Cycle of conception endometrial biopsy

Vol. 46, No.2, August 1986 Printed in U.8A.

FERTILITY AND STERILITY Copyrig~!. 0 1986 The American Fertility Society

Cycle of conception endometrial biopsy

Anne Colston Wentz, M.D.*t Carl M. Herbert III, M.D.* Wayne S. Maxson, M.D.* George A. Hill, M.D. * Donald E. Pittaway, M.D., Ph.D.t Vanderbilt University Medical Center, Nashville, Tennessee and Bowman Gray School.of Medicine, Winston-Salem, North Carolina

Although controversial, the diagnosis of luteal phase inadequacy and its therapy may improve reproductive outcome, but an endometrial biopsy in the cycle of conception (COC) might theoretically interrupt'an intrauterine pregnancy. Fifty-four biopsies obtained in the COC were identified, and patient outcome was 'documented. Eleven (20%) of the 54 women who underwent COC biopsy did not deliver viable infants. Two patients had ectopic pregnancies, and nine had early abortions, including one whose biopsy specimen contained an early implantation site and another with a trisomy 16 fetus. Although COC endometrial biopsy did not appear to increase the incidence of fetal wastage, biopsy information provided no predictive information suggestive of ultimate pregnancy outcome. Because no useful information is gained from a COC biopsy, we recommend either that pregnancy be avoided or a sensitive pregnancy test be employed for detection in a cycle in which a biopsy is to be performed. Fertil Steril46:196, 1986

The endometrial biopsy has become a routine and frequently used diagnostic procedure in the evaluation of luteal phase adequacy in patients manifesting recurrent fetal wastage or infertility. Although Driessenet al. l have reported that endometrial biopsy findings have not affected the diagnosis or outcome of infertility, others2 -4 have

Received December 23, 1985; revised and accepted March 27,1986. *Center for Fertility and Reproductive Research (C-FARR), Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Vanderbilt U ni versi ty Medical Center. tReprint requests: Anne Colston Wentz, M.D., Director, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Vanderbilt University, Nashville, Tennessee 37232. :j:Department of Obstetrics and Gynecology, Bowman Gray School of Medicine.

196

Wentzet aI. Cycle of conception endometrial biopsy

shown that the diagnosis of luteal phase inadequacy and its therapy have improved reproductive outcome. However, an endometrial biopsy might theoretically interrupt an early intrauterine pregnancy in a patient presenting with infertility. We have identified 54 cycle of conception (COC) endometrial biopsies obtained in our infertility patients and demonstrated a 20% incidence of fetal wastage among them. The details of these patients and their biopsies are the subject of this report. MATERIALS AND METHODS

All endometrial biopsies performed by the senior author from September 1977 to September 1985 and those performed by the accompanying authors from July 1981 to September 1985, constitute the subject material. The overall number Fertility and Sterility

Table 1. Pregnancy Outcome of Endometrial Biopsy during the Cycle of Conception No.

%

Viable pregnancy Spontaneous abortion Ectopic pregnancy

43 9 2

79.6 16.7 3.7

Total

54

100

of biopsies undertaken by this group during the period of review was approximately 1500. All biopsies were obtained anteriorly, fixed, stained, and interpreted histologically as previously reported,3, 4 and all COC biopsies were reviewed blindly (unidentified) by the senior author. All biopsies retrospectively found to have been taken in a COC were logged separately, and the outcomes in these patients were documented. Only one patient was lost to follow-up; her obstetric records documented a normal pregnancy up to 31 weeks' gestation when she relocated without a forwarding address. The date of the last menstrual period, the date of the endometrial biopsy, and the biopsy interpretation were established in all patients. The presence or absence of ovulation induction agents, supplementary progesterone, and other medications was recorded. In most patients, the date of presumptive ovulation was available, defined for the purpose of this report as the day of the nadir before the continuous rise on the basal body temperature chart. This day was arbitrarily called day 14 and used as a reference point for establishing the day of biopsy; the "expected" day

was determined in this manner, to define the "expected" endometrial pattern to be compared with the "observed" endometrial pattern read from the biopsy material. This is the only means of determining the "expected" endometrial dating,5, 6 because these patients did not have either an ensuing menstrual period or endocrine studies during the cycle of conception. As a control, 100 consecutive endometrial biopsies not taken in a cac were reviewed and the distribution of dating determined to indicate the usual cycle day of biopsy in infertility patients under evaluation by this group. Dates were statistically evaluated with the use of the two tailed t-test.

RESULTS Eleven of the 54 women who underwent COC biopsy did not deliver viable infants (Table 1). Two of these women had ectopic pregnancies, and nine had early abortions. Four of the nine wqmen were taking clomiphene citrate (CC) for ovulation induction, and three of the other five had a history of recurrent early fetal wastage (Table 2). One of these women aborted a fetus with trisomy 167 and another had the implantation site rerisk moved. Only two women who aborted had factor for abortion by history (recurrent miscarriage, CC administration, or luteal phase inadequacy). The observed biopsy dating was compared with the calculated "expected" dating. A statistically

no

Table 2. Nonviable Pregnancies Patient

Age

G/P/Ab

Diagnosis

2/0/2 3/0/3 11011 2/111 0 2/2/0 11110 0 2/0/2 0 0

Ec, PPS LPD LPD

CC?

CC cycles

Biopsy-secretory day Expected Observed

yrs

1 2 3 4 5 6 7 8 9 10 11

26 34 25 33 26 31 30 26 34 26 27

Mean SD t P

peo ? PPS LPD

peo LPD PPA PPS

50 x 5 100 x 5

1 2

150 x 5 100 x 5

5 1

22-23 22-23 22-23 18-19 25-26 22-23 22-23 27-28 24-25 27-28 21-22

26 27 25 23 28 28 24 25 25 28 26

23.91 2.66

25.91 1.70 2.80

< 0.02

Ec, previous ectopic; PPS, previous pelvic surgery; LPD, luteal phase defect; peo, polycy'stic ovaries; PPA, post-pill amenorrhea. Vol. 46, No.2, August 1986

Wentz et aI. Cycle of conception endometrial biopsy

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Table 3. Observed and Expected Endometrial Dating in Viable and Nonviable Pregnancies Viable I Nonviable Observed Expected Observed Expected

43 24.26 1.31

n

Mean

SD t Two tailed t-test

11 23.91 2.66

43 26.02 1.52

6.98 P < 0.001

11 25.91 1.70

2.80 P < 0.02

significant difference was found in both viable and nonviable pregnancy groups; endometrial biopsies obtained in a eoe were assigned earlier dates than that calculated from the expected date (Table 3). These endometrial biopsy samples manifested an edematous stroma, with a poorly developed pseudodecidual reaction, and a disparity between the developmental patterns of the glands and stroma. When the endometrial dating patterns of all nonviable pregnancies (including the ectopics) were compared with dating patterns in viable pregnancies, there was no statistical difference in the endometrial biopsy readings obtained or in the expected dates. The distribution of biopsies in pregnant and nonpregnant patients indicates that 61% of the biopsies in nonpregnant women were dated secretory day 25 or later, compared with 48.8% in viable and 36.4% in nonviable pregnancies dated secretory day 25 or later. There were two instances of premature but viable delivery. The remaining pregnancies were term deliveries of viable infants, and none with a documented congenital anomaly. DISCUSSION

The incidence of coe biopsy in our series is about 4%; this compares with 1.2% reported by

Buxton and Olson in 19698 and 2.8% reported by Karow et a1. 9 in 1971. The 20% early fetal wastage in this study is no higher than that anticipated for a high-risk infertility population,lO and compares favorably with the abortion rates reported by others performing eoe biopsy ll-15 (Table 4). Further, the two ectopic pregnancies were unlikely to be related to taking a eoe endometrial biopsy. The pregnancy involving trisomy 16 was also unrelated to the biopsy. Six of the remaining patients could conceivably have a predisposing factor (recurrent early fetal wastage, ovulation induction, and luteal phase inadequacy), leaving only 2 of all 54 patients without some predisposition for miscarriage. Thus, no increase in the abortion rate among patients undergoing eoe biopsy was observed; nevertheless, the possibility of a direct detrimental effect upon the pregnancy needs consideration. The number of days from biopsy to reported spontaneous miscarriage ranged from 9 to 110 days, with a mean of 39 days. There was no abortion prior to 9 days after biopsy, and only two occurred within the first 3 weeks subsequent to biopsy. This distribution, and the fact that trophoblastic tissue was found in only one biopsy specimen, makes a direct detrimental effect unlikely in most cases. Therefore, a eoe biopsy is usually not a threat to the pregnancy; however, whether useful information was obtained also needs consideration. Little is learned from a eoe endometrial biopsy. The difference between the observed and the expected biopsy readings is statistically significant, but there is no difference between those patients with viable pregnancies, and those who aborted or had an ectopic gestation. The histologic findings of an endometrial biopsy specimen taken in the cycle of conception may suggest pregnancy by the degree of edema and poor matu-

Table 4. Spontaneous Abortions Following Endometrial Biopsy in the Cicle of Conception Author

Total no. biopsies

Wilson et aI., 196611 Buxton and Olson, 19698 Karow et aI., 1971 9 Arronet et a1. 12 Rosenfeld and Garcia, 197513 Wentz, 198ff3 Jacobson and Marshall, 198014 Sulewski, 198015 Present series

Nsa 1700 1000

NS NS 210 35 288 1500

TotaIin COC(%)

18 22 (1.3) 28 (2.8) 23 18 10 (4.8) 7 (20.0) 18 (6.3) 54 (3.6)

First-trimester abortions

2 7 1 0 1 4 9

Ectopic

1 1 2

pregnancy Delivered (%) Total wastage (%)

18 20 (91) 22 (79) 14 (61) 15 (83) 9 (90) 6 (86) 14 (78) 40 (74)

0 2 (9) 6 (21) 7 (30) 1(6) 1 (10) 1 (14) 4 (22) 11 (20)

aNS, not stated. 198

Wentz et al.

Cycle of conception endometrial biopsy

Fertility and Sterility

rational development; but, contrary to the report by Sulewski et al.,15 the biopsy pattern has no predictive value. In summary, the incidence of endometrial biopsies taken during a cycle of conception is about 3% to 5%. The overall incidence of early fetal wastage after biopsy during a COC in our highrisk infertility population was 20%. Excluding the ectopic pregnancies, the spontaneous abortion rate with a COC biopsy in this study was 16.7%. However, only two patients had no predisposing cause other than infertility. The risk of interrupting a pregnancy by performing a biopsy on the implantation site was < 2% for pregnant patients and 0.067% of our entire biopsy population. Despite an apparent lag of endometrial development in COC biopsies, there was no predictive value suggestive of ultimate pregnancy outcome. Although the risk of early pregnancy loss when late luteal phase endometrial biopsies are performed during a COC is not significantly increased, no useful information is gained from these biopsies. We recommend, therefore, that a barrier method of contraception be advised for those patients who do not wish to run the 3% to 5% risk of COC biopsy or, alternatively, that a sensitive test for pregnancy be employed before performance of a late luteal phase biopsy.

Vol. 46, No.2, August 1986

REFERENCES 1. Driessen F, Holwerda PJ, Putte SCJ, Kremer J: The significance of dating an endometrial biopsy for the prognosis of the infertile couple. Int J Fertil 25: 112, 1980 2. Daly DC, Walters CA, Soto-Albors CE, Riddick DH: Endometrial biopsy during treatment ofluteal phase defects is predictive of therapeutic outcome. Fertil Steril 40:305, 1983 3. Wentz AC: Endometrial biopsy in the evaluation of infertility. Fertil Steril 33:121, 1980 4. Wentz AC, Herbert CM, Maxson WS, Garner CH: Outcome of progesterone treatment of luteal phase inadequacy. Fertil Steril 41:856, 1984 5. Moszkowski E, Woodruff JD, Jones GES: The inadequate luteal phase. Am J Obstet Gynecol 83:363, 1962 6. Jones GS: The luteal phase defect. Fertil Steril 27:351, 1976 7. Wentz AC, Martens P, Wilroy RS Jr: Luteal phase inadequacy and a chromosomal anomaly in recurrent abortion. Fertil Steril 41:142, 1984 8. Buxton CL, Olson LE: Endometrial biopsy inadvertently taken during conception cycle. Am J Obstet Gynecol 105: 702, 1969 9. Karow WG, Gentry WC, Skeels RF, Payne SA: Endometrial biopsy in the luteal phase of the cycle of conception. Fertil Steril 22:482, 1971 10. Jansen RPS: Spontaneous abortion incidence in the treatment of infertility. Am J Obstet Gynecol 143:451, 1982 11. Wilson RB, Lee RA, Jensen PA: Inadvertent infertility investigations in pregnant women. Fertil Steril 17:126, 1966 12. Arronet GH, Bergquist CA, Parekh MC, Latour JPA, Marshall KG: Evaluation of endometrial biopsy in the cycle of conception. Int J Fertil 18:220, 1973 13. Rosenfeld DL, Garcia CR: Endometrial biopsy in the cycle of conception. Fertil Steril 26:1088, 1975 14. Jacobson A, Marshall JR: Detrimental effect of endometrial biopsies on pregnancy rate following human menopausal gonadotropin/human chorionic gonadotropin-induced ovulation. Fertil Steril 33:602, 1980 15. Sulewski JM, Ward SP, McGaffic W: Endometrial biopsy during a cycle of conception. Fertil Steril 34:548, 1980

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