflect an adaptive response to an intrauterine environment that cannot offer the fetus optimal conditions for growth.18
Preeclampsia is a heterogeneous syndrome, with varying effects on fetal growth. In mild cases, fetal growth is usually appropriate,7 whereas fetal growth restriction is commonly observed in severe preeclampsia or in preeclampsia with early onset.7 These subtypes of preeclampsia are characterized by abnormally shallow decidual trophoblast invasion, hypoxia, and reduced uteroplacental blood flow.7,8,19 A few studies have reported lower IGF-I and IGFBP-3 and higher IGFBP-1 in umbilical cord blood levels from preeclamptic pregnancies complicated by low birth weight.15,20 One study found that alterations in IGF-I and IGFBP-1 were more pronounced in preeclampsia than could be expected from the smaller size of the offspring,20 suggesting that preeclampsia may contribute with an effect independent of the relation to birth weight. In this large case-control study, we wanted to find out whether preeclampsia is associated with alterations in IGF-I and its binding proteins IGFBP-1 and IGFBP-3, independent from changes attributed to reduced birth weight.
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MATERIALS AND METHODS |
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From the Medical Birth Registry, we initially identified approximately 1300 cases with clinical information that might indicate preeclampsia. After verifying and supplementing this information with details from the hospital records, we identified 307 singleton pregnant women with certain preeclampsia, and umbilical cord blood was available from 258 of these women. We used a previously described definition of preeclampsia in this study.23 Briefly, for preeclampsia to be diagnosed, persistent diastolic blood pressure of at least 90 mm Hg had to develop after 20 weeks of gestation, and diastolic blood pressure had to increase by at least 25 mm Hg. In addition, proteinuria had to be present, and cut-off was defined as 0.3 mg/L (semiquantitative dipstick 1+) in at least one urine sample after 20 weeks of gestation without simultaneous urinary infection.
Preeclampsia was classified as severe (n = 67) if diastolic blood pressure increased to at least 110 mm Hg, along with proteinuria 3+ on dipstick, or at least 500 mg per 24 hours. Cases with eclampsia and suspected hemolysis, elevated liver enzymes, low platelets syndrome were also regarded as severe preeclampsia, whereas all other cases of preeclampsia were classified as mild (n = 191).
For comparison, two women without preeclampsia were selected per case of preeclampsia from the cohort of birthing women at the Rogaland Central Hospital, as previously described.22 Among 619 women without preeclampsia initially selected, cord blood was available from 609. For the whole study population, information on baseline data were obtained at around 12 weeks of pregnancy, at the first maternal visit. All infant data were collected from hospital records. In Table 1
, we have described some characteristics of the groups.
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Birth weight was standardized as the ratio between the observed and expected birth weight, where the expected birth weight was adjusted for offspring gender and gestational age at birth. We used standards of expected birth weights derived from the results of weight curves based on ultrasonographic measurements in a large Scandinavian population.24 Gestational age at birth was calculated from routine ultrasonographic measurements at 18 weeks’ gestation. In tables and text, standardized weight is expressed as the mean value with 95% confidence intervals. Small-for-gestational-age (SGA) was defined as an observed birth weight two standard deviations or more below the expected, which corresponds to a ratio lower than 0.76, or to a birth weight reduction of approximately 840 g for a term infant.
Cord plasma IGF-I and IGFBP-3 were assayed by commercially available radioimmunoassay kits (Mediagnost, Tuebingen, Germany). All samples were run in duplicates, and all procedures were run as suggested by the producer, except that we used half volumes. IGF-I and IGFBP-3 were detected in all plasma samples, and detection limits were 4.8 ng/mL and 370 ng/mL, respectively. Cord plasma IGFBP-1 was assayed by a commercially available enzyme immunoassay (Mediagnost, Tuebingen, Germany), and single samples were analyzed. The detection limit of the assay was 4.6 ng/mL, and IGFBP-1 was detected in all but one sample. The three assays were run in 11 sequences, and for all three, the intra-assay variation was on average less than 4%. The intra-assay coefficients of variation for IGF-I, IGFBP-3, and IGFBP-1 were 12%, 10%, and 16%, respectively.
For the IGF-I analyses, plasma samples were available from 609 controls and 191 cases of mild and 67 cases of severe preeclampsia. For the IGFBP-1 analyses, plasma samples were available from 604 controls and 190 cases of mild and 66 cases of severe preeclampsia. For the IGFBP-3 analyses, plasma samples were available from 601 controls and 190 cases of mild and 65 cases of severe preeclampsia.
IGFBP-1 had a skewed distribution and was, therefore, expressed as the median value (ng/mL, interquartile range). Student t test and Mann-Whitney U test were used to compare continuous variables between groups. Differences between proportions were assessed by 
2 tests. The standardized birth weight was divided into four clinical categories: <0.76 corresponded to a strict definition of SGA, and 0.76–0.89 was a broad category of relatively small infants. The category 0.90–1.09 included infants with appropriate weight for their gestational age, and the category >1.09 included large babies. For each level of birth weight, we estimated values of IGF-I, IGFBP-1, and IGFBP-3 between the preeclampsia group and controls, and tested the linear association (yielding a P value for trend) across birth weight categories for each of the three components of the IGF system in multiple regression analyses. We also assessed the independent contribution of birth weight and preeclampsia to levels of IGF-I and IGFBP-1, and adjusted for gestational age, using multiple regression analyses. All statistical analyses were calculated using the Statistical Package for the Social Sciences 10.05 (SPSS, Inc., Chicago, IL).
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RESULTS |
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), the severe preeclampsia group had lower levels of IGF-I (P <.01) and IGFBP-3 (P <.05) in umbilical cord plasma than controls. For IGFBP-1, the severe preeclampsia group had values two times higher than controls (P <.01). The measured values varied only modestly with length of gestation. It is, therefore, unlikely that the differences between the groups can be attributed to differences in gestational age at birth. For all three factors, the results for mild preeclampsia did not significantly differ from those of controls (Table 2).
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shows that the most dramatic differences between the groups can be attributed to severe preeclampsia with early onset of symptoms (34 weeks’ gestation and earlier). In the "early onset" group, IG-FBP-1 (median 611 ng/mL) was more than six times higher than in controls (97 ng/mL). Compared with "late onset" preeclampsia, the median value in the "early onset" group was four times higher (P <.01). Nonetheless, in severe preeclampsia with late onset, IGF-I and IGFBP-1 were still significantly different from controls (both P <.01).
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, IGF-I and the binding proteins IGFBP-1 and IGFBP-3 were related to predefined categories of standardized birth weight, and adjusted for gestational age and offspring gender. There was a consistent decrease in IGF-I from the largest to the smallest babies (SGA), both within the severe preeclampsia group and among controls (both P for trend <.01), with more than a two-fold difference in IGF-I between the highest and the lowest categories of birth weight. For each level of birth weight, however, IGF-I was significantly lower in the severe preeclampsia group than among controls, after controlling for differences in gestational age.
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For IGFBP-3, there was a decrease in birth weight within each study group. By comparing the groups at each level of birth weight, however, there were no significant differences in IGFBP-3 between the severe preeclampsia group and controls.
In the multivariate analyses (Table 5), we found that severe preeclampsia and birth weight were strongly associated with IGF-I levels, after adjustment for gestational age. Table 5 also shows that birth weight, but not severe preeclampsia, was associated with IGFBP-1.
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DISCUSSION |
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The reason for being small may influence the relation between IGF-I, IGFBPs, and infant birth weight. Previously, two studies have compared different groups of neonates who were small for gestation, but for different reasons.10,18 One group had suffered from intrauterine growth restriction most likely caused by placental disease, whereas the other group was born small for gestational age for a variety of reasons other than placental disease. The results were similar for maternal10 and umbilical18 measurements: fetuses with placental insufficiency had the lowest IGF-I and the highest levels of IGFBP-1. In our study, low birth weight in the control group may also have been caused by a variety of reasons, and some infants will simply be constitutionally small. In contrast, infants born after severe and early onset preeclampsia may be a relatively homogeneous group with placental insufficiency.19 Consequently, the lower values of IGF-I and the very high values of IGFBP-1 associated with the combination of severe preeclampsia and fetal growth restriction may reflect placental disease.
The shallow trophoblast invasion typical for severe or early preeclampsia is associated with highly elevated expression of IGFBP-1 in the decidua,7,8 and high levels of maternal IGFBP-1 in early pregnancy may be associated with increased risk of severe, but not mild preeclampsia.25,26 Those results may support the hypothesis that mild and severe preeclampsia may represent separate disease entities, and suggest that IGFBP-1 is involved in initial mechanisms at the maternal-placental interface that may culminate in severe preeclampsia.7,8 However, our results indicate that IGFBP-1 is more closely linked to birth weight than to preeclampsia, and this could suggest that IGFBP-1 is involved in compensatory or adaptive responses to insufficient fetal nutrition that will accompany severe preeclampsia.18 On the other hand, the close association between IGF-I and severe preeclampsia may reflect compromised trophoblast function.27,28 Thus, low IGF-I levels in severe preeclampsia may be the consequence of placental dysfunction rather than the underlying cause.
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Footnotes |
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The authors thank the Norwegian Medical Birth Registry for assistance.
Received June 21, 2001. Received in revised form September 17, 2001. Accepted September 24, 2001.
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REFERENCES |
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