Risk Factors for Young Premenopausal Women With

Endometrial Cancer
Pamela T. Soliman, MD, Jonathan C. Oh, MD, Kathleen M. Schmeler, MD,
Charlotte C. Sun, DrPh, Brian M. Slomovitz, MD, David M. Gershenson, MD,
Thomas W. Burke, MD, and Karen H. Lu, MD
OBJECTIVE: Endometrial cancer is the most common gynecologic malignancy in the United States. The mean age at
diagnosis is 61 years; however, 530% of women are aged
younger than 50 years at the time of diagnosis. The objective of this study was to conduct a clinical and pathologic
review of endometrial cancers diagnosed in premenopausal women aged younger than 50 years, to better identify the risk factors for this subgroup of women.
METHODS: We conducted a retrospective cohort study of
patients with histologically confirmed endometrial cancer
treated at the University of Texas, M. D. Anderson Cancer
Center from 1989 to 2003. Clinical characteristics including
age, body mass index (BMI), parity, diabetes, and personal
or family history of cancer were obtained from the medical
record. Pathologic information was obtained from pathology reports.
RESULTS: Twelve percent (188/1531) of all patients with
endometrial adenocarcinoma were aged younger than 50
years. The mean age at diagnosis was 41 years (range 21 49
years). Mean BMI was 34 kg/m2 (range 18 68); 58% of
patients had a BMI of 30 or greater. Fifty-five percent were
nulliparous and 39% reported irregular menstrual cycles.
The incidence of both diabetes and hypertension was 23%.
Thirty-six patients (19%) had synchronous ovarian cancers.
CONCLUSION: We found that the majority of patients diagnosed with endometrial cancer at a young age were obese
and nulliparous. In addition, we found a high incidence of
synchronous primary ovarian cancers in this cohort of
young, premenopausal women. (Obstet Gynecol 2005;
105:575 80. 2005 by The American College of Obstetricians and Gynecologists.)
LEVEL OF EVIDENCE: III

In the United States endometrial cancer is the most

common malignancy of the female genital tract, with
40,320 new cases and 7,090 cancer-related deaths estimated for 2004.1 Although endometrial cancer tends to
be diagnosed in older, postmenopausal women with a
From the Department of Gynecologic Oncology, The University of Texas M. D.
Anderson Cancer Center, Houston, Texas.

VOL. 105, NO. 3, MARCH 2005

2005 by The American College of Obstetricians and Gynecologists.
Published by Lippincott Williams & Wilkins.

mean age of 61 years, between 5% and 30% of endometrial cancers are diagnosed in young women.2 6 Several studies have compared young and older endometrial cancer patients to estimate whether there was any
differences in outcome. Although some reports have
shown that younger women diagnosed with endometrial
cancer have a more favorable prognosis,6 8 other studies
have reported no differences between these groups.4,9
To date, the published studies examining this population
of young women have been limited by small numbers. In
addition, few studies have focused on the risk factors
associated with endometrial cancer in women diagnosed
at a young age.
The development of endometrial cancer is predominantly related to excess estrogen exposure. Risk factors
include obesity, nulliparity, late menopause, diabetes
mellitus, unopposed estrogen therapy, tamoxifen therapy, and use of sequential oral contraception. Excess
estrogen from any of these sources produces continued
stimulation of the endometrial lining, which can result in
endometrial hyperplasia and, potentially, endometrial
cancer. Obesity has the highest associated risk ratio. The
risk is increased 3-fold in women 9 23 kg more than
ideal body weight, and 10-fold in women more than 23
kg heavier than ideal body weight. Diabetes has been
found to have a relative risk (RR) of 2.7, and nulliparity
has been associated with a RR of 2.0.10 The purpose of
this study was to review the clinical and pathologic
characteristics in a large cohort of women diagnosed
with endometrial cancer aged younger than 50 years.
We hypothesize that risk factors such as obesity, nulliparity, irregular menses, and possibly polycystic ovary
syndrome (PCOS) are also relevant in the development
of endometrial cancer in this group of women.

MATERIALS AND METHODS

After obtaining approval from the Institutional Review
Board, our study population was identified through a

0029-7844/05/$30.00
doi:10.1097/01.AOG.0000154151.14516.f7

575

Table 1. Demographic Characteristics of Young Endometrial Cancer Patients

Characteristic

All Patients
(n 188)

Age 40 y
(n 79)

Age 4145 y
(n 49)

Age 4649 y
(n 60)

Mean age (y)

Mean BMI
25 kg/m2
2529.9 kg/m2
30 kg/m2
Nulliparity
Diabetes*
Hypertension*
HNPCC

41 (2149)
34.2(1868)
47 (25)
31 (17)
106 (58)
102 (54)
44 (23)
43 (23)
6 (3.2)

35
35.1 (1857)
19 (25)
10 (13)
48 (62)
55 (71)
21 (27)
14 (18)
2 (2.5)

43
33.7 (2056)
11 (23)
12 (25)
25 (52)
23 (49)
10 (20)
12 (25)
2 (4.1)

47
33.4 (1968)
17 (29)
9 (15)
33 (56)
24 (41)
13 (22)
17 (28)
2 (3.3)

BMI, body mass index; HNPCC, hereditary nonpolyposis colorectal cancer.

Values are n (range) or n (%).
* Reported by patient as part of medical history.

Met revised Amsterdam criteria for HNPCC.

search of the Tumor Registry database maintained by

the Department of Medical Informatics. Between 1989
and 2003, 1,531 patients with histologically confirmed
adenocarcinoma of the endometrium were evaluated
and treated at the University of Texas M. D. Anderson
Cancer Center. Of the 1,531 patients, 188 women
(12.3%) were both premenopausal and aged younger
than 50 years at the time of diagnosis.
Clinical data, including age at diagnosis, presenting
symptoms, race, body mass index (BMI), gravidity, parity, menstrual history, oral contraceptive pill use, history
of diabetes, hypertension, and personal and family history of cancer were obtained from medical records.
Pathologic information such as histology, grade, depth
of myometrial invasion, lymph-vascular space invasion,
and lymph node involvement was collected from surgical pathology reports generated by our gynecologic pathology department at the time of diagnosis or referral.
Endometrial cancer stage was assigned based on the
surgical staging criteria set forth by the International
Federation for Gynecology and Obstetrics.11 Survival
and time to recurrence were also evaluated.
One hundred eighty-seven patients underwent surgical evaluation with hysterectomy and bilateral salpingooophorectomy. One patient did not undergo hysterectomy to preserve fertility and is being followed. The
primary surgical management was performed at the
M. D. Anderson Cancer Center in 112 of the patients.
The remaining 75 patients were referred after initial
surgical management at an outside institution. The
pathologic specimens for all 187 cases were reviewed by
gynecologic pathologists at our institution. Patients with
malignant mixed mesodermal tumors of the uterus were
excluded from the study.
Data were analyzed using SPSS 11.5 software (SPSS
Inc., Chicago, IL). The 2 test was used to assess the
significance of differences in categorical clinical and

576

Soliman et al

Young Women With Endometrial Cancer

pathologic variables. Continuous variables were analyzed using t tests and analysis of variance. Kaplan-Meier
survival analyses were generated and compared using
the log-rank test. A P value of less than .05 was used to
determine statistical significance.
RESULTS
The clinical characteristics of all 188 patients are shown
in Table 1. The mean age at the time of diagnosis was 41
years (median 42, range 21 to 49 years). All of the
patients were premenopausal. The mean BMI was 34.2
kg/m2 (median 33, range 18 to 68). Forty-seven patients
(25%) were in the normal weight range (BMI 25), 31
patients (17%) were overweight (25 BMI 30), and
106 patients (58%) met criteria for obesity (BMI 30).12
One hundred two women (54%) were nulliparous.
Twenty-five patients reported a history of infertility.
Seventy-three women (39%) had a history of irregular
menstrual cycles. Fourteen patients reported a history of
PCOS. Six patients had pathologic findings consistent
with the diagnosis; more than 12 follicles in each ovary
measuring 29 mm in diameter or increased ovarian
volume ( 10 mL).13 Twenty-three percent (44/144) of
patients had diabetes, and 23% (43/144) had hypertension. Sixty-four patients (34%) reported taking oral contraceptive pills for at least 1 year. When patients were
divided into groups based on age at the time of diagnosis,
there were no significant differences among the subgroups (Table 1).
Forty-eight patients (26%) had a second primary cancer (Table 2). Thirty-six patients (19%) were noted to
have synchronous ovarian cancer at the time of their
endometrial cancer diagnosis. The diagnosis of synchronous ovarian and endometrial cancers was made based
on the criteria outlined by Scully et al14 in the Atlas of
Tumor Pathology.

OBSTETRICS & GYNECOLOGY

Table 2. History of Synchronous or Metachronous Cancer

Site (n 48)

Metachronous

Ovary
Breast
Colon
Cervix
Fallopian tube
Renal
Neuroblastoma
Urachal

1
4
3*
...
...
...
1
1

36*
...
...
1
1
1
...
...

Values are number of cancers.

* One patient had both a metachronous colon cancer and a synchronous ovarian cancer.

One of these patients also had a prior history of colon

cancer. One patient was diagnosed with ovarian cancer 8
years before her endometrial cancer diagnosis. Two
patients had a history of colon cancer. Three patients
had a history of breast cancer and 1 patient had a history
of ductal carcinoma in situ. None of these patients were
treated with tamoxifen. The other second primary cancers were cervical cancer, fallopian tube cancer, renal cell
carcinoma, urachal adenocarcinoma, and neuroblastoma.
Family history data were available for 177 patients.
Three percent (6/177) reported a family history that met
the revised Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC).15 An additional 23
patients (13%) reported having at least one first-degree
relative with an HNPCC-related cancer (colon, endometrial, ovarian, gastric, or small bowel).
One hundred sixty-eight patients (89%) had pure endometrioid histology (Table 3). Six patients (3.5%) had
at least a component of papillary serous carcinoma and 7
patients (3.5%) had a component of clear cell carcinoma.
The remaining 7 patients had either mixed or undifferentiated histology. Forty-five percent of patients had
grade 1 tumors, 40% had grade 2 tumors, and 15% had
grade 3 or undifferentiated tumors. Twenty-eight percent of patients had disease confined to the endometrium, 48% had superficial myometrial invasion, and
22% had deep myometrial invasion. Lymph-vascular
space invasion was present in 31% of tumors. The stage
distribution is shown in Table 4. Sixty-one percent of
patients were stage I, 12% were stage II, 18% were stage
III, and 8% were stage IV.
In the subgroup of patients with synchronous primary
cancers of the ovary (n 36), 21 patients (58%) had
endometrioid histology of both the endometrium and
the ovary. Of the remaining 15 patients, 13 had endometrioid histology of the endometrium and nonendometrioid histology of the ovary. Two patients had mixed
endometrioid/clear cell tumors of the endometrium, with
endometrioid/clear cell and endometrioid/clear cell/se-

VOL. 105, NO. 3, MARCH 2005

Table 3. Characteristics of Endometrial Cancer

Synchronous

n (%)
(N 188)

Characteristic
Histology
Endometrioid
Clear cell
Papillary serous
Mixed with serous component
Mixed without serous component
Undifferentiated
Other
Grade
1
2
3/undifferentiated
Myometrial invasion
None
50%
50%
Missing
Vascular space invasion
Yes
No
Unknown
Lymph node status
Negative
Positive
Not done

168 (89)
1 (0.5)
1 (0.5)
5 (3)
6 (3)
4 (2)
3 (2)
84 (45)
76 (40)
28 (15)
53 (28)
90 (48)
41 (22)
4 (2)
58 (31)
87 (46)
43(23)
70 (37)
25 (13)
93 (50)

rous tumors of the ovary. At the time of surgery, gross

ovarian disease was found in 28/36 (78%) of patients and
microscopic disease was identified in 4/36 (11%) of patients. Information was not available on 4 patients.
For all patients, median follow-up was 32 months
(range 1166 months). Ninety-five patients received adjuvant therapy. Forty-eight patients were treated with
radiation, 31 patients were treated with chemotherapy,
and 16 patients received a combination of radiation and
chemotherapy. Twenty-eight patients (15%) developed
recurrent disease. The median time to recurrence was 24
months (range 4 to 99 months). Advanced stage disease
was a poor prognostic factor (median survival was not
reached for stage I compared with 24 months for stage
Table 4. Uterine Cancer Stage
Stage

n (N 188)

IA
IB
IC
IIA
IIB
IIIA
IIIB
IIIC
IVA
IVB
Unknown

46
56
11
12
12
14
2
19
1
13
2

25
30
6
6
6
7
1
10
1
7
1

Soliman et al

Young Women With Endometrial Cancer

577

Table 5. Risk Factors: Literature Review

Study/Age Criterion (y)

Age (y)

Obesity

Population

Nulliparity

Irregular
Menses

Diabetes

Hypertension

Jeffrey et al5 (1983) 45 (n 22)

Gallup et al3 (1984) 40 (n 16)
Gitsch et al8 (1995) 45 (n 16)
Leo et al16 (1996) 45 (n 17)
Evans-Metcalf et al4 (1998) 45 (n 40)
Yamazawa et al7 (2000) 45 (n 20)
Tran et al9 (2000) 45 (n 41)
Parslov et al17 (2000) 50 (n 237)
Present Study
50 (n 188)
45 (n 128)
40 (n 79)

Mean 39 (2644)
NA (2940)
Mean 40 (3145)
Median 39 (3145)
Mean 39
Mean 39 (2745)
Median 40 (1645)
Mean 44 (2749)

NA
NA
37*
29*
NA
35
NA
18*

Canadian
American
Australian
Italian
American
Japanese
American
Danish

41
44
50
59
48
50
51
19

NA
NA
NA
29
NA
NA
NA
17

5
6
0
0
20
20
7
2

9
31
NA
6
NA
5
10
7

Mean 41 (2149)
Mean 38 (2145)
Mean 35 (2140)

56*
58*
62*

American
American
American

55
62
71

39
45
54

23
24
27

23
20
18

NA, not available.

Values are n (range) or %.
* Body mass index 30 kg/m2.

Body mass index 26.4 kg/m2 (Japanese criterion).

IV, P .001). At the time of analysis, 33 patients were

deceased. Median overall survival in this subgroup was
25 months (range 2 to 124 months). Causes of death
included uterine cancer (n 13), synchronous uterine
and ovarian cancer (n 11), colon cancer (n 1),
cervical cancer (n 1), and fallopian tube cancer (n 1).
The cause of death was unknown in 6 patients.
DISCUSSION
Endometrial cancer is traditionally considered a disease
of the sixth and seventh decades of life; however, there
are a considerable number of patients who are diagnosed
before the age of 50 years. Previous studies have reported a wide range in the incidence of endometrial
cancers diagnosed in young patients. This variation may
be related to the definition of young in this study
population. Gallup et al3 described a cohort of patients
who were less than 40 years of age at the time of
diagnosis. Several other authors have included patients
younger than the age of 45 at the time of diagnosis.4,5,7
9,16 In our study, we chose to evaluate patients diagnosed
with endometrial cancer aged younger than 50 years
because it is the criterion generally used for hereditary
cancer syndromes. In addition, the mean age of menopause in the United States is 51 years, and our intent was
to capture patients who were premenopausal at the time
of diagnosis. We performed a subset analysis comparing
patients aged 40 and younger, 41 to 45, and 46 to 49
years and found no significant differences in nulliparity,
obesity, diabetes, hypertension and family history
among the 3 subgroups.
In our cohort of 188 patients, we found that 56% met
criteria for obesity (BMI 30 kg/m2). The incidence of
obesity was slightly higher in the subset of patients aged

578

Soliman et al

Young Women With Endometrial Cancer

40 years or younger at the time of diagnosis (n 79,

62%). These findings were consistently higher than the
incidence of obesity reported in previous studies (Table
5). The referral pattern at our institution may contribute
to the higher percentage of obese patients in this cohort.
In addition, several of the other studies were performed
in countries with lower rates of obesity, such as Japan,
Denmark, Italy, and Australia.7,8,16,17 The 2 larger studies conducted in the United States focused primarily on
outcome, and information on obesity was not available
for comparison.4,9
We found that 55% of patients were nulliparous, with
an incidence of 71% in women aged 40 years or younger.
Previous studies have reported similar findings, with the
exception of a study by Parslov et al17 who reported
nulliparity in only 19% of young endometrial cancer
patients in Denmark. Thirty-nine percent of our patients
reported a history of irregular menstrual cycles defined
as irregular periods for at least 1 year before the time of
diagnosis. This information was only available in a limited number of the previous studies. Twenty-three percent of our cohort reported a history of diabetes. This is
significantly higher than previous studies, and is likely
related to our higher percentage of obese patients.
It is clear from our study that a high proportion of
young women who develop endometrial cancer are
obese, nulliparous, and report irregular menstrual cycles. Historically, these characteristics, coupled with hirsutism and infertility, have been associated with polycystic ovarian syndrome.13 The association between
endometrial cancer and PCOS has been suggested for
many years;18 however, the diagnostic criteria used to
define PCOS have varied, making it difficult to assess the
relationship between PCOS and endometrial cancer

OBSTETRICS & GYNECOLOGY

risk.19 Despite the recent revision in the diagnostic criteria for PCOS, it is difficult to evaluate this disease retrospectively. Although some of our findings may suggest
that PCOS may be a risk factor for these women, prospective evaluation of young patients with endometrial
cancer would be necessary to define the relationship
between PCOS and endometrial cancer risk.
A high number of patients in our study (19%) were
found to have synchronous ovarian cancer at the time of
surgery. Previous studies have reported an incidence of
synchronous primary ovarian cancers in young endometrial cancer patients ranging from 7% to 29%.4,8,9 In our
previous review of patients with synchronous primary
cancers of the endometrium and ovary, we found that
50% of these women were aged younger than 50 years at
the time of diagnosis.20 In our current study, 78% of
patients with synchronous ovarian cancer were noted to
have gross ovarian disease at the time of surgery. This
finding highlights the need for careful evaluation of the
adnexa at the time of surgery for young women with a
preoperative diagnosis of endometrial cancer. In addition, 4 patients had microscopic ovarian cancer noted at
the time of pathologic review. It is unclear whether
bilateral oophorectomy should be offered to all young
patients with endometrial cancer.
In young patients diagnosed with cancer, and in particular those diagnosed with multiple primary cancers,
familial cancer syndromes should be considered.
Women with HNPCC have up to a 60% lifetime risk of
developing endometrial cancer.21 In our cohort of patients, only 6 patients (3%) reported a family history that
met the revised Amsterdam Criteria for the diagnosis of
HNPCC. Two of these patients had synchronous ovarian cancers, and 1 had metachronous colon cancer.
Similar to previous reports, our findings indicate that it is
unlikely that HNPCC accounts for a significant number
of young, endometrial cancer patients.22 Although family history data has several limitations, at the present
time this is the primary source of information used to
determine whether patients are at risk for HNPCC. We
are currently conducting a prospective clinical trial evaluating the prevalence of HNPCC mutations in women
diagnosed with endometrial cancer aged younger than
50 years, regardless of family history. This will help
determine whether diagnosis at a young age alone warrants genetic testing.
In summary, our study represents a large cohort of
endometrial cancer patients aged younger than 50 years
treated at a single institution. We found that 12% of
patients evaluated with endometrial cancer between
1989 and 2003 at our institution were younger than age
50 years at the time of diagnosis. In this cohort, there was
a high incidence of obesity, nulliparity, and irregular

VOL. 105, NO. 3, MARCH 2005

menstrual cycles. In addition, there were a high number

of synchronous primary ovarian cancers. These findings
suggest that hormonal factors may play a role in the
development of endometrial cancer. Further studies are
needed to better understand the causes and risk factors
of endometrial cancer in young women.
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Reprints are not available. Address correspondence to: Karen
H. Lu, MD, The Department of Gynecological Oncology, The
University of Texas M.D. Anderson Cancer Center, 1515
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Received October 14, 2004. Received in revised form November 29,
2004. Accepted December 8, 2004.

OBSTETRICS & GYNECOLOGY