Footnotes for "Citizen Petition to the U.S. Food and Drug Administration on RU 486" by Americans United for Life
- The comments submitted
herein are limited to RU 486 as an abortifacient drug product.
This petition does not, therefore, oppose or address in any manner
the use of RU 486 in the treatment of diseases, such as breast
cancer or meningiomas (brain tumors).
- See FDCA 505(d), 21 U.S.C. 355(d).
- 21 U.S.C. 355(b)(1)(A).
- See FDCA 505(d)(1) (emphasis
added), 21 U.S.C. 355(d)(1).
- See FDCA 505(d)(4) (emphasis
added), 21 U.S.C. 355(d)(4).
- The phrase "subsequent
born children" is defined for the purpose of this document
as children born as a result of a pregnancy continued after a
failed RU 486 abortion as well as any additional children conceived
and born after exposure to RU 486.
- 21 U.S.C. 355(d)(5).
- 21 U.S.C. 355(d).
- See Warner-Lambert Co.
v. Heckler, 787 F.2d 147, 155 (1986).
- See United States v.
Rutherford, 442 U.S. 544, 553 n.9 (1979); Warner-Lambert
Co. v. Heckler, 787 F.2d at 155 (discussing United States
- See 21 C.F.R. 312.120,
- See 21 C.F.R. 314.106
- Dr. Meredeth Turshen has
raised concerns about the accuracy of the complication and failure
rates being reported by foreign studies funded by Roussel Uclaf
(the French manufacturer of RU 486), in light of the results that
have been obtained by some independent researchers, which have
not been published. Dr. Turshen was a fellow at INSERM (the French
equivalent of NIH) during 1989-90. See Comments by Dr. Turshen
at "Contraceptive Technology: Promises and Politics"
workshop at the annual meeting of the Am. Public Health Assoc.
(Oct. 2, 1990); "Researcher suggests side effects of RU-486
may be underreported" Am. Medical News, Oct. 26, 1990,
at 8; Boston Herald, July 31, 1992, at 25.
- An average value for the
frequency of complete abortion with RU 486 alone is approx. 63%.
WHO Task Force On Post-Ovulatory Methods For Fertility Regulation,
Termination Of Early Human Pregnancy With RU 486 (Mifepristone)
And The Prostaglandin Analogue Sulprostone: A Multi-Centre, Randomized
Comparison Between Two Treatment Regimens, 4 Hum. Reprod.
718, 719 (1989) (hereafter "WHO Task Force, 1989").
See Table 1 for comprehensive statistics on complete abortion
- Grimes, Mifepristone
(RU 486) For Induced Abortion, 3 Women's Health Issues 171,
172 (1993) (hereafter "Grimes, 1993"); Grimes, et al.,
Early Abortion With A Single Dose Of The Antiprogestin RU-486,
158 Am. J. Obst. Gyn. 1307, 1308 (1988) (hereafter "Grimes,
et al., 1988") (10% failure with 600 mg dose in women less
than or equal to 49 days from last menstrual period ("LMP");
and Shoupe, et al., Pregnancy Termination With A High And A
Medium Dosage Regimen Of RU 486, 33 Contraception 455 (1986)
(hereafter "Shoupe, et al., 1986") (90% failure in high
dose group -- 400 mg/day for 4 days (N=5) or 200 mg/day for 4
days (N=5) -- all women within 49 days of first day of LMP). For
statistics on incomplete abortion rates, see Table 2.
- With RU 486 alone, from
8.3% to 46.3% of pregnancies continue. See Table 9 for reported
- Grimes, et al., found that
the risk of failure from RU 486 alone for women in the largest
body mass group studied was 2.9 times greater than that of women
in the lowest body mass group studied. Grimes, et al., Predictors
Of Failed Attempted Abortion With The Antiprogestin Mifepristone
(RU 486), 162 Am. J. Obst. Gyn. 910, 913-14 (1990) (hereafter
"Grimes, et al., 1990") (risk with a Quetelet's index
[weight(kg)/height(m2)] greater than 23.81 was 2.9 times the risk
with index less than 20.25); see also Grimes, 1993, at 172 (1993).
See discussion infra Section 3.d.
- See Chan, et al., Blood
Loss In Termination Of Early Pregnancy By Vacuum Aspiration And
By Combination Of Mifepristone And Gemeprost, 47 Contraception
85 (1993) (hereafter "Chan, et al., 1993") (medical
termination of pregnancy carries risk of incomplete abortion that
requires surgical intervention).
- See Raymond, et al., RU
486: Misconceptions, Myths And Morals 38 (1991) (hereafter
"Raymond, et al., 1991") ("Incomplete abortions
. . . necessitate that the products of conception are removed
by conventional abortion methods. Incomplete evacuation can be
accompanied by severe bleeding. . . . This adverse effect of RU
486/PG abortion may lead to . . . pelvic inflammatory disease
(PID) from infection, to infertility, and possibly uterine cancer.")
For statistics on the incidence of infection with pharmaceutical
abortion, see Table 3.
- See Pons, et al., Development
After Exposure To Mifepristone In Early Pregnancy, 338 Lancet
763 (1991) (hereafter "Pons, et al., 1991") (although
the researchers couldn't determine whether the abnormalities were
related to RU 486, they concluded that "a deleterious effect
of mifepristone cannot be ruled out."). See also infra
Section 4.b.(1) and accompanying footnotes.
- Micrognathia is an abnormality
characterized by smallness of the jaw, especially the underjaw.
Stedman's Medical Dictionary 875 (5th ed. 1982). Hygroma
is a cystic swelling, usually of the neck area, containing serous
fluid. See Stedman's Medical Dictionary 668 (5th ed.);
Dorland's Illustrated Medical Dictionary 789 (28th ed.
- Swahn, et al., Effect
Of Oral Prostaglandin E2 On Uterine Contractility And Outcome
Of Treatment In Women Receiving RU 486 (Mifepristone) For Termination
Of Early Pregnancy, 4 Hum. Reprod. 21, 27 (1989) (hereafter
"Swahn, et al., 1989"). See also, Zheng Shu-rong, RU
486 (Mifepristone): Clinical Trials In China, 149 Acta Obst.
Gyn. Scand. Suppl. 19 (1989) (hereafter "Zheng Shu-rong,
1989") (4 patients (1.34%) suffered heavy bleeding, necessitating
emergency curettage after receiving RU 486); The RU 486 Collaboration
Group, Termination Of Early Pregnancy By RU 486 Alone Or In
Combination With Prostaglandin, 25 Chinese J. Obst. &
Gyn. 31 (1990) (clinically significant [177.4 ml] mean blood loss
after complete abortion reported).
- Researchers have noted
that the total amount of blood lost by women treated with RU 486
is not reduced with a RU 486/PG regimen. Swahn, et al., 1989,
at 27 (1989); Rodger & Baird, Blood Loss Following Induction
Of Early Abortion Using Mifepristone (RU 486) And A Prostaglandin
Analogue (Gemeprost), 40 Contraception 439 (1989) (hereafter
"Rodger & Baird, 1989"); Cameron, et al., Therapeutic
Abortion In Early Pregnancy With Antiprogestogen RU 486 Alone
Or In Combination With Prostaglandin Analogue (Gemeprost), 34
Contraception 459 (1986). But see, Zheng Shu-rong, 1989 (reporting
a lower volume of blood loss with RU 486/PG regimen [52 ml (RU
486/PG) v. 117 ml (RU 486)] in women who aborted within 49 days
- Thong & Baird, Induction
Of Abortion With Mifepristone And Misoprostol In Early Pregnancy,
99 Br. J. Obst. Gyn. 1004, 1006 (1992) (hereafter "Thong
& Baird, 1992"). See also Couzinet, et al., Termination
Of Early Pregnancy By The Progesterone Antagonist RU 486 (Mifepristone),
315 N. Eng. J. Med. 1565, 1569 (1986); Sitruk-Ware, et al., The
Use Of The Antiprogestin RU 486 (Mifepristone) As An Abortifacient
In Early Pregnancy -- Clinical And Pathological Findings; Predictive
Factors For Efficacy, 41 Contraception 221, 239-40 (1990);
El-Refaey & Templeton, Early Induction Of Abortion By A
Combination Of Oral Mifepristone And Misoprostol Administered
By The Vaginal Route, 49 Contraception 111, 113-14 (1994)
(hereafter "El-Refaey & Templeton, 1994"); Rodger
& Baird, 1989, at 444; UK Multicentre Trial, The Efficacy
And Tolerance Of Mifepristone And Prostaglandin In First Trimester
Termination Of Pregnancy, 97 Br. J. Obst. Gyn. 480, 485 (1990)
(hereafter "UK Multicentre Trial, 1990"); Chan, et al.,
1993, at 85; Wu, et al., Clinical Trial On Termination Of Early
Pregnancy With Ru 486 In Combination With Prostaglandin, 46
Contraception 203, 209 (1992) (hereafter "Wu, et al., 1992").
- For statistics on complete
abortion rates using RU 486 alone, see Table 1 (average complete
abortion rate [approx.] 63%); compare to complete abortion rates
of 84.4% to 99% using RU 486/oral or vaginal misoprostol up to
63 days amenorrhea (Table 4). Complete abortion rates of 75.3%
to 99% using RU 486 in combination with other prostaglandins up
to 63 days amenorrhea are reported in Table 5.
- McKinley, et al., The
Effect Of Dose Of Mifepristone And Gestation On The Efficacy Of
Medical Abortion With Mifepristone And Misoprostol, 8 Hum.
Reprod. 1502 (1993) (hereafter "McKinley, et al., 1993")
(regimen of either 200 or 600 mg RU 486 followed by 600 ug misoprostol
48 hrs. later).
- Id. at 1502. See also Ulmann,
Warning On Low Dose Mifepristone Use, 6 PharmacoEconomics
90 (1994) ("Currently available information suggests that
the efficacy of misoprostol following mifepristone is significantly
lower in pregnancies above 49 days of amenorrhea. The efficacy
rate drops to only 90% for pregnancies between 49 and 63 days
of amenorrhea, a value that is medically unacceptable.").
- Aubeny & Baulieu, Contragestion
With RU 486 And An Orally Active Prostaglandin, 312 C.R. Acad.
Sci. Paris (III) 539 (1991) (31%); Thong & Baird, 1992 (21%);
Peyron, et al., Early Termination Of Pregnancy With Mifepristone
(RU 486) And The Orally Active Prostaglandin Misoprostol,
328 N. Eng. J. Med. 1509 (1993) (hereafter "Peyron, et al.,
1993") (33.2% in study 1 and 25.4% in study 2); McKinley,
et al., 1993 (36.4% and 26.4% in the two groups given 200 or 600
mg RU 486); Thong, et al., What Do Women Want During Medical
Abortion?, 46 Contraception 435 (1992) (hereafter "Thong,
et al., 1992") (29%).
- Thong, et al., 1992, at
- See Thong & Baird,
1992, at 1006, reporting:
The 3% incidence of ongoing pregnancies with this regimen is slightly
higher than that reported using a combination of mifepristone
with gemeprost or sulprostone (Sylvestre et al. 1990; UK Multicentre
Trial, 1990). We have previously reported ongoing pregnancies
in two out of 21 women (up to 56 days amenorrhea) who were given
200 mg mifepristone followed by 200 ug and 400 ug of misoprostol
(Norman et al. 1991). Therefore, in a consecutive series of 121
women treated with mifepristone and misoprostol in our centre,
the ongoing pregnancy rate was 4% (95% CL 0.6-8.6%). In a consecutive
series of 470 pregnancies (<56 days) terminated with mifepristone
(50-600 mg) and gemeprost (0.5 mg-l mg) in our institution, there
has been only one ongoing pregnancy (0.2%). If the higher incidence
of ongoing pregnancies is confirmed by a larger study . . . ,
the clinical usefulness of this combination of mifepristone and
oral misoprostol for routine clinical use would be in doubt.
Two other British researchers
reported a 3% (5 patients) ongoing pregnancy rate in a series
of 150 patients receiving oral misoprostol 800 ug after 200 mg
RU 486. El-Refaey & Templeton, 1994, at 112.
- Peyron, et al., 1993.
- For data on RU 486/oral
misoprostol abortion, see Table 6 (pain reported in from 79.1
to 85% patients; analgesia needed in from 12.5 to 57.1% patients).
For data reported for RU 486 with other prostaglandins, see Table
7. See also WHO, Pregnancy Termination With Mifepristone And
Gemeprost: A Multicenter Comparison Between Repeated Doses And
A Single Dose Of Mifepristone, 56 Fertility & Sterility
32, 39 (1991) (hereafter "WHO, 1991") ("As anticipated,
mifepristone-induced uterine contractions and vaginal bleeding
were associated with lower abdominal pain, which became almost
universal after gemeprost administration."); UK Multicentre
Trial, 1990, at 484 (where 16% reported mild, moderate or severe
pain the first 24 hours after mifepristone compared to 84% who
reported pain 2 hours after gemeprost); Thong & Baird, 1992,
at 1005 (11% reported abdominal pain before misoprostol administration
and 85% 2 hours afterwards); McKinley, et al., 1993, at 1504 (53.6%
reported abdominal pain before misoprostol administration and
79.1% 2 hours afterwards).
- Zheng Shu-rong, 1989, at
22 (reporting a higher incidence of abdominal pain resulting from
uterine cramping and diarrhea in women given RU 486 plus a PG);
Thong & Baird, 1992, at 1005-06 (reporting an expected increase
in PG-related side effects 2 hrs. following administration of
misoprostol, including vomiting, pain, faintness and diarrhea);
McKinley, et al., 1993, at 1504 (reporting increases in vomiting,
pain, diarrhea and fainting 2 hrs. after taking misoprostol);
UK Multicentre Trial, 1990, at 484 (where 3% and 0.5% reported
vomiting and diarrhea during the first 4 hours after mifepristone
compared to 26% and 13% during the first 4 hours after gemeprost).
See also Sachs, A., Abortion Pills on Trial, Time, Dec.
5, 1994, at 45-46.
- See Ulmann, et al., Medical
Termination Of Early Pregnancy With Mifepristone (RU 486) Followed
By A Prostaglandin Analogue, 71 Acta Obst. Gyn. Scand. 278
(1992) (hereafter "Ulmann, et al., 1992") (reporting
3 myocardial infarctions (1 fatal) and 3 cases of severe hypotension
after sulprostone injection); Anonymous, A Death Associated
With Mifepristone/Sulprostone, 337 Lancet 969 (1991) (discussing
the same death reported in Ulmann, et al., 1992). See also Institute
of Medicine, Clinical Applications Of Mifepristone (RU 486)
And Other Antiprogestins 27 (1993) (hereafter "Institute
of Medicine, 1993") (reporting one patient death during the
first trial of RU 486 with oral misoprostol).
- WHO Task Force On Post-ovulatory
Methods Of Fertility Regulation, Termination Of Pregnancy With
Reduced Doses Of Mifepristone, 307 BMJ 532 (1993) (hereafter
"WHO Task Force, 1993") (reported significant decrease
in pulse rate during the first few hours after gemeprost (3-4
beats/min.); WHO, 1991 (reported significant (P<0.001) decrease
in pulse rate during 4-hour period after gemeprost).
- Peyron, et al., 1993, at
- Id. (researchers attributed
the hypotension to a vagal reaction secondary to painful uterine
- This list is based on expert
review of the medical literature cited in Attachment 2.
- Wilcox, et al., Hysterectomy
In The United States, 1988-1990, 83 Obst. & Gyn. 549 (1994)
(fibroid tumor was reported as the primary diagnosis for 61% of
African-American women and 29% of Caucasian women having hysterectomy);
Kjerulff, et al., Hysterectomy And Race, 82 Obst. &
Gyn. 757 (1993) (in study of more than 53,000 hysterectomies,
African-American women were more than twice as likely to have
a diagnosis of uterine fibroids as Caucasian women).
- Gohdes, et al., Diabetes
In American Indians, 16 Suppl. 1 Diabetes Care 239 (1993);
Gohdes, Diabetes In American Indians: A Growing Problem,
9 Diabetes Care 609 (1986); Freeman, et al., Diabetes In American
Indians Of Washington, Oregon, And Idaho, 12 Diabetes Care
282 (1989); Knowler, et al., Diabetes Mellitus In The Pima
Indians: Incidence, Risk Factors And Pathogenesis, 6 Diabetes/Metabolism
Reviews 1 (1990); Knowler, et al., Diabetes Incidence And Prevalence
In Pima Indians: A 19-Fold Greater Incidence Than In Rochester,
Minnesota, 108 Am. J. Epidem. 497 (1978); Gardner, et al.,
Prevalence Of Diabetes In Mexican Americans--Relationship To
Percent Of Gene Pool Derived From Native American Sources,
33 Diabetes 86 (1984); Carter, et al., Diabetes Mortality Among
New Mexico's American Indian, Hispanic, And Non-Hispanic White
Populations, 1958-1987, 16 Suppl. 1 Diabetes Care 306 (1993).
- Grimes, et al., 1990, at
913-14 (risk with a Quetelet's index [weight(kg)/height(m2)] greater
than 23.81 was 2.9 times the risk with index less than 20.25);
see also Grimes, 1993, at 172.
- See WHO Task Force, 1989,
at 722, 724 (subjects where RU 486/sulprostone failed weighed
65.7 + or - 10.2 kg; those with complete abortion, 54.7 + or -
8.3 kg; and those with incomplete abortion, 54.5 + or - 10.6 kg).
But see Thong & Baird, 1992 (complete abortion rate not influenced
by body mass index; however, the study focused on the clinical
efficacy of RU 486/misoprostol abortion in only 100 subjects,
not on predictors of failed attempted abortion).
- WHO, 1991, at 35, 38 (women
with vaginal bleeding prior to gemeprost administration had significantly
greater weight (56.1 + or - 7.5 kg) and ponderal index (2.14 +
or - 0.26) than those who started to bleed after gemeprost (53.7
+ or - 7.4 kg; 2.06 + or - 0.23).
- See discussion infra
Section 4.a.(5) and accompanying footnotes.
- One study found a higher
rate of failure in patients over the age of 34. Thonneau, et al.,
Analysis Of 369 Abortions Conducted By Mifepristone (RU 486)
Associated With Sulprostone In A French Family Planning Center,
61 Fertility & Sterility 627, 629-30 (1994) (hereafter "Thonneau,
et al., 1994") ("The patient characteristics that correlated
with failure were age over 34 years (6% <35 years versus 14%
>34 years; P=0.05) . . . .") ("We are not aware of
other studies indicating that age (>35 years) is a risk factor
for failure. However, age over 35 has been considered to be a
risk factor for morbidity. . . .").
- For data on RU 486/oral
misoprostol abortion, see Thong & Baird, 1992 (4% of users:
1 woman needed emergency curettage for heavy bleeding due to incomplete
abortion; 3 women were given intramuscular ergometrine for heavy
bleeding at the time of expulsion of products); Peyron, et al.,
1993 (0.4% of patients (2 women) in study 1 had hemorrhage requiring
hemostatic curettage, with one patient needing a blood transfusion
9 days after misoprostol when hemoglobin fell from 13.0 g/dl to
6.1 g/dl); McKinley, et al., 1993 (5.5% had a drop in hemoglobin
>2 g/dl, but no blood transfusions). For additional data on
this complication with RU 486 and other prostaglandins, see Table
- See Table 6 for pain data
on RU 486/oral misoprostol abortion. For pain data on RU 486 with
other prostaglandins, see Table 7.
- For infection data on RU
486 with prostaglandins other than misoprostol, see Table 3.
- For data on RU 486/oral
misoprostol abortion, see Peyron, et al., 1993, at 1511 (6 women
(1.2%) had a "substantial but transient decrease in blood
pressure (more than 30 mm Hg for the systolic pressure and 15
mm Hg for the diastolic pressure) attributable to a vagal reaction
secondary to painful uterine cramps."). For data on RU 486
with other prostaglandins, see Ulmann, et al., 1992 (reporting
3 myocardial infarctions (1 fatal) and 3 cases of severe hypotension
after sulprostone injection).
- FDA should consider that
complications with pharmaceutical abortion may result regardless
of whether the abortion is complete. See Birth Control Trust,
Mifepristone In Practice: Running An Early Medical Abortion
Service, 38 (1994) (hereafter "Birth Control Trust, 1994")
(an early complication rate of 14% among women who had a medical
abortion (RU 486/gemeprost) even though 94% had a complete abortion);
A World Health Organization ("WHO") study reported that
2.6% of the women with complete abortions (92.7%) required antibiotics
to prevent or cure suspected genitourinary infection during a
six week follow-up period. WHO, 1991, at 37. See also, WHO Task
Force, 1989, at 722 (1.3% of subjects w/complete abortion (88.8%
of subjects) given antibiotic therapy because of clinically suspected
- The three largest studies
only followed patients for approximately one week after PG administration.
Ulmann, et al., 1992, at 279 ("approximately one week later.
. . the final outcome of treatment was evaluated."); Aubeny,
RU 486 Combined With PG Analogs In Voluntary Termination Of
Pregnancy, 7 Adv. Contraception 339, 341 (1991) ("fourth
visit took place on day 8-12 after expulsion."); Wu, et al.,
1992, at 204 ("On the 8th day after medication, the woman
returned to the clinic for evaluation of the result . . . . If
complete abortion could not be confirmed, further follow-up on
the 14th day was required."). The remaining studies typically
follow patients until the onset of their next menstrual period
(one, two and four or six weeks after the RU 486 abortion procedure).
See, e.g., UK Multicentre Trial, 1990 and the WHO studies.
- See infra section
3.f. and accompanying footnotes for statistics on lack of patient
- Rodger, et al., Induction
Of Early Abortion With Mifepristone (RU 486) And Two Different
Doses Of Prostaglandin Pessary (Gemeprost), 39 Contraception
497, 501 (1989) (hereafter, "Rodger, et al., 1989")
("Careful follow-up is essential following treatment to exclude
the presence of a continuing pregnancy."); Peyron, et al.,
warned that "[e]ctopic pregnancy is difficult to detect very
early, and its possible occurrence makes a follow-up visit 8 to
15 days after the treatment mandatory . . . ." Peyron, et
al., 1993, at 1512; Ulmann, et al., 1992, at 283 (RU 486/PG abortion
is an "acceptable alternative to surgical procedures, provided
that . . . the protocol recommended by the manufacturer is strictly
followed."); Rodger & Baird, Induction Of Therapeutic
Abortion In Early Pregnancy With Mifepristone In Combination With
Prostaglandin Pessary, Lancet ii: 1415, 1417-1418 (1987) ("The
occurrence of incomplete abortion after medical termination of
pregnancy . . . makes careful follow-up a necessity.").
- UK Multicentre Trial, 1990.
A study by Ulmann, et al., indicates a lower, but still significant
incidence of noncompliance: (1) 0.3% of women given RU 486 were
lost to follow-up prior to PG administration; and (2) 0.8% never
received a PG even though they had not aborted. Thus, 1.1% of
women who received RU 486 as part of an RU 486/PG protocol did
not return and/or refused to take the prostaglandin analog. In
addition, 2.6% of the women in the study were lost to follow-up
after RU 486/PG administration. Ulmann, et al., 1992, at 280 (There
were other protocol violations reported in this study: 11.6% took
PG either before or after the protocol time (36-48 hr. after RU
486 intake); and 13.6% had pregnancies beyond the 7 week protocol
cut-off (i.e., more than 49 days amenorrhea calculated from the
first day of the last menstrual period). Id.
- See also Grimes, et al.,
1990 (2.5% of patients were lost to follow-up after RU 486 administration;
study did not include PG); Peyron, et al., 1993 (2.8% of the women
in study 1 did not return for follow-up after RU 486/misoprostol
administration; and 27.6% of the women in study 2 who had not
aborted within 4 hours after 400 ug of misoprostol declined to
take an additional 200 ug dose); Henshaw, et al., Comparison
Of Medical Abortion With Surgical Vacuum Aspiration: Women's Preferences
And Acceptability Of Treatment, 307 BMJ 714 (1993) (4% of
patients in a study comparing medical to surgical abortion did
not return for follow-up visit 16 days later); Hill, et al., The
Efficacy Of Oral Mifepristone (RU 38,486) With A Prostaglandin
E1 Analog Vaginal Pessary For The Termination Of Early Pregnancy:
Complications And Patient Acceptability, 162 Am. J. Obst.
Gyn. 414 (1990) (7%, 15%, and 13% of patients did not attend for
follow-up at 7, 14, and 28 days after PG administration, respectively);
Thonneau, et al., 1994, at 628-29 ("Sixteen patients (4.3%)
did not return for follow-up on day 14, and no data about either
efficacy or complications are available for these women.");
WHO Task Force, 1993, at 534 ("Two women refused the gemeprost
pessary . . . . Six other women received both mifepristone and
gemeprost and attended the follow up visit one week later, but
they defaulted from attending further follow up visits and attempts
to contact them failed."); Indian Council of Medical Research
Task Force On Hormonal Contraception, A Multicentre Clinical
Trial With RU 486 Followed By 9-Methylene-PGE2 Vaginal Gel For
Termination Of Early Pregnancy: A Dose-Finding Study, 49 Contraception
87, 91, 97 (1994) (4 patients (0.88%) did not come back for the
PG gel: 3 for "personal reasons" and 1 was lost to follow-up);
Maria & Stampf, Termination Of Early Pregnancy Using Mifepristone
In Combination With Prostaglandin Analogs, 149 Acta Obst.
Gyn. Scand. Suppl. 31 (1989) (4.9% (13 patients) were lost from
study and did not receive the follow-up exam on day 10); Swahn
& Bygdeman, Termination Of Early Pregnancy With RU 486
(Mifepristone) In Combination With A Prostaglandin Analogue (Sulprostone),
68 Acta Obst. Gyn. Scand. 293, 294 (1989) (hereafter "Swahn
& Bygdeman, 1989") (0.85% (one woman) withdrew from study
24 hours after RU 486 administration -- prior to PG administration
-- due to nausea); WHO Task Force, 1989, at 720 (0.4% (one woman)
stopped RU 486 and did not receive the PG "for personal reasons
unrelated to the treatment . . . ." And 0.4% (one) was lost
to follow-up.); Broome, Using Mifepristone In A Family Planning
Clinic, 20 Br. J. Family Planning 11 (1994) (11.2% failed
to keep follow up appointment. "This rate has become much
worse in the last few months. . . .").
- Ulmann, et al., 1992, at
280-81 (reporting that the success rate was significantly lower
(88.6% instead of 95.3%) in the absence of PG administration and
the incidence of ongoing pregnancy was higher (4.6% as opposed
to 1.2% overall).
- Id. at 281. Ulmann reported
4.2% of patients who did not receive the PG required vacuum aspiration
or D&C because of incomplete abortion (compared to 2.8% of
total patients). Also, 2.6% of the group not receiving PG required
a hemostatic surgical procedure (compared to 0.7% of total patients).
- The protocol followed in
most published studies calls for administration of an anti-D immunoglobulin
injection for Rh negative women at the time of PG administration.
See Thong, et al., Changes In The Concentration Of Alpha-Fetoprotein
And Placental Hormones Following Two Methods Of Medical Abortion
In Early Pregnancy, 100 Br. J. Obst. & Gyn. 1111 (1993);
Urquhart & Templeton, Reduced Risk Of Isoimmunisation In
Medical Abortion, 335 Lancet 914 (1990).
- Id. at 280-81. Ulmann reported
that the time lapse between RU 486 and PG intake had a significant
effect on the complete abortion rate. This rate was highest (95.8%)
at 36-48 hours, but dropped to 92.8% at less than 36 hours, and
93.9% at more than 48 hours.
- UK Multicentre Trial, 1990;
Ulmann, et al., 1992, at 283. See also Wu, et al., 1992, at 209
("It seems that the treatment regimen when followed carefully
plays an important role on the effectiveness of the method.").
- "With RU-486, Will
More Physicians Provide Abortions?," Amer. Med. News,
Apr. 12, 1993, at 3.
- There is some published
medical literature on RU 486 which medical experts assume is scientifically
valid. However, this assumption may not be warranted and therefore
FDA should not rely on the published literature without verification
of the raw data supporting the publication.
- Vessey, et al., Oral
Contraceptive Use And Abortion Before First Term Pregnancy In
Relation To Breast Cancer Risk, 45 Br. J. Cancer 327 (1982)
(this study is composed almost entirely of women who had a spontaneous
abortion, with "only a handful" of patients who had
undergone induced abortion.); Gandra, et al., Risk Factors
For Breast Cancer: A Case-Control Study, 6 Acta Medica Portuguesa
- Lindefors-Harris, et al.,
Risk Of Cancer Of The Breast After Legal Abortion During First
Trimester: A Swedish Register Study, 299 Br. Med. J. 1430
(1989) (authors achieved a borderline significant negative association
only by inexplicably excluding women aborted after age 30, and
by comparing aborted women to the general population rather than
to a bona fide control group. Since the general population
had a 20% higher nulliparity rate than the study population of
aborted women (49% versus 41%), the known protective effect of
parity could account for the apparent protective effect of abortion.).
- Several studies are published
in more than one report.
- See Dvoirin & Medvedev,
Role of women's reproductive status in the development of breast
cancer, Methods And Progress In Breast Cancer Epidemiology
Research 53 Tallinn, Estonia (1978) (hereafter "Dvoirin
& Medvedev, 1978"); La Vecchia, et al., Long-Term
Impact Of Reproductive Factors On Breast Cancer, 53 Int. J.
Cancer 215 (1993) (hereafter "La Vecchia, et al., 1993")
(This study has appeared in at least four separate reports.);
Ewertz & Duffy, Risk Of Breast Cancer In Relation To Reproductive
Factors In Denmark, 58 Br. J. Cancer 99 (1988) (hereafter
"Ewertz & Duffy, 1988"); Brinton, et al., Reproductive
Factors In The Aetiology Of Breast Cancer, 47 Br. J. Cancer
757 (1983) (hereafter "Brinton, et al., 1983"); Rosenberg,
et al., Breast Cancer In Relation To The Occurrence And Time
Of Induced And Spontaneous Abortion, 127 Am. J. Epidem. 981
(1988) (hereafter "Rosenberg, et al., 1988"); Moseson,
et al., The Influence Of Medical Conditions Associated With
Hormones On The Risk Of Breast Cancer, 22 Int. J. Epidem.
1000 (1993) (hereafter "Moseson, et al., 1993"); Daling,
et al., Risk Of Breast Cancer Among Young Women: Relationship
To Induced Abortion, 86 J. Nat'l Cancer Inst. 1584 (1994)
(hereafter "Daling, et al., 1994").
- Controls are generally
younger than the cancer patients so relative risk estimates tend
to be underestimated and confidence intervals are wider.
- This study reports relative
risks of 1.2-1.3, despite the fact that the median patient age
was 12 years greater than the median control age.
- See Adami, et al., Absence
Of Association Between Reproductive Variables And The Risk Of
Breast Cancer In Young Women In Sweden And Norway, 62 Br.
J. Cancer 122 (1990) (hereafter "Adami, et al., 1990");
Nishiyama, The Epidemiology Of Breast Cancer In Tokushima Prefecture,
38 Shikoku Med. J. 333 (1982) (hereafter "Nishiyama, 1993");
Hirohata, et al., Occurrence Of Breast Cancer In Relation To
Diet And Reproductive History: A Case-Control Study In Fukuoka,
Japan, 69 Natl. Cancer Inst. Monogr. 187 (1985) (hereafter
"Hirohata, et al., 1985"); Le, et al., "Oral Contraceptive
Use And Breast Or Cervical Cancer: Preliminary Results Of A French
Case-Control Study, Hormones And Sexual Factors In Human Cancer
Aetiology 139 (Elsevier, Amsterdam 1984) (hereafter "Le,
et al., 1984"); Andrieu, et al., Familial Risk Of Breast
Cancer And Abortion, 18 Cancer Detection & Prevention
51 (1994) (hereafter "Andrieu, et al., 1994"); Pike,
et al., Oral Contraceptive Use And Early Abortion As Risk Factors
For Breast Cancer In Young Women, 43 Br. J. Cancer 72 (1981)
(hereafter "Pike, et al., 1981"); Howe, et al., Early
Abortion And Breast Cancer Risk Among Women Under Age 40,
18 Int. J. Epidem. 300 (1989) (hereafter "Howe, et al., 1989");
Laing, et al., Breast Cancer Risk Factors In African-American
Women: The Howard University Tumor Registry Experience, 85
J. Nat'l Med. A. 931 (1993) (hereafter "Laing, et al., 1993").
- But see Parazzini, et al.,
Menstrual And Reproductive Factors And Breast Cancer In Women
With Family History Of The Disease, 51 Int. J. Cancer 677
(1992) (a large case-control study in Milan, Italy). In Italy,
over three-quarters of legal abortions occur among women who have
already had one or more children. See Figa-Talamanca, et al.,
Epidemiology Of Legal Abortion In Italy, 15 Intl. J. Epidem.
343 (1986). This means that these women are at a lower risk of
breast cancer anyway, because of the previous live birth.
- Lindefors-Harris, et al.,
Response Bias In A Case-Control Study: Analysis Utilizing Comparative
Data Concerning Legal Abortions From Two Independent Swedish Studies,
134 Am. J. Epidem. 1003 (1991); Lindefors-Harris, et al., Risk
Of Cancer Of The Breast After Legal Abortion During First Trimester:
A Swedish Register Study, 299 Br. Med. J. 1430 (1989).
- For a general discussion
of the biological changes in breast tissue during pregnancy, see
Russo, et al., Differentiation Of The Mammary Gland And Susceptibility
To Carcinogenesis, 2 Breast Cancer Res. Treat. 5 (1982) (hereafter
"Russo, et al., 1982").
- Brooks S.C. & Pauley
R.J., Breast Cancer Biology, Encyclopedia Of Human Biology
(R. Dulbecco, ed. 1991). A full-term pregnancy protects against
breast cancer by bringing breast cells into their specialized
forms. These mature cells have almost no vulnerability to cancer.
Abortion interrupts this process, leaving terminal end buds (immature
cells) suspended in high risk transitional states.
- Russo, et al., 1982.
- Rosenberg, Induced Abortion
And Breast Cancer: More Scientific Data Are Needed, 86 J.
Nat'l Cancer Inst. 1569 (1994).
- Rosenberg, et al., 1988.
- Soini, Risk Factors
Of Breast Cancer In Finland, 6 Intl. J. Epidem. 365 (1977);
Hadjimichael, et al., Abortion Before First Livebirth And Risk
Of Breast Cancer, 53 Br. J. Cancer 281 (1986).
- Lehrer, et al., An Estrogen
Receptor Polymorphism And A History Of Spontaneous Abortion --
Correlation In Women With Estrogen Receptor Positive Breast Cancer
But Not In Women With Estrogen Receptor Negative Breast Cancer
Or In Women Without Cancer, 26 Breast Cancer Res. Treat. 175
- Lentz, The Phylogeny
Of Oncology, 2 Mol. Biother. 137 (1990).
- Gatanaga, et al., Identification
Of TNF-LT Blocking Factor(s) In The Serum And Ultrafiltrates Of
Human Cancer Patients, 9 Lymphokine Res. 225 (1990a); Gatanaga,
et al., Purification And Characterization Of An Inhibitor (Soluble
Tumor Necrosis Factor Receptor) For Tumor Necrosis Factor And
Lymphotoxin Obtained From The Serum Ultrafiltrates Of Human Cancer
Patients, 87 Proc. Nat'l Acad. Sci. 8781 (1990b).
- Lentz & Saltonstahl,
Apheresis Of Low Molecular Weight Protein Fraction And The
Onset Of Labor, 5 J. Clin. Apheresis 62 (1990) (hereafter
"Lentz & Saltonstahl, 1990").
- Lentz, Continuous Whole
Blood Ultrapheresis Procedure In Patients With Metastatic Cancer,
8 J. Biol. Response Modif. 511 (1989).
- Lentz & Saltonstahl,
- Clark & Chua, Breast
Cancer And Pregnancy: The Ultimate Challenge, 1 Clin. Oncol.
- Spitz & Bardin, Clinical
Pharmacology Of RU 486 -- An Antiprogestin And Antiglucocorticoid,
48 Contraception 403 (1993) (hereafter "Spitz & Bardin,
1993"); Weiss, RU 486: The Progesterone Antagonist,
2 Arch. Fam. Med. 63 (1993).
- See, e.g., Healy, Clinical
Status Of Antiprogesterone Steroids, 3 Clin. Reprod. &
Fertility 277, 284 (1985) ("RU 486-induced blockade of the
cortisol receptor may prevent the usual glucocorticoid stress
response to anaesthesia and surgery in a patient who needs curettage
after RU 486 treatment. This might make anaesthesia complex in
- See Laue, et al., Effect
Of Chronic Treatment With The Glucocorticoid Antagonist RU 486
In Man: Toxicity, Immunological, And Hormonal Aspects, 71
J. Clin. Endocrin. & Metab. 1474 (1990) (hereafter "Laue,
et al., 1990") (in study designed to examine immune function,
blockade of cortisol receptors with RU 486 in 11 healthy males
was associated with marked compensatory elevations of plasma ACTH
and cortisol; RU 486 (10 mg/kg/day) was administered twice a day
for 7-14 days; however, one subject developed signs and symptoms
consistent with adrenal insufficiency).
- Brogden, et al., Mifepristone:
A Review Of Its Pharmacodynamic And Pharmacokinetic Properties,
And Therapeutic Potential, 45 Drugs 384, 405 (1993) (hereafter
"Brogden, et al. 1993"); Heikinheimo, Antiprogesterone
Steroid RU 486: Pharmacokinetics And Receptor Binding In Humans,
69 Acta Obstet. Gynecol. Scand. 357 (1990).
- See Grimes, et al., 1990,
at 913-14 (reporting that risk of failure of RU 486 as single-agent
abortifacient was 2.9 times greater for obese women than for women
in the lowest body mass group studied). See also infra
Section 3.d. and accompanying footnotes.
- Spitz & Bardin, 1993,
at 409; Heikinheimo, Antiprogesterone Steroid RU 486: Pharmacokinetics
And Receptor Binding In Humans, 69 Acta Obstet. Gyn. Scand.
- Lahteenmaki, et al., Pharmacokinetics
And Metabolism Of RU 486, 27 J. Steroid Biochem. 859 (1987);
see also, Heikinheimo, et al., Pharmacokinetics Of The Antiprogesterone
RU 486: No Correlation To Clinical Performance Of RU 486,
123 Acta Endocrinologica 298 (1990).
- Avrech, Mifepristone
(RU 486) Alone Or In Combination With A Prostaglandin Analogue
For Termination Of Early Pregnancy: A Review, 56 Fertility
& Sterility 385, 386 (1991).
- CDC, "Abortion Surveillance
-- United States, 1990," 42 (SS-6) Morbidity & Mortality
Weekly Report 29 (Dec. 17, 1993).
- See Birth Control Trust,
1994, at 43.
- WHO, 1991, at 35 (when
both study groups [repeated doses and single dose RU 486] were
combined, the difference between Chinese and non-Chinese subjects
was significant [Chinese women: median -- 12 days bleeding;
range -- 3 - 45 days, 95th percentile: 37.6 days, n=115; non-Chinese
women: median: 10 days bleeding; range 2 - 54 days, 95th percentile:
23.8 days, n=224; P<0.01]). But see, WHO Task Force, 1993,
at 534 (reporting no significant difference between Chinese women
and non-Chinese subjects).
- Chan, et al., 1993 (2 women
(2.08%) required emergency suction evacuation for heavy bleeding;
because of heavy bleeding, researchers concluded that "strict
supervision is mandatory" for RU 486/PG abortion).
- Id. at 93 (commenting on
a study conducted by Rodger & Baird, see Rodger & Baird,
- Id. at 93 (citing Wong,
et al., The Effect Of Oral Contraceptives On Coagulation And
Fibrinolytic Parameters In The Chinese -- A Prospective Study,
48 Thromb. Haemostas. (Stuttgart) 263 (1982).
- WHO, 1991, at 37; Spitz
& Bardin, 1993, at 411. See also WHO Task Force, 1989, at
721; Swahn & Bygdeman, 1989, at 298; Shoupe, et al., 1986,
at 457; Swahn, et al., 1989, at 24.
- Herting & Nissen, Overview
Of Misoprostol Clinical Experience, 31 Dig. Diseases &
Sci. 47S, 51S (Feb. 1986 Suppl.) (hereafter "Herting &
- Namely, glucocorticoids
reduce fluid movement from the blood to the tissues; decrease
the permeability of blood vessels. This limits leukocyte migration
to the site of tissue injury and reduces the body's ability to
fight invading bacteria. Also research suggests that glucocorticoids
affect transport of glucose, amino acids, and RNA in lymphocytes;
and down regulate gene transcription within the lymphocyte. They
also affect the intracellular ability of neutrophils to destroy
ingested microorganisms and affect protein expression in lymphoid
tissues and lymphoid function. Schulster, et al., Molecular
Endocrinology Of The Steroid Hormones 282 (1976).
- Laue, et al., 1990; Van
Voorhis, et al., The Effects Of RU 486 On Immune Function And
Steroid-Induced Immunosuppression In Vitro, 69 J. Clin. Endocrin.
& Metab. 1195 (1989) (hereafter "Van Voorhis, et al.,
1989"); Bertagna, et al., Peripheral Antiglucocorticoid
Action Of RU 486 In Man, 28 Clin. Endocrin. 537 (1988); Emilie,
et al., Inhibition Of In Vitro Immunosuppressive Effects Of
Glucocorticosteroids By A Competitive Antagonist RU-486, 8
Immunology Letters 183 (1984).
- Van Voorhis, et al., 1989.
- Redgrave, et al., An
In Vitro Comparison Of The Immunosuppressive Potential Of Synthetic
Prostaglandin Analogues, 23 Transplant. Proceed. 346 (1991)
(an in vitro study which reported that a PGE1analog enhanced
the immunosuppressant effects of cyclosporine); Moran, et al.,
Prevention Of Acute Graft Rejection By The Prostaglandin E1
Analogue Misoprostol In Renal-Transplant Recipients Treated With
Cyclosporine And Prednisone, 322 N. Eng. J. Med. 1183, 1187
(1990) (hereafter "Moran, et al., 1990") (reporting
that misoprostol acted in a synergistic manner with two known
immunosuppressant drugs -- cyclosporine and prednisone (a glucocorticoid)
in an in vivo study of kidney transplant recipients). By
itself, misoprostol has not demonstrated any adverse effects on
the immune system. See Waymack, et al., Effect Of Prostaglandin
E On Immune Function In Normal Healthy Volunteers, 175 Surg.
Gyn. & Obstet. 329 (1992); Herting & Nissen, 1986, at
51S; Moran, et al., 1990, at 1187.
- Moran, et al., 1990, at
- Herve, et al., Evidence
For Differences In The Binding Of Drugs To The Two Main Genetic
Variants Of Human Alpha 1-Acid Glycoprotein, 36 Br. J. clin.
Pharmac. 241 (1993); Bree, et al., Comparison Of Drug Binding
Capacities Of Three AAG Glycan Variants Of Human Origin, 300
Prog. Clin. Biol. Res. 405 (1989).
- See Grimes, et al., 1988,
- With RU 486 alone, from
8.3% to 46.3% of pregnancies have continued. See Table 9 for complete
statistics. After RU 486/oral misoprostol administration, from
0.45% to 9.5% of pregnancies have continued (see Table 10 for
statistics); and after medical abortion with RU 486 and other
prostaglandins, from 0.4% to 6.2% of pregnancies have continued
(see Table 11 for statistics).
- Hill, et al., Transplacental
Passage Of Mifepristone And Its Influence On Maternal And Fetal
Steroid Concentrations In The Second Trimester Of Pregnancy,
6 Hum. Reprod. 458 (1991) (hereafter "Hill, et al., 1991");
Hill, et al., The Placental Transfer Of Mifepristone (RU 486)
During The Second Trimester And Its Influence Upon Maternal And
Fetal Steroid Concentrations, 97 Br. J. Obst. Gyn. 406 (1990b)
(hereafter "Hill, et al., 1990b"); Frydman, et al.,
Transplacental Passage Of Mifepristone, ii Lancet 1252
- Raymond, et al., 1991,
- van der Schoot & Baumgarten,
Effects Of Treatment Of Male And Female Rats In Infancy With
Mifepristone On Reproductive Function In Adulthood, 90 J.
Reprod. Fert. 255 (1990).
- Jost, Animal Reproduction
-- New Data On The Hormonal Requirement Of The Pregnant Rabbit:
Partial Pregnancies And Fetal Abnormalities Resulting From A Treatment
With A Hormonal Antagonist Given At Sub-Abortive Dosage, 303
C.R. Acad. Sci. III 281 (1986); Silvestre, et al., Voluntary
Interruption Of Pregnancy With Mifepristone (RU 486) And A Prostaglandin
Analogue, 322 N. Eng. J. Med. 645 (1990) (hereafter "Silvestre,
et al., 1990") (deformities were reportedly "attributed
to uterine contractions secondary to decreased progesterone activity.").
- Wolf, et al., Tolerance
Of Perinidatory Primate Embryos To RU 486 Exposure In Vitro And
In Vivo, 41 Contraception 85 (1990) (hereafter "Wolf,
et al., 1990"); see also, Raymond, et al., 1991, at 78.
- Wolf, et al., 1990, at
- Id. Furthermore, one study
in mice found that RU 486 retarded embryonic development in
vivo and acted directly on the embryo, interfering with its
development in vitro. Yang & Wu, RU 486 Interferes
With Egg Transport And Retards The In Vivo And In Vitro Development
Of Mouse Embryos, 41 Contraception 551 (1990).
- Institute of Medicine,
1993, at 28.
- See Pons, et al., 1991
(although the researchers couldn't determine whether the abnormalities
were related to RU 486, they concluded that "a deleterious
effect of mifepristone cannot be ruled out."). For explanation
of micrognathia and hygroma see infra footnote 21.
- See Pons & Papiernik,
Mifepristone Teratogenicity, 338 Lancet 1332 (1991). In
addition, the published studies on human fetal exposure to RU
486 during the second trimester are inconclusive. Hill, et al.,
1991 found no statistically significant changes in fetal
concentrations of progesterone, oestradiol or cortisol, but a
significant increase in fetal aldosterone occurred 4 and 24 hours
after drug intake. However, researchers concluded that "[t]he
importance of the increased fetal aldosterone levels is uncertain.
In view of the small number of patients in each group this may
have occurred by chance and similarly because of the study size,
any effect of mifepristone on the other parameters studied cannot
be totally excluded." Id. at 461. See also Hill, et al.,
- Silvestre, et al., 1990;
Raymond, et al., 1991 at 89-90; Schonhofer, Brazil: Misuse
Of Misoprostol As An Abortifacient May Induce Malformations,
337 Lancet 1534 (1991); Collins & Mahoney, Hydrocephalus
And Abnormal Digits After Failed First-Trimester Prostaglandin
Abortion Attempt, 102 J. Pediatrics 620 (1983).
- Fonseca, et al., Misoprostol
And Congenital Malformations, 338 Lancet 56 (1991); Fonseca,
et al., Misoprostol Plus Mifepristone, 338 Lancet 1594
(1991) (hereafter "Fonseca, et al., 1991").
- Mobius syndrome is characterized
by congenital facial diplegia and a developmental bilateral facial
paralysis associated with oculomotor or other neurological disorders.
See Stedman's Medical Dictionary 1391 (5th ed. 1982).
- Gonzalez, et al., Limb
Deficiency With Or Without Mobius Sequence In Seven Brazilian
Children Associated With Misoprostol Use In The First Trimester
Of Pregnancy, 47 Am. J. Med. Genetics 59 (1993) (hereafter
"Gonzalez, et al., 1993").
- Many children exposed to
misoprostol in utero appear normal. Schuler, et al., obtained
information on 17 babies born to women who took misoprostol as
an abortifacient during the first trimester and did not abort.
No major malformations were found, although one child had a preauricular
tag. Schuler, et al., Teratogenicity Of Misoprostol, 339
Lancet 437 (1992). "However, . . . we cannot evaluate the
exposure risk since we do not know the drug effect in embryos
(or fetuses) that are aborted." Gonzalez, et al., 1993, at
- Fonseca, et al., 1991.
- Cekan, et al., Levels
Of The Antiprogestin RU 486 And Its Metabolites In Human Blood
And Follicular Fluid Following Oral Administration Of A Single
Dose, 4 Hum. Reprod. 131 (1989) (researchers note that "the
morphological appearance and cleavage rate of the oocytes fertilized
in vitro were not affected by the treatment with RU 486").
However, the fertilized eggs were only developed to the four-
to eight-cell stage. And "the developmental capacity of the
oocytes after fertilization in vitro could not be fully
determined, since the cleaving embryos were not replaced in a
recipient uterus." See Raymond, et al., 1991, at 75 (citing
Messinis & Templeton, The Effect Of The Antiprogestin Mifepristone
(RU 486) On Maturation And In-Vitro Fertilization Of Human Oocytes,
95 Br. J. Obst. & Gyn. 592 (1988) (hereafter "Messinis
& Templeton, 1988"). Interestingly, the women who received
RU 486 had fewer eggs which fertilized in vitro as compared
to the controls, although the difference was not statistically
significant. Messinis & Templeton, 1988, at 593.
- Spitz & Bardin, 1993,
at 417; Grimes, 1993, at 173.
- Wiedemann, et al., in a
limited study, examined the role of glucocorticoids in sleep and
demonstrated that RU 486 as a glucocorticoid receptor blocker
disrupts sleep patterns. See Wiedemann, et al., Antiglucocorticoid
Treatment Disrupts Endocrine Cycle And Nocturnal Sleep Pattern,
241 Eur. Arch. Psych. Clin. Neurosci. 372 (1992).
- Hill, et al., 1991 reported
"a trend to higher . . . fetal cortisol concentrations 24
and 48 h after treatment, [however,] this increase failed to reach
statistical significance. . . ." Id. at 460-61.
- See additional discussion
infra Section 6.
- See Table 4.
- Rodger & Baird, 1989,
at 445 ("It is likely that as pregnancy advances and the
fetus and placenta increases in size, there is a larger vascular
area from which bleeding can occur.").
- According to D. Danforth
& J. Scott, there are several methods used to determine gestational
age. Because of the unreliability of alternative methods, sonography
is recommended as a standard abortion practice for assessing gestational
age. Alternative methods include: (1) patient's menstrual history
(least reliable method -- predictive only to within a margin of
3 weeks with 90% confidence, even if date of last menstrual period
is known with certainty); (2) pelvic examination (inaccurate to
plus/minus 2 weeks; with retroverted uterus (30% of women) inaccuracy
reaches plus/minus 4 weeks); (3) maternal perception of fetal
movement (only useful as "rough estimate"); and (4)
measurement of fundal height (useful only to corroborate other
clinical estimations of gestational age). Danforth & Scott,
Obstetrics & Gynecology 263, 365-66 (5th ed. 1986);
Hern, Abortion Practice 69-70, 109, 207 (1984) (sonography "appears
to be considerably more accurate than are menstrual dates and
even a careful examination by an experienced physician."
Any doubt concerning length of gestation should be checked by
real-time ultrasound examination.).
- Rodger, et al., 1989, at
501 ("It is important that an intrauterine pregnancy be established
prior to treatment as mifepristone seems ineffective in the disruption
of ectopic pregnancy."); Weiss, RU 486: The Progesterone
Antagonist, 2 Arch. Fam. Med. 63, 66 (1993); Levin, et al.,
Mifepristone (RU 486) Failure In An Ovarian Heterotopic Pregnancy,
163 Am. J. Obst. Gyn. 543 (1990); Baulieu, Contragestion And
Other Clinical Applications Of RU 486, An Antiprogesterone At
The Receptor, 245 Science 1351 (1989).
- WHO Task Force, 1993 (1
patient in the study had undiagnosed tubal pregnancy which ruptured
2 weeks after an RU 486/PG abortion).
- Petitioners are unaware
of any studies demonstrating safety and/or effectiveness of RU
486 in the pediatric population.
- UK Multicentre Trial, 1990,
at 485 ("the procedure needs to be clinic based, and preferably
hospital based, in view of the small but definitive risk of severe
hemorrhage."); Roger, et al., 1989, at 501 ("Hospital
admission . . . for four hours following prostaglandin administration
is advisable."); Wu, et al., 1992, at 209 ("It should
be emphasized that RU 486 in combination with PG be used only
in clinics where emergency facilities are available."); Brogden,
et al., 1993, at 404 ("Mifepristone should be administered
in an environment where suitably experienced medical personnel
and resuscitation equipment are immediately available.");
Thonneau, et al., 1994, at 627 ("the risk of maternal morbidity
associated with sulprostone and also the risk of fetal malformations
in cases of continued pregnancy indicate that this method should
only be used in specialist centers."). See also footnote
- See Testimony Before
the Subcomm. on Regulation, Business Opportunities, and Technology
of the House Comm. on Small Business, 103d Cong., 2d Sess.
(May 16, 1994). Petitioners also urge FDA to compare the misuse
of misoprostol as an abortifacient in Brazil where its distribution
is not carefully regulated with the carefully controlled distribution
of RU 486 in France. See Costa & Vessey, Misoprostol And
Illegal Abortion In Rio de Janeiro, Brazil, 341 Lancet 1258
(1993); Coelho, et al., Misoprostol And Illegal Abortion In
Fortaleza, Brazil, 341 Lancet 1261 (1993).