Human Reproduction, Vol. 15, No. 8, 1834-1837,
August 2000
© 2000 European Society of Human Reproduction and Embryology
The feto–placental unit stimulates the pregnancy-associated increase in maternal bone metabolism
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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The aim of the study was to investigate role of the feto–placental unit in the pregnancy-induced increase in maternal bone metabolism. To achieve this, circulating concentrations of carboxy terminal pro-peptide of type I pro-collagen (PICP, a marker of bone formation) and cross-linked carboxy terminal telopeptide of type I collagen (ICTP, a marker of bone resorption) were measured in three groups of pregnant women. Group 1 comprised 12 women with singleton pregnancies; group 2, nine women with twin pregnancies; and group 3, 19 women with multifetal pregnancies (
3 fetuses) before and after selective fetal reduction to twin pregnancies. Blood samples were obtained at 10–12 weeks gestation (groups 1–3, pre-fetal reduction in group 3) and 4 weeks and 8 weeks later (groups 2 and 3). Before fetal reduction there was a significant correlation between the number of fetuses and the concentrations of both PICP and ICTP (r = 0.503 and P = 0.001 and r = 0.573 and P < 0.001 respectively). The circulating concentrations of PICP and ICTP were significantly higher in the pre-reduction multifetal pregnancies than in the twin pregnancies (P < 0.001 and P = 0.0013 respectively). The circulating concentrations of ICTP in multifetal pregnancies fell by 4 weeks after fetal reduction to those observed in control twins. Concentrations of PICP were unaltered after fetal reduction. Higher order multiple pregnancies had the greatest decline in ICTP concentrations. These data suggest that the increased bone turnover observed in the multifetal pregnancies is due to a factor derived from the feto–placental unit and that this factor acts primarily to stimulate bone resorption.
Key words: bone metabolism/feto-placental unit/maternal/pregnancy
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Introduction |
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Pregnancy is associated with marked changes in calcium metabolism with the presumed primary aim of ensuring the availability of adequate calcium for the mineralization of the fetal skeleton. Total calcium concentrations fall during pregnancy, reflecting the drop in albumin concentrations, but free calcium concentrations are unchanged (Pitkin et al., 1979
). Calcium absorption from the GI tract is enhanced by the higher concentrations of vitamin D (Vit-D; Ritchie et al., 1998). In addition, bone resorption is increased (Purdie et al., 1988). The increase in bone resorption occurs in the face of falling parathyroid hormone concentrations (PTH; Seki et al., 1991) and increased urinary calcium loss (Seely and Graves, 1993). The increase in loss of calcium is suggested to be due to increased renal perfusion (Heany and Skillman, 1971). If this were the case, PTH concentrations would be expected to rise to make up for the net loss of calcium. However, the fall in PTH concentrations at this time suggests that the origin of the increased calcuria is not loss secondary to increased renal perfusion. The alternative is that the increased loss is secondary to increased calcium availability. Indeed, Vit-D concentrations are increased resulting in enhanced GI calcium absorption. However, although this may explain the greater availability of calcium, it does not account for the increased bone breakdown. Our hypothesis is that the feto–placental unit stimulates bone breakdown that results in increased calcium availability and consequently calcium excretion.
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 feto–placental 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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Three groups of women were examined. Group 1, singleton pregnancies (n = 11), group 2, twin pregnancies (n = 9), both achieved following super-ovulation and IVF and embryo transfer recruited from the Assisted Conception Unit, King's College Hospital. Group 3, multifetal pregnancies (three to eight fetuses, n = 19) (three fetuses n = 9, four fetuses n = 6, five fetuses n = 1, six fetuses n = 1, eight fetuses n = 1 and 10 fetuses n = 1) undergoing selective fetal reduction to twin pregnancies, was recruited from The Harris Birthright Research Centre for Fetal Medicine, King's College Hospital. The multifetal pregnancies occurred after ovulation induction, followed by intrauterine insemination or IVF–embryo transfer. They were referred from a variety of units. Fetal reduction to twins was carried out by ultrasound guided trans-abdominal injection of potassium chloride into the fetal heart. Ultrasound demonstrated complete reabsorption of the feto–placental units 8–12 weeks after reduction.
In group 1, blood samples were obtained at 10–12 weeks gestation only. In group 2, blood samples were obtained at 10–12 weeks gestation and then 4 and 8 weeks afterwards. In group 3, blood was obtained before reduction at 10–12 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 2.1–3.7% and inter-assay coefficient variation of 3.6–6.6%. The reference range of PICP has been reported as 50–170 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 2.8–6.2% and inter-assay coefficient variation of 4.1–7.9%. 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 (Mann–Whitney 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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ICTP
There was a significant correlation between the concentrations of ICTP and the number of fetuses (r = 0.571, P < 0.001; Figure 1
). Over the study period, in twins, the concentrations of ICTP remained unchanged (Figure 2). Following fetal reduction in the multifetal pregnancies, the circulating concentrations of ICTP fell significantly (P = 0.006 and P = 0.015 at 4 and 8 weeks respectively; Figure 2). There was an association between the initial fetal number and the fall in ICTP concentrations (r = 0.433, P = 0.024 and r = 0.628, P = 0.0006 at 4 and 8 weeks respectively).
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The circulating concentrations of ICTP in the multifetal pregnancies were significantly higher than in the twin pregnancies at baseline (P = 0.0013, Table I
). At 4 and 8 weeks post-fetal reduction, the circulating concentrations of ICTP were similar in both groups (Table I).
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PICP
There was a significant correlation between the concentrations of PICP and the number of fetuses (r = 0.503 and P = 0.001, Figure 3
). The concentrations of PICP increased in twins over the study period, and were significantly higher at 4 and 8 weeks than at baseline (P = 0.046 and P = 0.011 respectively; Figure 4). In contrast, PICP concentrations in the multifetal pregnancies were unchanged after fetal reduction (Figure 4).
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PICP concentrations were higher in the multifetal pregnancies pre-fetal reduction, than in the twin controls (P < 0.0001), but due to the increase in PICP concentrations in twins, PICP concentrations were similar in both groups at 4 and 8 weeks (Table I
). 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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It was found that bone metabolism increased with fetal number and declined after fetal reduction. At the time of fetal reduction, the feto–placental calcium requirement is at its lowest; despite this, bone metabolism is increased and may be responsible for the elevated urinary calcium concentrations observed at this time. Thus, the data suggest that the feto–placental unit may actually stimulate bone metabolism. This conclusion is supported by (i) the findings of the multiple regression analysis which suggest that the prime impact of the feto–placental unit is on bone resorption; (ii) the relationship between the fall in ICTP concentrations and initial fetal number; and (iii) by the lack of change in the concentrations of the marker of bone formation, PICP, after fetal reduction in contrast to the significant drop in the concentrations of the marker of bone resorption, ICTP. Overall, these data suggest that the increased bone formation in multifetal pregnancies is secondary to an increase in bone breakdown and that the relationship between fetal number and PICP is probably indirect, mediated through the increase in bone breakdown.
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 feto–placental 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 feto–placental unit.
The mechanism by which the feto–placental 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 feto–placental unit stimulates bone breakdown. The mechanism may be indirect and involve feto–placental 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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We are grateful to WellBeing and the Charing Cross and Westminster Medical School Trustees for their financial support.
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Notes |
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4 To whom correspondence should be addressed at: Department of Maternal & Fetal Medicine, Division of Paediatrics, Obstetrics and Gynaecology, Imperial College School of Medicine, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK. E-mail: mark.johnson{at}ic.ac.uk
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Submitted on February 21, 2000; accepted on April 13, 2000.
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