Human Reproduction, Vol. 14, No. 11, 2876-2880,
November 1999
© 1999 European Society of Human Reproduction and Embryology
Bone density changes in pregnant women treated with heparin: a prospective, longitudinal study
1 Departments of Obstetrics & Gynaecology, 2 Clinical Physics & Bone Densitometry and 3 Medical Statistics & Evaluation, ICSM at St Mary's and 4 Hammersmith Hospital, Praed Street, London W2 1PG, UK
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Abstract |
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Heparin plus aspirin significantly improves the live birth rate of women with primary antiphospholipid syndrome. Osteopenia is a major concern of long-term heparin therapy. We studied prospectively the bone mineral density (BMD) changes during pregnancy and the puerperium in 123 women with primary antiphospholipid syndrome treated with low-dose aspirin and subcutaneous low-dose heparin (46 women took unfractionated heparin and 77 took low-molecular-weight heparin). Lumbar spine, neck of femur and forearm BMD were measured, using dual energy X-ray absorptiometry, at 12 weeks gestation, immediately postpartum and 12 weeks postpartum. The mean heparin duration was 27 weeks (range 22–29). During pregnancy, BMD decreased by 3.7% (P < 0.001) at the lumbar spine and by 0.9% (P < 0.05) at the neck of femur with no significant change at the forearm. Lactation was associated with a significant decrease in the lumbar spine and neck of femur BMD. There was no significant difference in BMD changes between the two heparin preparations. No woman suffered a symptomatic fracture. Long-term heparin treatment during pregnancy is associated with a small but significant decrease in BMD at the lumbar spine and neck of femur. This decrease is similar to that previously reported to occur in untreated pregnancies.
Key words: bone density/heparin/pregnancy/prospective study
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Heparin in combination with aspirin significantly improves the live birth rate of women with recurrent miscarriage and antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) (Kutteh, 1996
; Rai et al., 1997; Backos et al., 1999). A major concern regarding the long-term use of heparin during pregnancy is its reported association with the development of osteoporosis.
Heparin-induced osteoporosis was first reported in 1965 (Griffith et al., 1965). Several studies have since reported that long-term heparin treatment during pregnancy is associated with reduced bone density (de Swiet et al., 1983; Dahlman et al., 1990, 1994; Barbour et al., 1994; Douketis et al., 1996) and vertebral bone fractures (Squires and Pinch, 1979; Wise and Hall, 1980; Griffith and Liu, 1984; Dahlman, 1993; Haram et al., 1993). However, these findings may occur in pregnancies in which no pharmacological treatment is given (Drinkwater and Chestnut, 1991; Khastgir and Studd, 1994; Smith et al., 1995; Khastgir et al., 1996; Shefras and Farquharson, 1996). It is therefore unclear what proportion of the reported reduction in bone density associated with long-term treatment with heparin during pregnancy is attributable to pregnancy itself and what proportion may be caused by heparin. This is compounded by the fact that earlier studies reporting heparin-induced osteoporosis during pregnancy used relatively imprecise radiological methods which suffer from poor sensitivity and reproducibility (Dahlman et al., 1990). The recent introduction of dual photon X-ray absorptiometry (DEXA) has been an important step forward in assessing bone density.
We used DEXA to measure prospectively bone mineral density (BMD) at the lumbar spine (L2–L4), the neck of femur and the forearm during pregnancy and the puerperium in women with a history of recurrent miscarriage and antiphospholipid antibodies treated with low-dose heparin and low-dose aspirin.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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BMD was measured in 123 pregnant women (mean age 34 years; range 23–46) with a history of recurrent miscarriage (median 4; range 2–15). All women tested persistently positive for antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies) and were treated with low-dose aspirin and low-dose heparin during pregnancy. No woman had a history of bone disease and none had previously been treated with heparin. The demographic and clinical details of these women are shown in Table I
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Low dose aspirin (75 mg daily) was commenced as soon as the urinary pregnancy test was positive. Heparin therapy was commenced at a mean gestation of 7 weeks (range 5–12). The first 46 women received self-administered s.c. unfractionated calcium heparin (5000 U 12 hourly, Calciparine; Sanofi Winthrop, Guildford, Surrey, UK) and the remaining 77 women received self-administered s.c. low-molecular-weight heparin, enoxaparin sodium (20 mg daily, Clexane; Rhone–Poulenc Rorer, West Malling, Sussex, UK). Treatment with aspirin and heparin was discontinued at 34 completed weeks gestation or at the time of delivery if this occurred earlier. No pharmacological treatment, apart from folic acid for prophylaxis against neural tube defects, was prescribed and no calcium supplementation was given.
Bone densitometry
After obtaining informed patient consent, dual energy X-ray densitometry (DEXA, Lunar Corporation, Madison, Wisconsin, USA) was used to measure the BMD at the lumbar spine (L2–L4), neck of femur and the forearm at 12 weeks gestation (baseline), immediately postpartum (
2 weeks after delivery) and 12 weeks postpartum. The precision of DEXA for BMD is 1% at the lumbar spine and 2% at the femoral neck and the effective radiation dose at the lumbar spine and neck of femur is 1 µSv (WHO Study Group, 1994).This is less than the radiation exposure of a passenger on a trans-Atlantic flight (70 µSv).
Based on the T-score, i.e. the BMD of an individual relative to that of a reference population of young adults, women were classified as having a BMD that was either normal, osteopenic (between 1 and 2.5 SD below that of the normal range) or osteoporotic (>2.5 SD below that of the normal range) (WHO Study Group, 1994).
Statistical analysis
Differences within the groups were tested for normality with the Shapiro–Francia test (Altman, 1991) for normal data and found suitable for Student's t-test for paired data. Differences between the groups were estimated by Student's t-test for unpaired data, Fisher's exact test, and the Mann–Whitney U-test. Multiple regression analysis was used to predict the changes in bone density from demographic and clinical details. P < 0.05 was considered to be statistically significant.
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Results |
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The mean duration of heparin treatment was 27 weeks (range 22–29 weeks). Of the 123 women, 119 (97%) received heparin until 34 completed weeks of pregnancy. Four women (3%) delivered between 32 and 34 weeks gestation and discontinued heparin at this time. No woman voluntarily discontinued heparin therapy and none developed heparin-induced bleeding complications, thrombocytopenia or hypersensitivity. No woman suffered a symptomatic fracture. All women delivered live infants.
There was a significant decrease in the BMD at both the lumbar spine [mean decrease 0.046 g/cm2 (3.7%); P < 0.001] and at the neck of femur [0.01 g/cm2 (0.9%), P = 0.007] between 12 weeks gestation (baseline) and immediately post partum. There was no significant change in the BMD measurements at the forearm (Table II and Figure 1). Women who breast-fed had a significant bone density loss at the lumbar spine and femoral neck compared with women who did not breast-feed (Table III). There was no significant difference in BMD changes during pregnancy between those women receiving unfractionated heparin compared with those receiving low-molecular-weight heparin (Tables IV and V).
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Baseline BMD measurements (at 12 weeks gestation) were osteopenic at the lumbar spine in 10 women (8.1%) [mean T-score –1.6; range –2.3 to –1] and at the femoral neck in eight women (6.5%) [mean T-score –1.2; range –1.4 to –1)]. In view of this result, we questioned whether there was a decrease in BMD between starting heparin and the baseline measurement at 12 weeks gestation. BMD was therefore measured in a further cohort of nine women treated with aspirin and heparin (median age 32 years; range 24–35) prior to pregnancy and at 12 weeks gestation. The mean BMD increased by 1.8% (P = 0.01) at the lumbar spine and by 1.1% (not significant) at the femoral neck between these two time points (Table VI
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Multiple regression analysis demonstrated that age, body mass index, ethnic origin, smoking status, previous alcohol intake, previous number of miscarriages and live births, time elapsed since last pregnancy, baseline BMD and length of heparin treatment were not predictive of BMD changes during pregnancy.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Combination treatment with aspirin and heparin significantly improves the live birth rate among pregnant women with primary antiphospholipid syndrome (Kutteh, 1996
; Rai et al., 1997; Backos et al., 1999). Previous reports have raised concern that the long-term use of heparin during pregnancy may be associated with the development of osteopenia and vertebral bone fracture. However, many of these studies have been (i) retrospective, thereby including some women who may have been osteopenic prior to commencing heparin (de Swiet et al., 1983; Dahlman et al., 1990; Dahlman, 1993; Douketis et al., 1996; Nelson-Piercy et al., 1997), (ii) measured bone density after several months of lactation (de Swiet et al., 1983; Nelson-Piercy et al., 1997), or (iii) used less precise methods than DEXA in assessing BMD (de Swiet et al., 1983; Dahlman et al., 1990; Dahlman, 1993). Only one prospective study to date has assessed the effect of heparin on lumbar spine bone density during pregnancy using DEXA (Shefras and Farquharson, 1996). These authors reported that during pregnancy, a decrease in lumbar spine BMD of 5% in 17 women given low-molecular-weight heparin was not significantly greater than the loss (3%) in a control group of eight untreated pregnant women.
In this large prospective study, we used DEXA, a sensitive and precise method of assessing BMD, to determine the changes in BMD at three sites (lumbar spine, neck of femur and forearm) in pregnant women receiving aspirin and heparin. During pregnancy, there was a significant decrease in bone density of 3.7% at lumbar spine (which consists predominantly of trabecular bone) and of 0.9% at the femoral neck (predominantly cortical bone) with no significant change at the forearm. These results are similar to those of prospective studies of BMD changes in untreated pregnancies (Drinkwater and Chestnut, 1991; Barbour et al., 1994; Khastgir et al., 1996; Shefras and Farguharson, 1996). Whether high oestrogen concentrations during pregnancy mitigate against the osteopenic effect of heparin, if such exists, remains unclear.
The precision of DEXA for BMD is 2% at the femoral neck; thus the drop of 0.9% in femoral neck BMD during pregnancy in our study may not be important. The presence of a near-term fetus at 34 weeks of pregnancy precludes BMD lumbar spine (L2–L4) measurements, therefore we were not able to determine potential BMD changes between stopping the heparin at 34 weeks and the immediate postpartum period.
Importantly, we found that 8% of women were osteopenic at the lumbar spine at 12 weeks gestation despite the significant increase in bone density that occurred in the first trimester. This indicates that a considerable proportion of women have low bone density prior to pregnancy.
Prospective data relative to the effect of pregnancy on bone density (Drinkwater and Chestnut, 1991; Khastgir et al., 1996; Shefras and Farguharson, 1996) indicate a fall of 3% in the lumbar spine bone density between pre-conceptual and immediate postpartum measurements. Pregnancy and lactation impose stress on maternal calcium homeostasis. Mineralization of the fetal skeleton is normally met by a series of hormone-mediated adjustments in maternal calcium metabolism during pregnancy including increased levels of 1,25-dihydroxyvitamin D, calcitonin and parathyroid hormone-related protein. Pregnancy-associated osteoporosis may stem from a failure of these physiological changes (Smith et al., 1985). Alternatively, pregnancy may be a stress that unmasks a defective maternal skeleton in women with pre-existing osteopenia (Khastgir and Studd, 1994).
Heparin has been reported to have a number of effects on bone metabolism. Avioli (1975) has suggested that heparin (i) as a chelating agent, binds calcium ions, resulting in secondary hyperparathyroidism with enhanced bone resorption, (ii) has a direct effect on bone cells with decreased osteoblastic or increased osteoclastic activity, and (iii) exerts its effect on the skeleton by disturbance of the bone matrix mucopolysaccharides leading to defective ossification. In-vitro animal data show that heparin induces an increase in osteoclastic bone resorption through binding and enhancement of an osteoclastic resorption-stimulating activity present in serum (Fuller et al., 1991). More recently, it has been reported that in the absence of parathyroid hormone or serum, heparin can stimulate bone resorption in fetal rat calvaria (Shaughnessy et al., 1995). Heparin has also been shown to inhibit new bone formation via inhibition of collagen and DNA synthesis in fetal rat calvaria in vitro (Hurley et al., 1990).
Previous longitudinal bone density studies suggest that lactation is associated with reversible bone loss (Sowers et al., 1993; Kalkwarf et al., 1995). However, it is not clear whether this loss of bone density is simply due to the relative oestrogen deficiency of lactation or a more complex mechanism. The findings from our study are consistent with previous reports showing that women who breast-feed have a significant decrease in BMD at both the lumbar spine and the neck of femur compared with women who do not breast-feed.
Low molecular weight heparin offers the important advantage of requiring less frequent administration compared with unfractionated heparin preparations. Our data indicate that the use of low-molecular-weight heparin (enoxaparin 20 mg daily) during pregnancy is associated with a decrease in bone density of the same low magnitude (3–4%) as unfractionated heparin (calciparine 5000 U twice daily), with no significant difference between the two heparin preparations in BMD changes at all three sites studied.
In conclusion, pregnant women requiring thromboprophylaxis can be reassured that the loss in lumbar spine BMD associated with low-dose long-term heparin therapy is similar to that which occurs physiologically during pregnancy.
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Acknowledgments |
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We thank the women who participated in this study and Tracy McGrath, Clinic Co-ordinator, for her dedication to the Clinic, its staff and its patients.
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Notes |
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5 To whom correspondence should be addressed at: Department of Obstetrics & Gynaecology ICSM at St Mary's, Mint Wing, South Wharf Road, London W2 1NY, UK
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References |
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Submitted on April 13, 1999; accepted on July 22, 1999.
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