Osteonecrosis of the Femoral Head Associated with Pregnancy. A Preliminary Report*

MONTELLA, BRUCE J. M.D.†; NUNLEY, JAMES A. M.D.‡; URBANIAK, JAMES R. M.D.‡, DURHAM, NORTH CAROLINA

Journal of Bone & Joint Surgery - American Volume:
Article
Abstract

Background: Osteonecrosis is usually associated with trauma, use of corticosteroids, or alcohol abuse. We investigated the rare association of osteonecrosis of the femoral head and pregnancy, and we defined differences between the disorder in pregnant women and that in women of childbearing age who were not pregnant. The results of treatment with a free vascularized fibular graft were evaluated in terms of relief of pain and improvement of the Harris hip score after a minimum of two years of follow-up. Methods: Thirteen women (seventeen hips) had the onset of pain in the hip during pregnancy or within the first four weeks after delivery, and the pain persisted until a diagnosis of osteonecrosis of the femoral head was made on the basis of magnetic resonance imaging. No patient had any other risk factor for this disease. Information was obtained by means of clinical assessment, a review of the records and radiographs, and a telephone survey. Eleven women (fifteen hips) were managed with a free vascularized fibular graft, and nine of them (eleven hips) were evaluated, with regard to relief of pain and the Harris hip score, at a minimum of two years postoperatively. Results: The average age when the pain began was 31.5 years (range, twenty-five to forty-one years). Eleven of the thirteen women were primigravid, and the patients typically first had the pain late in the second trimester or in the third trimester of pregnancy. The women tended to have a small body frame and a relatively large weight gain during the pregnancy. Eight of the thirteen patients had swelling and varicosity of the lower extremities. The diagnosis was delayed an average of 10.3 months, with a range of three to thirty months. A common misdiagnosis was transient osteoporosis of the hip during pregnancy. A correct diagnosis was established for all hips on the basis of the finding of a double-density signal on magnetic resonance imaging or evidence of progression of the disease on plain radiographs. According the system of Marcus et al., the stage at the time of diagnosis ranged from II to V. All women had involvement of the left hip, and four had bilateral involvement. Of the eleven women (fifteen hips) who were managed with a free vascularized fibular graft, nine noted marked or complete relief of the preoperative pain. Two hips in a patient who had progressive pain were treated with a total hip arthroplasty. Two hips (one patient) were lost to follow-up. The nine patients (eleven hips) who were available for follow-up at a minimum of two years had an average improvement in the Harris hip score of 24 points. Conclusions: Occasionally, pain in the hip that begins during pregnancy is caused by osteonecrosis of the femoral head. A high index of suspicion and use of magnetic resonance imaging may lead to an earlier diagnosis and a better prognosis in this population of women. In this study, treatment with a free vascularized fibular graft was a useful option with which to obviate or postpone the need for total hip arthroplasty.

Author Information

†901 West Biesterfield Road, Suite 300, Elk Grove Village, Illinois 60007.

‡Division of Orthopaedic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710.

Article Outline

Osteonecrosis of the femoral head is most frequently attributable to trauma, use of corticosteroids, or alcohol abuse. A variety of other mechanisms45 have been implicated in the pathogenesis of the disease; they include mechanical vascular interruption, thrombosis and embolism, injury to or pressure on vessel walls, and vascular occlusion. Pfeifer48 was the first, to our knowledge, to report the relatively rare association of osteonecrosis of the femoral head with pregnancy. The literature contains descriptions of at least thirty-seven patients who had this association8,9,15,20,25,28,33,35,39,44,46-48,67,70. However, many of these patients had other known causes of osteonecrosis8,20,28,48, and some authors failed to exclude other known risk factors15,25,35,46. For at least three of these patients, the diagnosis of osteonecrosis was itself in question as it was based on information provided before the advent of magnetic resonance imaging44,70. The rare association of osteonecrosis of the femoral head and pregnancy has made it difficult to establish a causal relationship between these two conditions.

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Materials and Methods

Thirteen women (seventeen hips) (Table I) were seen at our institution between 1992 and 1995 with a history of pain that began during pregnancy or within the first four weeks after delivery. These women were otherwise healthy and had no other risk factors for osteonecrosis. Each patient chose to have operative intervention because of persistent pain, and use of a free vascularized fibular graft was selected for eleven patients (fifteen hips) on the basis of the promising results that have been obtained with that procedure at our institution66. One patient was managed with a core decompression, and one patient was managed with a proximal femoral osteotomy. The patients came to us from a wide referral base involving predominantly the eastern region of North America. Information was obtained from a review of the charts and radiographs, clinical evaluation, and a telephone survey. The results of treatment with a free vascularized fibular graft were evaluated at a minimum of two years for nine patients (eleven hips). The results were assessed in terms of relief of pain and the Harris hip score22.

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Results

The average age at the onset of symptoms was 31.5 years (range, twenty-five to forty-one years). Eleven of the thirteen women were primigravid. The patients were first seen with intermittent or constant pain that originated in the hip and at times extended to the groin and the lateral aspect of the thigh. The pain occurred late in the second trimester or in the third trimester in eleven patients, and it persisted until the time of diagnosis of osteonecrosis of the femoral head in all patients. The diagnosis was made on the basis of a finding of a double-density signal on magnetic resonance imaging or the presence of radiolucent areas, sclerosis, a crescent sign, and collapse on plain radiographs (Figs. 1-A, 1-B, and 2-A). A diagnosis of transient osteoporosis was excluded on the basis of the radiographic findings and the clinical course, as none of the patients had spontaneous remission of the symptoms or resolution of the radiographic abnormalities within a time-period (six to eight months) that was consistent with such a diagnosis21.

All thirteen patients had involvement of the left hip, and four patients had bilateral involvement. The average height of the patients was 63.5 inches (1.61 meters), the average weight was 123.5 pounds (56.0 kilograms), and the average weight gain during the pregnancy was thirty-six pounds (16.3 kilograms). The delay in the diagnosis after the patient first reported the pain in the hip to a physician averaged 10.3 months and ranged from three to thirty months. Frequent misdiagnoses that accounted for the delays in diagnosis included transient osteoporosis of the hip in association with pregnancy, pelvic relaxation in association with pregnancy, and muscle strain. The stage according to the system of Marcus et al.37, determined on the basis of plain radiographs, ranged from II to V at the time of diagnosis. In three of the four patients who had bilateral involvement, the stage was more advanced on the left (Table I).

The birth presentation was vertex for all of the deliveries. Four patients had a cesarean section, and two had a vaginal delivery assisted with instruments. The duration of the gestation averaged thirty-nine and one-half weeks (range, thirty-six to forty-two weeks). One pregnancy was complicated by mild toxemia; one, by abdominal pain and the discovery of a hepatic hemangioma; and one, by gestational diabetes. Eight of the thirteen patients had swelling and varicosity of the lower extremities, and two of them had greater swelling of the left lower extremity. At the instruction of their obstetricians, seven of the thirteen women slept exclusively on the left side for the third trimester of the pregnancy. Except for one patient who was taking antidepressant medication for a period of time, no patient was taking daily medication except for multivitamins. Three of six women who had evaluation of the baseline (prepregnancy) coagulation status were found to have a baseline hypercoagulable state on serological tests, which included measurement of resistance to activated protein C, the presence of anticardiolipin antibody, positive lupus anticoagulant, or the presence of protein-S deficiency. At the time of writing, no patient had had another pregnancy. No patient who had unilateral involvement had osteonecrosis in the contralateral hip at the time of follow-up, at a minimum of twenty-four months and an average of thirty-five months. Eleven patients requested a free vascularized fibular graft procedure. One patient was managed with a core decompression, and one patient was managed with a proximal femoral osteotomy.

Of the eleven women (fifteen hips) who were managed with a free vascularized fibular graft66, nine noted substantial or complete relief of the pain. One patient (two hips) needed conversion to a bilateral total hip arthroplasty, and one (two hips) was lost to follow-up. The remaining nine patients (eleven hips) were available for follow-up at two years, at which time they had an average improvement in the Harris hip score22 of 24 points compared with the preoperative assessment.

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Discussion

Osteonecrosis of the femoral head can occur in association with pregnancy in the absence of other known risk factors for the disease. However, it is difficult to demonstrate a causal relationship between pregnancy and osteonecrosis because the association is rare. It is difficult, if not impossible, to design a well controlled cohort study that will yield significant results to define and characterize this association. In addition, analysis of population prevalence rates is not plausible in light of the wide referral base. However, on the basis of a retrospective examination of more than 800 cases from the Osteonecrosis Data Bank (unpublished data), it appears that women in whom osteonecrosis develops during pregnancy share demographic features that distinguish them from nonpregnant women of childbearing age who have idiopathic osteonecrosis of the femoral head. Nonpregnant women who have idiopathic osteonecrosis of the femoral head are generally older than pregnant women who have osteonecrosis of the femoral head (average age, thirty-five years compared with 31.5 years in our study, a significant difference [p < 0.05]), and they are generally heavier (average weight, 72.9 kilograms compared with 56.0 kilograms in our study, a significant difference [p < 0.05]). Nonpregnant women have an equal prevalence of involvement of the right hip (60 percent) and the left hip (65 percent), whereas all thirteen of the pregnant women in our study had involvement of the left hip and four had involvement of the right hip (a significant difference [p < 0.05]). In addition, almost 50 percent of the nonpregnant women had bilateral involvement, whereas only four of the pregnant patients in our study had such involvement (a significant difference [p < 0.05]). It is notable that the women of childbearing age who were included in the Osteonecrosis Data Bank, which represents an approximate cross section of North American society, had a higher rate of full-term pregnancy (10 percent) than did an age-related sample of the normal population of women in the United States (6.9 percent)68.

There were similarities in the pregnancies that led to osteonecrosis of the femoral head. The women in our series tended to be older than average at the time of their first productive pregnancy. Their average age was 31.5 years, whereas in the United States the average age at the time of a first productive pregnancy is twenty-six years16 and more than 85 percent of women have their first productive pregnancy before the age of thirty years64,65. The women in our series also tended to be small in stature, with an average height of 63.5 inches (1.61 meters) and an average weight of 123.5 pounds (56.0 kilograms). According to the United States National Center for Health Statistics, only 30.7 percent of women of childbearing age are shorter than the average height in our series and only 31.4 percent are lighter than the average weight in our series68. The weight gain during the pregnancies in our series (16.3 kilograms) was also greater than the average (11.0 kilograms)29.

There has been much speculation regarding the mechanism of vascular interruption in patients in whom osteonecrosis develops during pregnancy. A number of factors probably contribute to the development of the osteonecrosis. Among the theories regarding these mechanisms, those proposing venous congestion and hypercoagulability as factors are compelling. Pregnancy is well known to produce a hypercoagulable state, with an overall monthly prevalence of 0.01 thrombotic event per 1000 women36. This prevalence tends to be higher in the third trimester36, a finding that corresponds to the timing of the onset of hip pain in women in whom osteonecrosis develops during pregnancy. In addition, in our series, three of six women who had serological tests, including measurement of resistance to activated protein C, the presence of anticardiolipin antibody, positive lupus anticoagulant, or the presence of protein-S deficiency, were found to have a predisposing baseline (prepregnancy) hypercoagulable state. Baseline hypercoagulability may be a common contributing factor in the pathogenesis of osteonecrosis of numerous atraumatic etiologies32. Hypercoagulability may contribute to the development of macrothromboembolic as well as microthromboembolic phenomena that lead to vascular occlusion or venous congestion, or both, with subsequent ischemic necrosis of bone.

The high prevalence of involvement of the left femoral head in the patients in the present series is also notable. Pregnant women are known to have a high prevalence of venous thrombosis on the left side. In one report, fifty-eight of sixty patients had involvement of the left lower extremity18. This phenomenon is often explained by the anatomy of venous drainage of the left lower extremity within the pelvis (Fig. 3). The left common iliac vein passes deep to the right common iliac artery and may be subject to excessive compression11 from the weight of the developing fetus. This anatomical consideration, as well as the fact that seven of the thirteen patients in our series slept primarily on their left side during the final trimester of pregnancy, could possibly have contributed to the high prevalence of involvement of the left hip in this study. Ficat and Arlet reported on six patients with biopsy-proved osteonecrosis of the femoral head in whom venous congestion was demonstrated on a venogram15.

There has been speculation regarding hormonal influences on the development of osteonecrosis of the femoral head during pregnancy. A number of molecules have been implicated. Unbound cortisol levels increase during pregnancy to three times those in nonpregnant women19,50. Production of estrogen and progesterone by the placenta alters fat metabolism in the liver and destabilizes endogenous plasma lipoproteins, which may result in the development of fat embolism44. During pregnancy, the level of serum progesterone greatly increases and approaches that of serum cortisol. Progesterone as well as synthetic progestins are known to exert a glucocorticoid-like effect in humans19,23,30,54. Pregnancy-related hyperplasia of the parathyroid gland and resulting hyperparathyroidism13 may also contribute to the development of osteonecrosis of the femoral head. The etiology and pathogenesis of this disease in pregnant women is probably multifactorial.

The diagnosis of osteonecrosis in the evaluation of hip pain during pregnancy and in the postpartum period is often delayed. The distinction between osteonecrosis and transient osteoporosis associated with pregnancy is particularly important because the disorders have distinctly different natural histories. Transient osteoporosis is a self-limiting disorder that resolves over the course of six to eight months. Fractures and serious long-term sequelae are rare4,12,53. Appropriate treatment usually includes limited weight-bearing and medication for symptoms. In contrast, osteonecrosis of the femoral head may be progressive, and the outcome may include the collapse of the articular surface and the development of degenerative joint disease. This poor prognosis justifies consideration of more invasive treatment options for this disease.

There are differences with regard to the etiology and the clinical and radiographic characteristics of the two disorders. The etiology of transient osteoporosis associated with pregnancy is unknown, but the condition is thought to be a variant of reflex sympathetic dystrophy or perhaps even osteonecrosis. Transient osteoporosis tends to become symptomatic acutely and with activity. Radiographs reveal generalized osteopenia of the femoral head, and bone scans reveal diffuse uptake. The etiology of osteonecrosis is myriad, with a perceived common final pathway resulting in the interruption of circulation to the femoral head. Symptoms tend to include non-activity-related aching, with the development of a limp only late in the course of the disease. Radiographs reveal sclerosis, mottled radiolucency, subchondral radiolucency (the crescent sign), and collapse. Bone scans reveal focal areas of increased uptake within the femoral head21. The advent of magnetic resonance imaging has aided in the early diagnosis of osteonecrosis. Osteonecrosis results in focal lesions typically in the anterolateral aspect of the femoral head. These lesions demonstrate decreased signal intensity on both T1 and T2-weighted images, with a frequent finding of a double-density signal surrounding the lesion. Findings on magnetic resonance imaging that are consistent with transient osteoporosis include a diffuse bone-marrow-edema-pattern signal with an increased signal intensity on T2-weighted images and a decreased intensity on T1-weighted images40,41.

Transient osteoporosis associated with pregnancy can be differentiated from osteonecrosis on the basis of the presentation, radiographic characteristics, and natural history. In our series, the two entities were distinguished by characteristic findings on magnetic resonance imaging, including a double-density signal40,41, or findings on plain radiographs that included a crescent sign, progression, and collapse, which are thought to be pathognomonic for the diagnosis of osteonecrosis. All thirteen of our patients had progressive, severe, and debilitating symptoms for longer than twelve months. This clinical course is highly consistent with the radiographic findings and diagnosis of osteonecrosis as distinguished from transient osteoporosis.

The natural history of osteonecrosis in association with pregnancy does not appear to differ from that of osteonecrosis with other atraumatic or idiopathic etiologies. However, we know of no rigorous cohort studies that have evaluated this possibility fully.

The optimum treatment of osteonecrosis associated with pregnancy is controversial. Accepted treatment options include restricted weight-bearing, osteotomy51,60-63, use of a nonvascularized structural graft2,3,7,49, electrical stimulation1,56-58, core decompression14,31,34,38,42,43,55,59, and use of a vascularized structural graft5,6,10,17,24,26,27,66,69. Overall, adequate assessment of the outcomes of treatment has been limited because of the small numbers of patients managed at many different centers. However, vascularized structural grafting has been demonstrated to be of benefit for the prevention of articular collapse and for obviating or delaying the need for total hip arthroplasty66. Core decompression is frequently suggested as a less technically demanding procedure with less operative morbidity, and it may be preferable to no treatment at all. However, survival analysis comparing hips treated with core decompression with hips treated with a vascularized fibular graft has indicated that the increased morbidity associated with vascular structural grafts is justified by the associated delay in or prevention of articular collapse in hips with Ficat stage-II or III disease52. In the present study, the clinical outcomes following the use of a free vascularized fibular graft in pregnant women who had osteonecrosis (Figs. 1-C, 1-D, and 2-B) were similar to the outcomes of this procedure for the treatment of other types of atraumatic osteonecrosis of the femoral head66.

In conclusion, the onset of pain in the hip during pregnancy is occasionally caused by osteonecrosis of the femoral head. Although a causal relationship has not been demonstrated, there are distinct demographic characteristics that differentiate women who have osteonecrosis of the femoral head in association with pregnancy from nonpregnant women of childbearing age who have idiopathic osteonecrosis of the femoral head. Pregnancy-associated osteonecrosis of the femoral head typically occurs in older primigravid women with a small body frame who gain a relatively large amount of weight during the pregnancy. There is a very high rate of involvement of the left hip. The pathophysiology of the relationship between pregnancy and this disorder is probably multifactorial and may involve mechanical, hormonal, and coagulation factors. The natural history of the disease is frequently progressive. At times, the presentation is confused with that of transient osteoporosis of the hip. Diagnosis is frequently delayed, and a high clinical suspicion as well as the use of magnetic resonance imaging after delivery may lead to an earlier diagnosis and a better prognosis. Use of a free vascularized fibular graft is a viable treatment option and has been shown to provide a better outcome, in terms of avoiding or delaying the need for a total hip arthroplasty, than core decompression. The association between osteonecrosis of the femoral head and pregnancy may be seen with increasing frequency as more women delay childbearing in favor of pursuing education and careers.

*No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.

Investigation performed at the Division of Orthopaedic Surgery, Department of Surgery, Duke University Medical Center, Durham

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