Intrauterine insemination: the University of Minnesota experience

FERTILITY AND STERILITY Copyright © 1985 The American Fertility Society

Vol. 43, No.5, May 1985 Printed in U.s A.

Intrauterine insemination: the University of Minnesota experience

Roger C. Toffie, M.D. * Theodore C. Nagel, M.D. George E. Tagatz, M.D. Shaila A. Phansey, M.D. Takashi Okagaki, M.D. Constance A. Wavrin, M.T.A.S.C.P. Department of Reproductive Endocrinology, University of Minnesota, Minneapolis, Minnesota

Forty-five patients initiated intrauterine insemination between October 1981 and August 1983. Indications for insemination included poor semen (count < 20 x 106/ml and/or motility < 40%), poor cervical mucus, presence of sperm antibodies, unexplained poor postcoital tests, or various combinations of the above. During this time period, 374 inseminations were performed in 163 cycles and resulted in eight pregnancies in the 45 patients receiving artificial insemination by homologous donor, for an overall pregnancy rate of 17.4%. The fact that five of the pregnancies occurred in the first insemination cycle and two in the second cycle was felt to indicate a cause-and-effect relationship. A trial of intrauterine insemination in selected patients would appear to be warranted. Fertil Steril 43:743, 1985

Divergent opinions exist as to the benefits to be obtained from the use of the homologous male's sperm to perform artificial insemination in an infertile couple. Potential indications for such efforts have included oligospermia, asthenospermia, poor postcoital tests, the presence of sperm antibodies, low semen volume, and anatomic abnormalities. l The methods by which such inseminations are carried out include instillation of the sperm within the vagina, cervix, or uterus. The purpose of this article is to review our experience with intrauterine insemination.

Received March 29, 1984; revised and accepted January 7, 1985. *Reprint requests: R. C. Toffle, M.D., Department of Reproductive Endocrinology, University of Minnesota, Box 395 Mayo Memorial Building, Minneapolis, Minnesota 55455. Vol. 43, No.5, May 1985

MATERIALS AND METHODS

Forty-five patients attending the Reproductive Endocrinology clinic at the University of Minnesota initiated a trial of intrauterine insemination between October 1981 and August 1983. Their charts were examined retrospectively for parity, age at the time ofthe first insemination, length of infertility, factors leading to the decision to perform intrauterine insemination, other potential causes of infertility, number of treatment cycles, total number of inseminations, and outcome. Infertility factors used as indications for intrauterine insemination were defined as follows: Abnormal semen. Oligospermia was defined as a count < 20 x 106 sperm/ml, and asthenospermia was defined as the presence of < 40% motile sperm 1 hour after ejaculation. Poor mucus. Poor mucus was scant, thick mucus or the absence of cervical mucus either due to present therapy, past cervical procedures, or anaToffle et aI. Intrauterine insemination

743

tomic changes related to diethylstilbestrol exposure. Cervical cultures failed to show the presence of Ureaplasma urealyticum, Chlamydia trachomatis, or enteric pathogens. Mucus qua:lity did not improve with estrogen or guaifenesin (Robitussin, A. H. Robins Company, Richmond, VA) therapy. Poor mucus and abnormal sperm. This was defined as the presence of poor mucus plus oligospermia and/orasthenospermia. Sperm antibodies. The presence of sperm antibodies in the male or in the female as suggested by testing for agglutination and/or immobilization in a modified Franklin-Dukes test were found iIi the absence of abnormal semen or poor mucus. Cervical cultures were negative for U. urealyticum, C. trachomatis, or enteric pathogens. Poor postcoital test. The finding of absent, immotile, or rare, sluggishly motile sperm at the time of the postcoital test despite adequate mucus, a normal semen analysis, and absence of documented infection constituted a poor test result. Antibody testing was either negative or had not been performed. Prior to considering intrauterine insemination,deficiencies in coital frequency, timing, and technique were ruled out by history and basal body temperature examinations. Other potential factors leading to infertility were defined as oligoovulation or anovulation, luteinized unruptured follicle as assessed by ultrasound or laparoscopy, luteal phase defect, tubal factor, prior pelvic surgery, endometriosis, and associated medical conditions leading to poor mucus production. When possible, these additional factors were treated prior to or in association with the use of intrauterine insemination. Unexplained infertility. This category includes patients who did not consistently fulfill the requirements to be placed in any of the preceding categories.

dry pellet, 0.5 ml of phosphate-buffered saline was added, and an even suspension was obtained with the Vortex.

SEMEN PREPARATION

Table 1. Demographic Data

The semen was collected by masturbation into a sterile plastic container and allowed to liquefy. Microscopic evaluation of motility was performed. The semen was then mixed with an equal volume ofphosphate-buffered saline which had been prepared and sterilized by the pharmacy service. The semen/buffer mixture was then well mixed with the Vortex (Vortex-Genie, Scientific Industries , Inc., Bohemia, NY). This mixture was then submitted to 15 minutes of centrifugation at 3 x g. The supernatant was "poured off so as to leave a

Total patients Parity Primary infertility Secondary infertility Age (yrs) Range Mean Median Duration of infertility (yrs) Range Mean Median Patients with additional fertility factors

744

Tome et' aI. Intrauterine insemination

METHOD OF INSEMINATION

Inseminations were performed at the time of expected ovulation as indicated by basal body temperature graphs and/or diagnostic ultrasound. The 0.5-ml suspension was drawn into a tuberculin syringe, and the syringe was attached to a 16- or 18-gauge Jelco (Gritikon, Inc., Tampa, ~L), which was then inserted into the distal portion of an 8 French pediatric feeding tube (Pharmaseal Inc., Toa Alta, PR). The needle portion of the Jelco was discarded, and the syringe was reattached to the Teflon portion of the Jelco, thus creating a flexible semen delivery system similar to that of Kremer.2 One patient required the use of a 3% French flexible pediatric umbilical catheter (Argyle Division of Sherwood Medical, St. Louis, MO) for entry into the endometrial cavity. A drop of the buffer/semen suspension was examined microscopically for motility, and the remainder of the suspension was slowly injected into the uterine cavity. After removal of the intrauterine catheter, the patient remained supine for approximately 5 minutes and was then free to leave the clinic with no restriction of activity.

RESULTS Of the 45 patients, 34 presented with primary infertility, and 11 presented with secondary infertility. Their ages ranged from 23 to 41.3 years, with a mean of 33.4 ± 4.1 years and a median age of 32.8 years. The length of infertility ranged from 2 to 13 years, with a mean duration of 5.38 ± 3.13 years and a median duration of 5 years (Table 1). In 22 instances, the semen analysis was

45 34 11 23.0-41.3 33.4 ±" 4.1 32.8 2-13 5.38 ± 3.13 5 39 (86.7%)

Fertility and Sterility

Table 2. Indications for Intrauterine Insemination Factor

No. of patients

No. pregnant

Abnormal semen only Poor mucus only Poor mucus plus abnormal semen Sperm antibodies Male autoantibody only ( + ) Abnormal semen ( + ) Poor mucus

14 10 7

3 2 2

2 0 1

0 0 0

3

0

4 1 1

1 0 0

6

1

4

0

1

0

Total Female antibody only ( + ) Abnormal semen ( + ) Poor mucus Total Poor postcoital test only Unexplained infertility

sulted. In seven instances, in the absence of antisperm antibody, there was abnormal semen as well as poor mucus. In these patients, two pregnancies were achieved. Sperm antibodies with or without abnormal semen or mucus were detected in nine couples, and within this group one pregnancy occurred. Of the 45 patients undergoing intrauterine insemination, 39 (86.7%) had additional factors that may have contributed to infertility. Factors leading to the use of intrauterine insemination are listed in Table 2. During the period of study, 374 inseminations were performed in 163 cycles. Eight pregnancies occurred (17.8%), with six pregnancies proceeding to term, one pregnancy resulting in a missed abortion at 10 weeks' gestation, and one pregnancy which is now in the third trimester (Table 3).

abnormal. Within this group, the mean number of sperm per ejaculate was 65 ± 58.9 x 106 , and the mean number of motile sperm per ejaculate was 21.3 ± 13.97 x 106 . Among these 22 couples in which semen quality played an apparent role in infertility, 5 women became pregnant. Within this subgroup, the mean number of sperm per ejaculate was 50.6 ± 27 x 106 , and the mean number of motile sperm was 17 ± 8.5 x 106 . ~bnormal semen alone was the only indication for intrauterine insemination in 14 cases, resulting in three pregnancies. In 19 instances cervical mucus was absent due to prior cone biopsy or was of poor quality and unresponsive to treatment. In ten instances this was the sole indication for intrauterine insemination, and two pregnancies re-

Inseminations were discontinued in one couple because of deterioration in sperm motility after centrifugation. There were no infections. The only physical complaints were those of occasional mild cramping at the time of catheter insertion. Subjective complaints also included the stress and inconvenience of repeated cycles of artificial insemination. DISCUSSION

Nachtigall et al.,! in their review of artificial insemination by homologous donor, found that spontaneous pregnancy rates in infertile couples averaged 14%, not unlike our finding of 17.8% when intrauterine insemination was employed. We have not provided a control group in this

Table 3. Patients Achieving Pregnancya Age

Parity

Length of infertility

Associated factors

Cycles

Inseminations

Tubal factor, erectile dysfunction Luteal phase defect, pelvic adhesions Luteal phase defect Luteal phase defect None Oligoovulation, minimal endometriosis Diethylstilbestrol exposure, T-shaped uterus, myomatous uterus, ovulatory dysfunction, endometriosis Luteal phase defect

1

2

1

2

2 1 1 1

4 3 2 2

2

5

6

15

yrs

3f)

1°

6

30

1°

3

31.8 32 27.4 30.8

2° 1° 1° 2°

3 3 2.5 2

32.6

1°

7

32.7

1°

2.5

aMean age, 31.7 ± 2.31; mean length of infertility, 3.63 ± 2,31 years; pregnancy rate, 8 of 45 (17.8%). Vol. 43, No.5, May 1985

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Table 4. Pregnancies per Treatment Cycle a Months

No. of patients pregnant or lost to follow-up

Pregnancies

Patients treated

1 2 3 4 5 6 7 8 9 10

8 12 6 5 5 3 3 0 2 1

5 2 0 0 0 1 0 0 0 0

45 37 25 19 14 9 6 3 3 1

Cumulative probability of pregnancy

Standard deviation

0.11 0.16

0.05 0.06

0.25

0.10

aKaplan-Meier survival curve, 162 months observed. Probability of pregnancy within 2 months, 7 of 44 or 16% (with 95% confidence interval, 0.04,0.28).

evaluation; but as of this point, only 1 of the 37 patients not achieving pregnancy with intrauterine insemination has achieved pregnancy with "normal intercourse." This fact, along with the finding that five of the eight pregnancies occurred in the first treatment cycle and two in the second treatment cycle, would appear to indicate a cause-and-effect relationship (Table 4). A review of the English literature since 1950 is summarized in Table 5. 2 - 10 Additional studies ll , 12 also report successful pregnancies after intrauterine insemination but were not included in Table 5 because of a lack of information as to the total number of pregnancies achieved in relation to the total number of patients who had received intrauterine insemination. The highly complex nature of a referral center's patient population is evidenced by the fact that 86.7% of our patients had one or more additional fertility factors in addition to those which led to the use of intrauterine insemination. This may explain the wide range of pregnancy rates achieved with this procedure as reported in the literature. The excellent results as reported by Barwin 5 may be the result of the absence of these additional factors, as indicated by his patient description in "Selection of Cases." The role of these additional factors in diminishing pregnancy rates in patients undergoing intrauterine insemination is unknown. The absence of such factors did not select out a group that was more likely to become pregnant in our series, because seven of the eight patients who achieved pregnancy also had one or more additional factors affecting their fertility. Although the majority of our couples who present with problems of semen quality are entered into our artificial insemination by heterologous 746

Tome et al. Intrauterine insemination

donor program, there are those couples who are unwilling to accept such an option. The fact that five pregnancies occurred in 21 couples in whom semen quality (in the absence of antibodies) played a role would suggest that a short trial of artificial insemination by homologous donor might be indicated when artificial insemination by heterologous donor is an unacceptable option. This may be particularly true when poor mucus quality is also present. While not statistically significant because of small numbers, this group had the highest rate of success, 28.6%. It is also of note that in those couples with deficient semen quality, the number of total and motile sperm per ejaculate was actually less in the subgroup that achieved pregnancy than in the group as a whole.

Table 5. Intrauterine Insemination: Review of the Literature Study Mastroianni et al. (1957)3 Ulstein (1973)4 Barwin (1974)5 White and Glass (1976)6 Speichinger and Mattox (1976)7 Glass and Ericsson (1978)8 Kremer (1979)2 Harris et al. (1981)9 Marrs et al. (1981)10 University of Minnesota (1983) (present study) Total

No. of patients

% Achieving Pregnancies pregnancy

29

1

3.4

35 50 9

10 31 5

28.6 62.0 56.0

I

1

100.0

19

0

0

60 20 11 46

17 3 2 8

28.3 15.0 18.2 17.4

280

78

27.9

Fertility and Sterility

This is important in that it rules out the possibility that pregnancies only occurred in couples in whom the semen quality approached normal parameters. In those nine instances in which an antibody was detected, there was only one pregnancy. In this patient, postcoital tests showed good mucus but no sperm despite a normal semen analysis and the postcoital test having been performed less than 4 hours after intracervical insemination. In this same patient, the modified Franklin-Dukes test showed only agglutination without immobilization of sperm. A similar constellation of findings was present in the one patient who became pregnant with "normal intercourse." This occurred 2 months after her single cycle of intrauterine insemination. In the four women in whom there were immobilizing antibodies, no pregnancies occurred. Variability in patient populations, methods of sperm preparation, techniques of intrauterine insemination, and methods of timing apparent ovulation make comparison of data difficult. Standardization of indications, ovulation timing, insemination technique, and the use of a control group is necessary for documentation ofthe benefits to be obtained with intrauterine insemination. Enthusiasm for the use of intrauterine insemination has been tempered by reports of violent cramps and shock 13 and the possibility of infection. 14 The presence of mild abdominal discomfort in association with intrauterine insemination has been reported to occur in 10% to 15% of patients. 5 , 8 In 400 inseminations, three of Barwin's patients required hospitalization for abdominal cramping. 5 After 6 months of intrauterine insemination, 50% of women with documented antisperm antibodies showed an increase in antibody titer, although one such patient still became pregnant. 2 The lack of significant complications within our own series, as well as reported by the investiga-

Vol. 43, No.5, May 1985

tors noted in Table 5,2-10 would indicate that attention to technique allows intrauterine insemination to be carried out with minimal risk to the patient. Techniques of sperm preparation that have been developed in association with in vitro fertilization and sperm penetration assays may well improve the results that can be obtained with intrauterine insemination. The efficacy of such techniques is being evaluated at this time. REFERENCES 1. Nachtigal! RD, Faure N, Glass RH: Artificial insemination of husband's sperm. Fertil Steril 32:141, 1979 2. Kremer J: A new technique for intrauterine insemination. Int J Fertil 24:53, 1979 3. Mastroianni L Jr, Laberge JL, Rock J: Appraisal of the efficacy of artificial insemination with husband's sperm and evaluation of insemination technics. Fertil Steril 8:260, 1957 4. Ulstein M: Fertility of husbands at homologous insemination. Acta Obstet Gynecol Scand 52:5, 1973 5. Barwin BN: Intrauterine insemination of husband's semen. J Reprod Fertil 36:101, 1974 6. White RM, Glass RH: Intrauterine insemination with husband's semen. Obstet Gynecol 47:119, 1976 7. Speichinger JP, Mattox JH: Homologous artificial insemination and oligospermia. Fertil Steril 27:135, 1976 8. Glass RH, Ericsson RJ: Intrauterine insemination of isolated motile sperm. Fertil Steril 29:535, 1978 9. Harris SJ, Milligan MP, Masson GM, Dennis KJ: Improved separation of motile sperm in asthenospermia and its application to artificial insemination homologous (AIR). Fertil Steril 36:219, 1981 10. Marrs RP, Vargyas JM, Saito H, Gibbons WE, Berger T, Mishell DR: Clinical applications of techniques used in human in vitro fertilization research. Am J Obstet Gynecol 146:477, 1983 11. Boettcher B, Kay DJ, Fitchett SB: Successful treatment of male infertility caused by anti spermatozoal antibodies. Med J Aust 2:471, 1982 12. Parez-Palaez M, Cohen MR: The split ejaculate in homologous insemination. Int J Fertil 10:25, 1965 13. Carruthers GB: Husband and donor insemination in infertility. Med J Gynaecol Sociol 5:13, 1970 14. Russell JK: Artificial insemination (husband) in the management of childlessness. Lancet 2:1223, 1960

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