FERTILITY AND STERILITY
6, June 1982
Copyright ~ 1982 The American Fertility Society
Possible interactions of antihistamines and antibiotics with oral
contraceptive effectiveness
Edward A. DeSano, Jr., M.D.*
Stephen C. Hurley, Pharm. D.
Bannock Memorial Hospital, Pocatello, Idaho
During a 2-year period 16 patients became
pregnant while taking an oral contraceptive (OC)
in conjunction with an antimicrobial and/or a
"cold tablet." The incidence of such "product fail-
ures" exceeds what would normally be expected.
The first clinical report of an adverse drug
interaction affecting OCs was in 1971 when Rei-
mers and Jezek reported that rifampin seemed to
cause a high incidence ofbreakthrough bleeding. 1
Later reports covering the period from 1973 to
1977 implicated rifampin as the cause of 17 preg-
nancies in women taking OCs. 2
In a brief letter, Dossetor clainied that three
patients on birth control pills became pregnant
when given ampicillin. 3 Hempel et al. 4 attributed
OC failure in two patients to a sulfonamide and
chloramphenicol. The most recently reported case
involved tetracycline. Nonantimicrobial drugs
such. as phenobarbital, phenytoin, primidone,
meprobamate, chlordiazepoxide, phenacetin, and
dihydroergotamine may have caused OC failure
followed by pregnancy.
MATERIALS AND METHODS
Between July 1978 and July 1980, 16 patients
who had become pregnant while on OCs in the
primary author's (E. D.) private obstetrics and
gynecology practice were asked whether they had
omitted· any of their birth control pills. If they
claimed to have been totally compliant with OC
therapy, they were asked if they had consumed
any other medications during the cycle when con-
ception took place.
Received December 8, 1981; revised and accepted February
18, 1982.
*Reprint requests: Edward A. DeSano, Jr., M.D., 1777 E.
Clark, Suite 220, Pocatello, Idaho 83201.
Vol. 37, No. 6, June 1982
Vol. 37, No.
Printed in U.S A.
RESULTS
Sixteen patients were found to have consumed
other medications during the time of conception.
They were certain they had not missed any of
their OCs. Fifteen admitted to using anti-
microbials and/or "cold tablets" during the sus-
pected time of conception, and one patient ha?
taken 1 gm of ascorbic acid along with multi-
vitamins. Indications for these antimicrobials
were primarily upper respiratory and urinary
tract infections.
Table 1 lists all medications taken by each pa-
tient and is organized to show the estrogen/
progestogen balance of each OC. Patients 1
through 7 were on products containing less than
50 f.lg estrogen, patients 8 through 13 were on prod-
ucts containing 50 f.lg estrogen, and patients 14
through 16 were on products containing more than
50 f.lg estrogen.
DISCUSSION
To date, the evidence for OC interactions has
been retrospective case analysis. A recent pro-
spective study failed to show any effect of am-
picillin in 14 patients taking 50 f.lg of ethinyl es-
tradiol and 1 mg of ethynodiol diacetate (Dem-
ulen, San Juan, Puerto Rico). Demulen continued
to exert its full suppression of luteinizing hor-
mone, follicle-stimulating hormone, estradiol,
and progesterone despite 1 gm of ampicillin per
day for 16 days. In addition, there was no differ-
ence between the effects of ampicillin and placebo
on testosterone-binding globulin, basal body tem-
peratures, or cervical mucus ferning patterns.
This study of 14 patients was well designed but
rather small. One patient on ampicillin did have
a brief midcycle rise in estradiol, indicating in-
• • 5
complete ovarian suppressiOn.
DeSano and Hurley Communications-in-brief 853
Table 1. Oral Contraceptive Drug Interactions
Patient Oral contraceptive Other medication
1 Ethinyl estradiol 30 JLg Penicillin, plus a "cold tablet" acetaminophen, doxylamine, ephedrine
Norgestryl 0.3 mg
2 Ethinyl estradiol 30 JLg Ascorbic acid 1 gm a day and multivitamins
Norgestryl 0.3 mg
3 Ethinyl estradiol 30 JLg Tetracycline 250 mg four times a day for a "cold"
Norethindrone 1.5 mg
4 Ethinyl estradiol 30 JLg Penicillin, caffeine, chlorpheniramine, aspirin, phenylephrine for a "cold"
Norethindrone 1.5 mg
5 Mestranol 35 JLg Sulfonamide for a urinary tract infection
Norethindrone 0.5 mg
6 Mestranol 35 JLg Sulfisoxazole for cystitis
Norethindrone 0.5 mg
7 Mestranol 35 JLg Cephalexin
Norethindrone 0.5 mg
8 Ethinyl estradiol 50 fLg Ampicillin plus a "cold tablet" for a "cold"
Norethindrone acetate 1 mg
9 Ethinyl estradiol 50 JLg Ampicillin 250 mg four times a day for a "cold"
Norethindrone 1 mg
10 Ethinyl estradiol 50 fLg Penicillin for a sore throat
Norethindrone 1 mg
11 Ethinyl estradiol 50 JLg Antihistamines for "hay fever"
Norethindrone 1 mg
12 Ethinyl estradiol 50 JLg Ampicillin for an abscessed tooth and a "cold tablet"
Norethindrone 1 mg
13 Ethinyl estradiol 50 JLg Ampicillin and a "cold tablet" for a "cold"
Ethynodiol diacetate 1 mg
14 Ethinyl estradiol 80 fLg Ampicillin and chlorpheniramine
Norethindrone 1 mg
15 Ethinyl estradiol 80 JLg Sulfisoxazole and "allergy tablet"
Norethindrone 1 mg
16 Ethinyl estradiol 80 JLg Clorazepate and a "cold tablet"
Norethindrone 1 mg

Medications could possibly interfere with the
action of OCs by (1) displacing them from their
biologic receptor site, (2) stimulating their he-
patic degradation, (3) increasing their urinary
excretion, (4) opposing their action through some
physiologic effect, (5) increasing their serum pro-
tein binding, or (6) reducing the amount of steroid
absorbed or reabsorbed from the gut. In the rat
antimicrobials interfere with the enterohepatic
reabsorption of synthetic estrogens and progesto-
gens, and in pregnant women antimicrobials
interfere with the enterohepatic reabsorption of
estriol. 6 If antihistamines, decongestants, and
analgesics interact with OCs, the most likely
mechanism would be the stimulation of their
hepatic degradation. It is hard to imagine how
small doses of multivitamins could interact with
OCs; however, large doses of ascorbic acid may
affect fertility by changing the viscosity of the
cervical mucus. 7
There are many questions that remain unan-
swered. It appears that OC interactions do not
predictably occur and may depend on other con-
founding factors such as concurrent health prob-
lems, including infection, and the woman's per-
sonal physiologic estrogen/progesterone.
REFERENCES
1. Reimers D, Jezek A: The simultaneous use ofrefampicin
and other antituberculous agents with oral contracep-
tives. Prax Klin Pneumol 25:255, 1971
2. Breckenridge AM, Back DJ, Orme M: Interactions be-
tween OCs and other drugs. Pharmacol Ther 7:617, 1979
3. Dossetor EJ: Drug interaction with OCs. Br Med J 4:467,
1975
4. Hempel E, Bohm W, Carol W, Klinger G: Medikamentose
enzyminduktion und hormonale kontrazeption. Zentralbl
Gynaekol 95:1451, 1973
5. Friedman CI, Huneke AL, Moon HK, Powell J: The effect
of ampicillin on OC effectiveness. Obstet Gynecol 55:33,
1980
6. Roberton YR, Johnson ES: Interactions between oral con-
traceptives and other drugs. Curr Med Res Opin 3:647,
1976
7. Briggs M: Vitamin C and infertility. Lancet 2:677, 1973

854 DeSano and Hurley Communications-in-brief Fertility and Sterility

FERTIUTY AND STERIIJTY
Copyright c 1982 The American Fertility Society
Male Fertility Potential
To the Editor:
MacLeod and Wang's response 1 to Sloan's
letter2 about male fertility potential is not en-
tirely satisfactory. They seem not to appreciate
that if either of his suggestions were correct, then
their observation (that there has been no long-
term trend in sperm counts in the male partners
in infertile matings) is nevertheless compatible
with a decline in male fertility potential in the
population. So it would be interesting to see Mac-
Leod's data on sperm counts from fertile men over
the last 30 years.
In any case, regardless of the situation in New
York, there can be no reasonable doubt that re-
ported sperm counts have declined in some places
elsewhere in recent years. This is shown by cross-
sectional data surveyed from publications from
different laboratories at different times 3 and by
longitudinal data from a single laboratory. 4
Bearing in mind the evidence of a long-term
decline in testosterone levels in the United
States, 5 there are very powerful grounds for sus-
pecting a substantial decline in male fertility po-
tential in recent years, at least in some places.
William H. James, Ph.D.
MRC Mammalian Development Unit
Wolfson House
(University College, London)
4 Stephenson Way, London NW1 2HE
England
April6, 1982
REFERENCES
1. MacLeod J, Wang Y: Response to Mr. Sloan's Letter to the
Editor. Fertil Steril 37:126, 1982
2. Sloan DG: Letter to the Editor. Fertil Steril 37:126, 1982
3. James WH: Secular trend in reported sperm counts. An-
drologia 12:381, 1980
4. Leto S, Frensilli FJ: Changing parameters of donor se-
men. Fertil Steril 36:766, 1981
5. Dai WS, Kuller LH, Laporte RE, Gutai JP, Falvo-Gerard
L, Caggiula A: The epidemiology of plasma testosterone
levels in middle aged men. Am J Epidemiol114:804, 1981
Vol. 37, No.6, June 1982
Vol. 37, No.6, June 1982
Printed in U.SA.
Bar Graphs
To the Editor:
I would like to draw attention to Figure 3 in the
article by Bates et al. 1 Figure 3 is a bar graph
giving ideal body weight prior to conception and
at conception. The bar graph contains slashes in-
dicating an interruption of the ordinates. This
type of "Time Magazine" bar graph is misleading,
because it invites comparison of the relative size
of the bars. When the intervening values are
omitted, this is quite misleading.
William H. Pfeffer, M.D.
Head, Division of Reproductive
Endocrinology
Department of Gynecology and Obstetrics
Henry Ford Hospital
Detroit, Michigan 48202
April12, 1982
REFERENCE
1. Bates GW, Bates SR, Whitworth NS: Reproductive failure
in women who practice weight control. Fertil Steril 37:
373, 1982
Liquefaction of Viscous Semen
To the Editor:
A recent paper1 presented data on the effect of
various mucolytic agents on viscid semen and
concluded that sputolysin was the most efficient
for liquefying semen and preserving sperm mo-
tility. However, the content (dithiothreitol) of this
agent may proscribe its use for clinical purposes
such as artificial insemination. I would like to
point out that a human enzyme (plasmin) is also
effective in liquefying viscid semen and main-
taining sperm motility for up to 6 hours at 37° C
(Clarke et al.: Effect of plasmin on viscous semen.
Presented at 2nd International Congress of An-
drology, 1981, Tel Aviv, Israel. Abstract to be
published in the Israel Journal of Medical Sci-
Letters to the editor 855
ences, 1982). Plasmin (hepatitis-screened) may be
a safer alternative for treating semen for the pur-
poses of artificial insemination. We have not yet
proceeded to clinical usage of plasmin, but con-
trolled clinical trials would seem to be warranted.
G. N. Clarke, B.Sc.(Hons), M.Sc.
Pathology Department
Royal Women's Hospital
Carlton, 3053, Australia
REFERENCE
1. ~padhyaya M, Hibbard BM, Walker SM: Use ofsputoly-
sm for liquefaction of viscid human semen. Fertil Steril
35:657' 1981
856 Letters to the editor
Reply of the Author:
We are in agreement with the findings of Dr.
Clarke that the presence of sulphur radical in
dithiothreitol (sputolysin) may prohibit its use in
vivo.
The presence of viscid seminal plasma makes
the evaluation of sperm concentration and mo-
tility difficult. Sputolysin was ·found to be most
efficient for the above investigations in the labo-
ratory. However, plasmin (hepatitis-screened),
may be safer for clinical applications.
Meena Upadhyaya, B.Sc.(Hons),
M.Sc., Research Officer
Department of Obstetrics and Gynecology
Welsh National School of Medicine
Heath Park, Cardiff CF4 4XN, Wales
March 5, 1982
Fertility and Sterility