1 Section of Obstetrics and Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, 2 The Harris Birthright Research Centre for Fetal Medicine, King's College Hospital Medical School, London, SE5 8RX and 3 Department of Chemical Pathology, Imperial College School of Medicine, Charing Cross Hospital, Fulham Palace Road, London, UK
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Abstract |
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Key words: bone metabolism/feto-placental unit/maternal/pregnancy
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Introduction |
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Circulating concentrations of carboxy terminal pro-peptide of type I pro-collagen (PICP) and cross-linked carboxy terminal telopeptide of type I collagen (ICTP) have previously been used to assess bone formation and breakdown respectively in the maternal and fetal circulations (Ogueh et al., 1998a,b
, 1999a
,Ogueh et al., b
). These markers increase from the first trimester, suggesting increased bone metabolism (Khastgir et al., 1994). In this study, in order to test the hypothesis that the fetoplacental unit stimulates bone breakdown, PICP and ICTP were measured in blood samples taken from women with multiple pregnancies before and after selective fetal reduction.
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Materials and methods |
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In group 1, blood samples were obtained at 1012 weeks gestation only. In group 2, blood samples were obtained at 1012 weeks gestation and then 4 and 8 weeks afterwards. In group 3, blood was obtained before reduction at 1012 weeks gestation and then at 4 and 8 weeks post-reduction. The Ethics Committee of King's College Hospital approved the study and the women gave informed consent.
Samples were stored at 20°C until analysed in a single batch. The serum concentration of PICP was determined by an equilibrium radioimmunoassay (Orion Diagnostica, Finland), using the method reported previously (Melkko et al., 1990). The assay showed a high precision with intra-assay coefficient variation of 2.13.7% and inter-assay coefficient variation of 3.66.6%. The reference range of PICP has been reported as 50170 µg/l in non-pregnant women. The sensitivity of the assay defined as the detectable concentration equivalent to twice the SD of the zero binding value was 1.2 µg/l. The serum concentration of ICTP was measured by a similar radioimmunoassay technique (Orion Diagnostica), which has also been described earlier (Risteli et al., 1993
). This also featured a high precision with intra-assay coefficient variation of 2.86.2% and inter-assay coefficient variation of 4.17.9%. In healthy adults, the ICTP concentration varied between 1.8 and 5 µg/l and the sensitivity of the assay was 0.5 µg/l.
The data were not normally distributed and non-parametric tests (MannWhitney U and Wilcoxon signed-rank) were used to analyse the data. Simple and multiple regression analyses were used to investigate the associations between analytes and fetal number. The data are presented as median and interquartile range.
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Results |
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Multiple regression analysis showed that the relationship between fetal number and the markers of maternal bone metabolism was much stronger for ICTP than for PICP (overall r = 0.7, F = 24.31 and P = 0.0001, ITCP partial F = 36.6 and P = 0.0001 and PICP partial F = 5.07 and P = 0.029).
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Discussion |
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Usually PICP and ICTP are closely related. In this study, two instances were observed when they appeared to dissociate. The first, in twin pregnancies when in the study period ICTP remained unchanged, while the concentrations of PICP rose, and the second when following fetal reduction the concentrations of ICTP fell and those of PICP remained unchanged. The second situation is easier to understand, as when the stimulus to bone resorption was partially removed by fetal reduction, the concentrations of ICTP fell. The failure of PICP concentrations also to fall probably reflects the maintenance of bone formation to redress the balance. This has been reported previously in cases of thyrotoxicosis. In this situation, pretreatment ICTP and PICP concentrations are elevated, but following correction of the hyperthyroidism ICTP concentrations fall, while PICP concentrations are maintained (Nagasaka et al., 1997). A similar pattern is seen following the surgical treatment of renal hyperparathyroidism (Katagiri et al., 1996
). It has previously been reported that free thyroxine concentrations fall after fetal reduction (Ogueh et al., 2000
), and the changes may be sufficient to explain the differences observed in the markers of bone formation in this study. In twin pregnancies, free thyroxine behaved in a similar but less marked manner (free thyroxine concentrations declined with time; Ogueh et al., 2000). Thus, changes in thyroid function may be responsible for the dissociation of ICTP and PICP in both fetal reduction and twin pregnancies. However, the degree of change in thyroid function was much greater in multifetal pregnancies than in twin pregnancies (Ogueh et al., 2000
). Therefore, if the increase in PICP observed in twin pregnancies was as a result of changes in thyroid function, then a more marked increase would have been expected to have occurred in the fetal reduction group. A longitudinal study of bone marker concentrations in multiple pregnancy is required in order to clarify these data.
The data presented here support those of Okah and colleagues, who also found higher concentrations of ICTP in the third trimester of multiple compared to singleton pregnancies (Okah et al., 1996). However, the origin of the increased bone metabolism in the third trimester is probably the increased calcium demand of the fetoplacental unit. In contrast, at the end of the first trimester there is no increase in calcium demands; thus the increase in maternal bone metabolism is probably a result of a direct stimulatory effect of the fetoplacental unit.
The mechanism by which the fetoplacental unit stimulates bone resorption is uncertain, but as was discussed above may involve changes in thyroid function. An alternative could be placental parathyroid hormone related peptide (PTHrP). Indeed, although immunoreactive concentrations of PTH fall during pregnancy, its bioactivity and renal cAMP generation (a sensitive marker of PTH bioactivity) are normal or increased (Davis et al., 1988; Seki et al., 1994
). Maternal concentrations of PTHrP increase throughout pregnancy (Bertolleni et al., 1994
) and are derived from the placenta predominantly in early pregnancy and later from the fetal parathyroid gland (Moniz, 1990). PTHrP is known to increase bone resorption and control placental calcium transfer (Moniz, 1990). Thus, PTHrP may be responsible for the changes in maternal bone metabolism seen during pregnancy. Indeed, the changes in ICTP concentrations after fetal reduction are similar to those reported previously for human chorionic gonadotrophin, which like PTHrP is predominantly placental in origin (Johnson et al., 1994
). These data offer some support for the idea that PTHrP is responsible for the pregnancy-associated increase in maternal bone resorption. However, to test this hypothesis, the concentrations of PTHrP will have to be measured before and after fetal reduction. Previously, insulin-like growth factor (IGF)-I has been associated with maternal PICP concentrations, suggesting that maternal IGF-I may promote type I collagen synthesis and so protect against bone breakdown (Puistola et al., 1993
). The impact of fetal reduction on maternal IGF-I concentrations is unknown and therefore its role in this situation uncertain.
This study supports the hypothesis that the fetoplacental unit stimulates bone breakdown. The mechanism may be indirect and involve fetoplacental stimulation of the maternal thyroid or be direct through placental synthesis of PTH-rP or another factor that stimulates maternal bone resorption.
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Acknowledgments |
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Notes |
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References |
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Submitted on February 21, 2000; accepted on April 13, 2000.