Noabort.net

Postfertilization Effects of Oral Contraceptives
and Their Relationship to Informed Consent
Walter L. Larimore, MD; Joseph B. Stanford, MD, MSPH Theprimarymechanismoforalcontraceptivesistoinhibitovulation,butthismecha-
nism is not always operative. When breakthrough ovulation occurs, then secondarymechanisms operate to prevent clinically recognized pregnancy. These secondary mecha-nisms may occur either before or after fertilization. Postfertilization effects would be problematic for some patients, who may desire information about this possibility. This article evalu-ates the available evidence for the postfertilization effects of oral contraceptives and concludes thatgood evidence exists to support the hypothesis that the effectiveness of oral contraceptives de-pends to some degree on postfertilization effects. However, there are insufficient data to quanti-tate the relative contribution of postfertilization effects. Despite the lack of quantitative data, theprinciples of informed consent suggest that patients who may object to any postfertilization lossshould be made aware of this information so that they can give fully informed consent for the useof oral contraceptives.
such effects has not been systematically re- viewed. The purpose of this article was to cations in the world,1 and are accessible review and grade the available evidence for postfertilization effects of OCs and dis- tries, although still virtually unavailable in uted to an increased acceptability of birth to whom postfertilization effects are im- control,2 although, for many patients, de- based on the best available evidence.13-15 moral, ethical, and religious implica-tions.3,4 For patients who believe that hu- For Author’s Comment
man life begins at fertilization (concep- see page 133
tion), a method of birth control that hasthe potential of interrupting develop- ment after fertilization (a postfertiliza- volved a review of the abstracts of all stud- tion effect) may not be acceptable.5,6 Post- ies of OCs published since 1970 available (when it is administered too late to pre- µg of estrogen) phasic combined oral con- vent ovulation),7,8 luteolytic agents (ie, RU- 486),9 and intrauterine devices,5 and these gestin-only pills [POPs]). We also reviewed some patients. Although postfertilization tions of several medical textbooks and ref-erence books.
Since there is variability in the defini- From the Department of Family Medicine, University of South Florida, Kissimmee(Dr Larimore), and Department of Family and Preventive Medicine, University of Utah, Salt Lake City (Dr Stanford). 2000 American Medical Association. All rights reserved.
Typical use is described as the full tions for fertilization, implantation, embryo, and preembryo.16 Preembryo week after fertilization, the term em- bryo is used. Implantation is the pro- fined postfertilization effects to in- the first year of typical use.1,10,12,17,18,20 EVIDENCE FOR
POSTFERTILIZATION EFFECTS
MECHANISMS OF OCs
the first year of typical use.1,10,12,17,18,20 ising method is the isolation of “early tilization effects also play a role.
2000 American Medical Association. All rights reserved.
Quality of Evidence*
tain a pregnancy in patients under-going in vitro fertilization has been Evidence obtained from at least one properly randomized Evidence obtained from well-designed controlled trials Evidence obtained from well-designed cohort or case-controlled analytic studies, preferably from more than one center or research group.
Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolledexperiments could also be regarded as this type Opinion of respected authorities based on clinical experience, descriptive studies and case reports, Integrin Changes Affecting
Fallopial Tube and Endometrial
OCs in the Physicians’ Desk Refer- Receptivity for Implantation
ity of evidence table46 (Table), we
culty of sperm entry into the uterus, and Endometrial Changes That May
Affect Endometrial Receptivity
integrins (␣1␤1, ␣4␤1, ␣V␤3) have III (poor to good) evidence (Table).
ers of normal fertility.”68 Of these 3, sion is significantly changed by OCs.
2000 American Medical Association. All rights reserved.
dow that “ . . . affords the opportunity tubal peristalsis that is associated with Increased Extrauterine
Pregnancy to Intrauterine
Pregnancy Ratio
2000 American Medical Association. All rights reserved.
PROVIDING INFORMED
for OCs is described in the Physi- cians’ Desk Reference,11 in Drug (level III) to very good (level II.2).
d e n c e b a s e d o n e n d o m e t r i a l til it is either definitely proven to ex- 2000 American Medical Association. All rights reserved.
and Preventive Medicine, University of Utah, 50 North Medical Dr, Salt 1. Hatcher RA, Trussell J, Stewart F, et al. Contra- ceptive Technology. 17th rev ed. New York, NY: 2. Asbell B. The Pill: A Biography of the Drug That 3. Wilkinson J. Ethical problems at the beginning of life. In: Wilkinson J, ed. Christian Ethics in Health Care: A Source Book for Christian Doc- tors, Nurses and Other Health Care Profession- als. Edinburgh, Scotland: Handsel Press Ltd; 4. Ryder RE. “Natural family planning”: effective birth control supported by the Catholic Church. BMJ.
5. Spinnato JA. Mechanism of action of intrauter- ine contraceptive devices and its relation to in-formed consent. Am J Obstet Gynecol. 1997;176: 6. Tonti-Filippini N. The pill: abortifacient or contra- ceptive? a literature review. Linacre Q. February 7. Grou F, Rodrigues I. The morning-after pill: how long after? Am J Obstet Gynecol. 1994;171:1529- CONCLUSIONS
8. Glasier A, Thong KJ, Dewar M, Mackie M, Baird DT. Mifepristone (RU 486) compared with high- dose estrogen and progestogen for emergencypostcoital contraception. N Engl J Med. 1992; 9. Weiss BD. RU 486: the progesterone antagonist.
10. Speroff L, Darney P. A Clinical Guide for Contra- ception. Baltimore, Md: Williams & Wilkins; 1992.
11. Physicians’ Desk Reference. Montvale, NJ: Medi- 12. Kastrup EK, ed. Drug Facts and Comparisons.
St Louis, Mo: Facts & Comparisons; 1997.
13. Alderson P, Goodey C. Theories of consent. BMJ.
14. Applebaum PS, Lidz CW, Meisel A. Informed Con- sent: Legal Theory and Clinical Practice. New York, NY: Oxford University Press; 1987:35-65.
15. Beauchamp TL. Informed consent. In: Veatch RM, ed. Medical Ethics. Boston, Mass: Jones & Bart- 16. American College of Obstetricians and Gynecolo- gists. Preembryo Research: History, Scientific Background, and Ethical Considerations. Wash- ington, DC: American College of Obstetricians and Gynecologists; 1994. ACOG Committee Opinion136.
17. Baird DT, Glasier AF. Hormonal contraception Accepted for publication March 18, (drug therapy). N Engl J Med. 1993;328:1543- 18. Hormonal Contraception. Washington, DC: Ameri- Chris Kahlenborn, MD, G. Gayle Ste- can College of Obstetricians and Gynecologists;October 1994. ACOG Technical Bulletin 198.
phens, MD, William Toffler, MD, and 19. Wolf DP, Blasco L, Khan MA, Litt M. Human cer- Randy Alcorn, MS, for their help with vical mucous, V: oral contraceptives and mucus conceptual development of this ar- rheologic properties. Fertil Steril. 1979;32:166- ticle and for identifying important Aref I, Hefnawi F, Kandil O, Abdel-Aziz MT. Effectof minipills on physiologic responses of human cervical mucous, endometrium, and ovary. Fertil 2000 American Medical Association. All rights reserved.
21. Somkuti SG, Sun J, Yowell CW, Fritz MA, Lessey nancy factor and its role in early pregnancy. J As- 58. Gonen Y, Casper RF, Jacobson W, Blankier J. En- BA. The effect of oral contraceptive pills on mark- dometrial thickness and growth during ovarian ers of endometrial receptivity. Fertil Steril. 1996; 40. Norman RJ, McLoughlin JW, Borthwick GM, et stimulation: a possible predictor of implantation al. Inhibin and relaxin concentrations in early in in-vitro fertilization. Fertil Steril. 1989;52:446- 22. Steiner M, Dominik R, Trussell J, Hertz-Picciotto singleton, multiple, and failing pregnancy: rela- I. Measuring contraceptive effectiveness: a con- tionship to gonadotropin and steroid profiles. Fer- 59. Schwartz LB, Chiu AS, Courtney M, Krey L, ceptual framework. Obstet Gynecol. 1996;88 Schmidt-Sarosi C. The embryo versus endome- 41. Taylor CA Jr, Overstreet JW, Samuels SJ, et al.
trium controversy revisited as it relates to pre- 23. Chowdhury V, Joshi UM, Gopalkrishna K, Betra- Prospective assessment of early fetal loss using dicting pregnancy outcome in in-vitro fertilization- bet S, Saxena BN. ‘Escape’ ovulation in women an immunoenzymometric screening assay for de- embryo transfer cycles. Hum Reprod. 1997;12: due to the missing of low dose combination oral tection of urinary human chorionic gonadotro- contraceptive pills. Contraception. 1980;22:241- pin. Fertil Steril. 1992;57:1220-1224.
60. Shoham Z, Di Carlo C, Patel A, Conway GS, Ja- 42. Wilcox AJ, Weinberg CR, O’Connor JF, et al. In- cobs HS. Is it possible to run a successful ovu- 24. Kumar TC, Dhah RS, Chitlange CM, et al. Effects cidence of the early loss of pregnancy. N Engl J lation induction program based solely on ultra- of intranasal administration of norethisterone on sound monitoring? the importance of endometrial follicular genesis, cervical mucus, vaginal cytol- 43. Miller JF, Williamson E, Glue J, Gordon YB, Grud- measurements. Fertil Steril. 1991;56:836-841.
ogy, endometrial morphology and reproductive- zinskas JG, Sykes A. Fetal loss after implantation: 61. Noyes N, Liu HC, Sultan K, Schattman G, Rosen- endocrine profile in women. Contraception. 1991; a prospective study. Lancet. 1980;2:554-556.
waks Z. Endometrial thickness appears to be a sig- 44. Zinaman MJ, Clegg ED, Brown CC, O’Connor J, nificant factor in embryo implantation in in-vitro 25. Grimes DA, Godwin AJ, Rubin A, Smith JA, La- Selevan SG. Estimates of human fertility and preg- fertilization. Hum Reprod. 1995;10:919-922.
carra M. Ovulation and follicular development as- nancy loss. Fertil Steril. 1996;65:503-509.
62. Vera JA, Arguello B, Crisosto CA. Predictive value sociated with three low-dose oral contracep- 45. Eskenazi B, Gold EB, Lasley BL, et al. Prospec- of endometrial pattern and thickness in the re- tives: a randomized controlled trial. Obstet Gynecol.
tive monitoring of early fetal loss and clinical spon- sult of in vitro fertilization and embryo transfer.
taneous abortion among female semiconductor Rev Chil Obstet Ginecol. 1995;60:195-198.
26. Van der Vange N. Seven Low-dose Oral Contra- workers. Am J Ind Med. 1995;28:833-846.
63. Check JH, Nowroozi K, Choe J, Lurie D, Diet- ceptives and Their Influence on Metabolic Path- 46. Berg AO. Dimensions of evidence. J Am Board Fam terich C. The effect of endometrial thickness and ways and Ovarian Activity [master’s thesis].
echo pattern on in vitro fertilization outcome in Utrecht, the Netherlands: Reijksuniversiteit te 47. Umapathysivam K, Jones WR. Effects of contra- donor oocyte-embryo transfer cycle. Fertil Steril.
ceptive agents on the biochemical and protein 27. Martinez-Manautou J, Giner-Velasquez J, Cortes- composition of human endometrium. Contracep- 64. Oliveira JB, Baruffi RL, Mauri AL, Petersen CG, Gallegos V, et al. Daily progestogen for contra- Borges MC, Franco JG Jr. Endometrial ultrason- ception: a clinical study. BMJ. 1967;2:730-732.
48. Bartoli JM, Moulin G, Delannoy L, Chagnaud C, ography as a predictor of pregnancy in an in- 28. Chi I. The safety and efficacy issues of progestin- Kasbarian M. The normal uterus on magnetic reso- vitro fertilization programme after ovarian stimu- only oral contraceptives: an epidemiologic per- nance imaging and variations associated with the lation and gonadotrophin-releasing hormone and spective. Contraception. 1993;47:1-21.
hormonal state. Surg Radiol Anat. 1991;13:213- gonadotrophins. Hum Reprod. 1997;12:2515- 29. Potter LS. How effective are contraceptives? the determination and measurement of pregnancy 49. Demas BE, Hricak H, Jaffe RB. Uterine MR imag- 65. Bergh C, Hillensjo T, Nilsson L. Sonographic evalu- rates. Obstet Gynecol. 1996;88(suppl 3):13S- ing: effects of hormonal stimulation. Radiology.
ation of the endometrium in in-vitro fertilization IVF cycles: a way to predict pregnancy? Acta Ob- 30. Sondheimer SJ. Cervical mucus and contracep- 50. McCarthy S, Tauber C, Gore J. Female pelvic stet Gynecol Scand. 1992;71:624-628.
tion. Semin Reprod Endocrinol. 1986;4:383- anatomy: MR assessment of variations during the 66. Lessey BA. Endometrial integrins and the estab- menstrual cycle and with use of oral contracep- lishment of uterine receptivity. Hum Reprod. 1998; 31. Fraser IS, Jansen RP. Why do inadvertent preg- nancies occur in oral contraceptive users? effec- 51. Brown HK, Stoll BS, Nicosia SV, et al. Uterine junc- 67. Ilesanmi AO, Hawkins DA, Lessey BA. Immuno- tiveness of oral contraceptive regimens and in- tional zone: correlation between histologic find- histochemical markers of uterine receptivity in the terfering factors. Contraception. 1983;27:531- ings and MR imaging. Radiology. 1991;179:409- human endometrium. Microsc Res Tech. 1993; 32. Chang MC, Hunt DM. Effects of various pro- 52. Fleischer AC, Herbert CM, Sacks GA, Wentz AC, 68. Somkuti SG, Yuan L, Fritz MA, Lessey BA. Epi- gestins and estrogen on the gamete transport and Entman SS, James AE Jr. Sonography of the en- dermal growth factor and sex steroids dynami- fertilization in the rabbit. Fertil Steril. 1970;21: dometrium during conception and nonconcep- cally regulate a marker of endometrial receptivity tion cycles of in vitro fertilization and embryo trans- in Ishikawa cells. J Clin Endocrinol Metab. 1997; 33. Alvarez F, Brache V, Fernandez E, et al. New in- fer. Fertil Steril. 1986;46:442-447.
sights on the mode of action of intrauterine con- 53. Rabinowitz R, Laufer N, Lewin A, et al. The value 69. Sulz L, Valenzuela JP, Salvatierra AM, Ortiz ME, traceptive devices in women. Fertil Steril. 1998; of ultrasonographic endometrial measurement in Croxatto HB. The expression of alpha(v) and beta3 the prediction of pregnancy following in vitro fer- integrin subunits in the normal human Fallopian 34. Baird DD, Weinberg CR, Wilcox AJ, McCon- tilization. Fertil Steril. 1986;45:824-828.
tube epithelium suggests the occurrence of a tubal naughey DR, Musey PI, Collins DC. Hormonal pro- 54. Ueno J, Oehninger S, Brzyski RG, Acosta AA, implantation window. Hum Reprod. 1998;13: files of natural conception cycles ending in early Philput CB, Muasher SJ. Ultrasonographic ap- unrecognized pregnancy loss. J Clin Endocrinol pearance of the endometrium in natural and stimu- 70. Hoshino K, Kumasaka T. Contractile respon- lated in-vitro fertilization cycles and its correla- siveness of the isolated guinea pig oviduct to 35. Stewart DR, Overstreet JW, Nakajima ST, Lasley tion with outcome. Hum Reprod. 1991;6:901- autacoids at different phases of the sexual cycle BL. Enhanced ovarian steroid secretion before im- or under ovarian steroid treatment [in Japa- plantation in early human pregnancy. J Clin En- 55. Glissant A, de Mouzon J, Frydman R. Ultrasound nese]. Nippon Sanka Fujinka Gakkai Zasshi.
study of the endometrium during in vitro fertil- 36. Stewart DR, Celniker AC, Taylor CA Jr, Cragun JR, ization cycles. Fertil Steril. 1985;44:786-790.
71. Stanford JB, Daly KD. Menstrual and mucus cycle Overstreet JW, Lasley BL. Relaxin in the peri- 56. Abdalla HI, Brooks AA, Johnson MR, Kirkland A, characteristics in women discontinuing oral con- implantation period. J Clin Endocrinol Metab. 1990; Thomas A, Studd JW. Endometrial thickness: a traceptives [abstract]. Paediatr Perinat Epide- predictor of implantation in ovum recipients? Hum 37. Cavanagh AC. Identification of early pregnancy fac- 72. Task Force on Intrauterine Devices for Fertility tor as chaperonin 10: implications for understand- 57. Dickey RP, Olar TT, Taylor SN, Curole DN, Matu- Regulation, The World Health Organization’s Spe- ing its role. Rev Reprod. 1996;1:28-32.
lich EM. Relationship of endometrial thickness and cial Programme of Research Development and Re- 38. Cavanagh AC. An update on the identity of early pattern to fecundity in ovulation induction cycles: search Training in Human Reproduction. A mul- pregnancy factor and its role in early pregnancy.
effect of clomiphene citrate alone and with hu- tinational case-control study of ectopic pregnancy.
J Assist Reprod Genet. 1997;14:492-495.
man menopausal gonadotropin. Fertil Steril. 1993; 39. Bose R. An update on the identity of early preg- 73. Mol BW, Ankum WM, Bossuyt PM, Van der Veen 2000 American Medical Association. All rights reserved.
F. Contraception and the risk of ectopic preg- vei R. The incidence of ectopic pregnancy in Hord- 87. Vessey M, Meisler L, Flavel R, Yeates D. Out- nancy: a meta-analysis. Contraception. 1995;52: aland County, Norway 1976-1993. Acta Obstet Gy- come of pregnancy in women using different meth- ods of contraception. Br J Obstet Gynaecol. 1979; 74. Job-Spira N, Fernandez H, Coste J, Papiernik E, 80. Coste J, Job-Spira N, Aublet-Cuvelier B, et al. In- Spira A. Risk of chlamydia, PID, and oral contra- cidence of ectopic pregnancy: first results of a 88. Lauritsen JG. The significance of oral contracep- population-based register in France. Hum Re- tives in causing chromosome anomalies in spon- 75. Thorburn J, Berntsson C, Philipson M, Lindblom taneous abortions. Acta Obstet Gynecol Scand.
B. Background factors of ectopic pregnancy, I: fre- 81. Aboud E. A five-year review of ectopic pregnancy.
quency distribution in a case-control study. Eur Clin Exp Obstet Gynecol. 1997;24:127-129.
89. Sackoff J, Kline J, Susser M. Previous use of oral J Obstet Gynecol Reprod Biol. 1986;23:321-331.
82. De Muylder X. Ectopic pregnancy in Zimbabwe.
contraceptives and spontaneous abortion. Epide- 76. Coste J, Job-Spira N, Fernandez H, Papiernik E, Int J Gynaecol Obstet. 1991;35:55-60.
Spira A. Risk factors for ectopic pregnancy: a case- 83. Liukko P, Erkkola R, Laakso L. Ectopic pregnan- 90. Gray RH, Pardthaisong T. In utero exposure to ste- control study in France, with special focus on in- cies during use of low-dose progestogens for oral roid contraceptives and survival during infancy.
fectious factors. Am J Epidemiol. 1991;133:839- contraception. Contraception. 1977;16:575- 91. Grimes DA, Cook RJ. Mifepristone (RU 486): an 77. Kalandidi A, Doulgerakis M, Tzonou A, Hsieh CC, 84. Bonnar J. Progestagen-only contraception and abortifacient to prevent abortion? N Engl J Med.
Aravandinos D, Trichopoulos D. Induced abor- tubal pregnancies. Lancet. 1974;1:170-171.
tions, contraceptive practices, and tobacco smok- 85. Lawson P. Experience with norethisterone 0.35 92. Grimes DA. Emergency contraception-expand- ing as risk factors for ectopic pregnancy in Athens, mg daily as an oral contraceptive. Br J Fam Plann.
ing opportunities for primary prevention. N Engl Greece. Br J Obstet Gynaecol. 1991;98:207-213.
78. Franks AL, Beral V, Cates W Jr, Hogue CJ. Con- 86. Sheth A, Jain U, Sharma S, et al. A randomized 93. Katz J. The Silent World of Doctor and Patient. New traception and ectopic pregnancy risk. Am J Ob- double-blind study of two combined and two pro- stet Gynecol. 1990;163(4, pt 1):1120-1123.
gestin-only oral contraceptives. Contraception.
94. Cruz P. Angry over withheld information. Life Ad- 79. Storeide O, Veholmen M, Eide M, Bergsjo P, Sand- I haveprescribed“thePill”since1978.MywifeandIusedthePillforyears,havingnomoralconcernsaboutit.Then,
in 1995 my friend and practice partner John Hartman, MD, showed me a patient information brochure—given to himby a friend—that claimed the Pill had a postfertilization effect causing “ . . . the unrecognized loss of preborn chil- dren.” John asked me if I had ever heard of such a thing. I had not. I did read the brochure and its claims seemed to beoutlandish, excessive, and inaccurate. So, I decided to begin a literature search to disprove these claims to my partner, my-self, and any patients who might ask about it. The more research I did, the more concerned I became about my findings. Icalled researchers around the country and interviewed them. During this process I met Joe Stanford, MD. Joe volunteered toassist in the research that ultimately became this systematic review. We were concerned enough about our findings and aboutthe fact that so many of our colleagues and patients seemed to share our ignorance about this potential effect that we pre-sented the preliminary results of our research at a number of research forums, just to see if we were off base. Most of thereviewers suggested that, although this evidence was new to them (as it was to us), it seemed accurate and not off target.
Furthermore, several said that they thought it would change the way family physicians informed their patients about the Pilland its potential effects.
The most difficult part of this research was deciding how to apply it to my practice. I discussed it with my partners, my patients, ethicists I know and respect, and pastors in my community. I studied the ethical principle of double effect anddiscussed the issue with religious physicians of several faiths. Finally, after many months of debate and prayer, I decided in1998 to no longer prescribe the Pill. As a family physician, my career has been committed to family care from conception todeath. Since the evidence indicated to me that the Pill could have a postfertilization effect, I felt I could no longer, in goodconscience, prescribe it—especially since viable alternatives are available. The support and encouragement that my part-ners, staff, and patients have given me has been unexpectedly affirming. It seems that my patients have appreciated the in-formation I have given them. Many have been surprised or even shocked (as I was) to learn about this potential effect. Manyof my patients have chosen to continue taking the Pill, and we have physicians in our practice and community who willprescribe it for them. Patients who take the Pill tell me that they are much more careful with their compliance. Others havechosen other birth control options—especially one of the modern methods of natural family planning. So, this is researchthat has changed my soul and my practice. It has been an extraordinarily difficult issue with which I have had to wrestle. Isuspect it will be so for many who thoughtfully read and consider the evidence contained in this review.
Walter L. Larimore, MDKissimmee, Fla 2000 American Medical Association. All rights reserved.

Source: http://noabort.net/files/Postfertilization%20effects%20of%20oral%20contraceptives%20and%20their%20relationship%20to%20informed%20consent.pdf