CONTRACEPTION
A RANDOMIZED
DOUBLE BLIND
STUDY
OF TWO ORAL CONTRACEPTIVES
Herr&
Regional Western
2.
Associate,
3.
Project Director, Columbia, Maryland.
4.
Former Western
5.
Advisor, San Jo&,
6.
Former Medical Port-of-Spain,
Accepted
JULY
Director, Hemisphere The
Sivin
Sushi I
Kumar Kessler
Armando
Carrasco,
Yee,
’
3
Marjorie
4 M.D.5
6
M.D.
International Planned Parenthood Region, New York, New York.
Population
Council,
Westinghouse
Research Assistant, Hemisphere Region, Family Costa
M.D.
2
Irving
Joyce
1.
Sanhueza,
Planning Rica. Director, Trinidad.
for publication
1979 VOL. 20 NO. 1
New York,
Electric
New York.
Corporation,
lnternat ional Planned New York, New York. Program,
Family
June
Costa
Federation/
Rican
Planning
Health
Parenthood
Social
Association,
Security
Trinidad
Systems,
Federation/
Institute,
& Tobago,
6, 1979
29
CONTRACEPTION
ABSTRACT
To study the question of whether one brand of oral contraceptives may be as acceptable as another for use in publiclyassisted family planning programs, a double blind study of two well-known brands, Ovral and Norinyl, was undertaken in Costa Rica and Trinidad. The pills were randomly assigned to 1,200 women. Common side effects - nausea, dizziness, vomiting, headaches Differences in event were associated with both Norinyl and Ovral. rates for these conditions were much more marked by country than by the pill used. Ovral was associated with increases in A higher percentage skin problems, notably chloasma, in Costa Rica. of women using Norinyl reported intermenstrual bleeding and spotting in both countries. In Costa Rica continuation rates for Norinyl were adversely affected by this. With these exceptions there appear to be no important differences between the brands that would affect their use in family planning programs.
30
JULY
1979 VOL. 20 NO. 1
CONTRACEPTION
INTRODUCTION
Publicly recipients of
assisted specific
or funded brands of
family pills,
planning clinics IUDs, condoms or
often other
are
contraceptive methods which represent the choice or requirements of a central health agency or a foreign donor agency, but are not Within the Western Hemisphere the choices of the clinic directors. Region (WHR) of the International Planned Parenthood Federation (IPPF), the exigencies of the supply system led to the use of a single brand of pill in several countries of the region, in place of the Clinic medical directors in some previously locally used brands. countries reported increased side effects attendant upon the use Concerned about widespread complaints, of the newly-supplied brand. yet uncertain that the reported side effects of the new brand differed from the old in frequency or intensity or in effect on continuation rates, IPPF/WHR decided to undertake a rigorous double blind study of the newly-supplied brand and of one which had been widely supplied. Two (2) IPPF affiliates in the region agreed to participate in the study of the brands, the results of which are presented below.
MATERIALS
AND METHODS
Between March, 1976, and April, 1977, 1,197 out of a planned 1200 women enrolled at four IPPF-associated clinics in Trinidad and at Enrollment was equally four clinics in Costa Rica. divided between the two countries. Women participating in the study had to be between the ages of and 39, not currently pregnant nor breast-feeding, and had to have had at least menses subsequent to termination of their one last pregnancy. Use of oral contraceptives in the three months preceding screening for the study was a contraindication to acceptance, Excluded from the as was previous use of injectables. study were women with a history of and/or clinical evidence of cardiovascular disease and other standard contraindications.
18
Women agreeing to participate and having no contraindications were assigned at random to the use of Norinyl 1+50 or of Ovral. Norinyl 1+50 contains 0.05 mg of mestranol, the estrogen, and Ovral contains 1 mg of norethindrone, the progestational agent. the estrogen, and 0.5 mg of 0.05 mg of ethinyl estradiol, norgestrel, the progest in. Materials were supplied by the manufacturers. Tablets for each compound were manufactured to be
JULY
1979 VOL. 20 NO. 1
31
CONTRACEPTION identical also free identical contents letters and the
in shape and color. from indications of
The containers brand name, and
carrying the pills were also made
were
for the two types of pill. ldent if icat ion of the of individual packets was made by central assignment of the “A” and “B” to Norinyl and Ovral, respectively, in Trinidad, letters “C” and “D” to Norinyl and Ovral in Costa Rica.
The clinical staff did not know which particular contained in the variously lettered packets; to 597 women and Ovral to 600. Prior to entry, women agreed to return examinations at months 1, 3, 6, 9 and 12. drug was to be discontinued.
formulation was Nor inyl was assigned
for After
During the course of each follow-up visit,a symptoms commonly associated with the use of The initial and final visits included was made. and a standard gynecological examination. and
supplies and one year, the
study
recording of signs oral contraceptives a general physical
Analysis of the clinical and socio-demographic data is by The life table first -- t, z, F, and X2 tests. standard techniques as amended by segment2rates use the actuarial method of estimation’ Tietze, for oral contraception, and by Jain and Sivin.3 Of particular importance is the treatment of those women lost to Tietze’s recommendation for pill use is that the women follow-up. lost carry after
to follow-up be considered as having terminated this recommendation forward to include those intial enrollment.
use. who are
We never
seen
Statistical analysis of multiple decrement life table rates fol lows the procedures4recommended by Potter. The “log-rank” method was adapted by R. Taylor of the International as used by Azen s & Fertility Research Program to monthly ratherthan daily computations, was used for significance tests for single decrement life table rates. Estimates of characteristics and of life table rates have been made by treating the two countries as strata with equal weights rather than regarding the sample as a simple random sample from a larger universe. The cut-off date for this study was 1 January, 1978.
CHARACTERISTICS
and
OF ACCEPTORS
two study sites differ substantially in their heritages, The Virtually all the and social characteristics. ethnic compositions, study subjects in Costa Rica were white (Table I), whereas in Trinidad 71.6 percent were black and 9.2 percent were of mixed ethnic Women of East Indian origin accounted for 17.7 percent of the origin.
32
JULY
1979 VOL. 20 NO. 1
CONTRACEPTION
enrolled
group
in
Trinidad.
had never been married, married in Trinidad.
In
Costa
which contrasts Ovral was assigned
Rica,
22
percent
of
with the 62 percent to a significantly
the
women
never higher
proportion of never married women (PC.05) and to a significantly lower proportion of currently married women than was Norinyl. This difference may have been an artifact of the way in which some women reported marital status. There was no significant difference between drugs in the proportion ever pregnant. The average age of the acceptors was 22.9 in Trinidad similar, 23.6, in Costa Rica. There was no difference in age of the women using the two varieties of pill.
and was the mean
Educational attainment of the acceptors in Trinidad was somewhat higher than in Costa Rica (years). Forty-five percent of the Trinidadian women had completed eleven or more years of schooling as compared to 12 percent of the Costa Rican acceptors. A very large majority cigarettes at all (Table 80 percent reported they
of the participants did not smoke I), and among women who did smoke, more had fewer than five cigarettes per day.
than
Past experiences with contraception, and especially with the pill, was notably different in the two countries, reflecting the differences in percentages in current martial status and never having been pregnant. Three-fifths of the participants in Costa Rica and five-sixths of the women in Trinidad had never previously used the pill.
JULY
1979 VOL. 20 NO. 1
33
CONTRACEPTION TABLE
CHARACTERISTICS
CHARACTERISTIC
Trinidad
% White
1.3
b. % Black
71.6
a.
BY COUNTRY
Costa
AND
R.
BY DRUG
Norinyl
Ovral
50.0
50.2
1.5
37.0
35.7
98.5
C.
% Never
Married
62.3
22.1
38.9
45.3*
d.
% Never
Pregnant
30.5
10.4
18.3
22.5
1.1
1.5
1.3
1.3
22.9
23.7
23.4
23.2
8.4
6.4
7.6
7.3
93.2
78.6
85.6
86.1
53.1
53.0
52.9
53.3
84.0
59.9
72.0
71.8
597
600
597
600
e. Mean No. of Living Children f. Mean
Age
g. Mean No. Schooling
Years of Completed
h. % Do Not
Smoke
i. Mean J.
Weight
% Never
Used
No. of Women
34
OF ACCEPTORS
I
(Kg) Pill
JULY 1979VOL.20NO.l
CONTRACEPTION RESULTS
Four results are reported. First we report types of the verbal statements of the acceptors concerning common side This is followed by results of effects of oral contraceptives. Next are descriptions by physical examinations and measurements. the acceptors of their menstrual patterns since beginning the study. Fourth are the termination and continuation rates. There were some differences between drugs in the participants’ reports of the occurrence of moderate or severe nausea, vomiting, dizziness and headache, but differences between drugs were not significant for any of these four commonly recorded effects associated with the use of orals (Table II). Women using Ovral in Costa Rica reported acne and chloasma in significantly greater numbers than did women using Norinyl. Participants in the Trinidad study were virtually free of such complaints (Tables I II and IV). Physical examinations conducted at termination substantiated these different ial reports, particularly Ovral affected significantly for chloasma among Costa Rican women. more users both with regard to chloasma, and with regard to all skin conditions, than did Norinyl (Table V). Physical examination also revealed a moderate excess of cervicitis and cervical erosion among Ovral users in Trinidad, In Costa Rica, although the differences were not significant. cervical erosion was noted in 13 percent of the users of either drug white cervicitis was noted in three percent of each group (Table VI). Average blood pressure readings rose somewhat in both countries and for both drugs. The percentages of women with high readings showed an upward but not a significant rise (Table VI I). Both brands of orals reduced the average number of days of menstrual bleeding in the two countries, and both pills effected a reduction in the percentage of women reporting relatively heavy menstrual flow (Table VIII). On the other hand, intermenstrual spotting or bleeding was strongly associated with use of Norinyl. In both countries the percentage of women using Norinyl who reported intermenstrual bleeding events was at least twice that of the Ovral users. The differences in the percentages were highly significant (Table IX).
JULY
1979 VOL. 20 NO. 1
35
CONTRACEPTION
TABLE
PERCENTAGE
OF WOMEN
MODERATE
OR SEVERE
WHILE
CONDITION
Vomiting
Headache
Dizziness
N
Ovral 12.2
16.8
TOTAL
12.2
14.5
1.7
2.4
Rica
4.7
5.4
TOTAL
3.2
3.9
9.5
5.4
Rica
24.1
26.5
TOTAL
16.8
16.0
6.1
2.0
Rica
14.6
15.0
TOTAL
10.4
8.5
567
573
Trinidad Costa
Nor inyl
16.8
Trinidad Costa
REGIMEN
Rica
Trinidad Costa
REPORTING CONDITIONS
7.5
Trinidad Costa
36
USING
Country
Nausea
II
JULY
1979 VOL. 20 NO. 1
CONTRACEPTION
TABLE
PERCENTAGE
OF WOMEN
III
REPORTING
INCREASED ACNE
Norinyl
Ovral
Trinidad
0.0
0.0
Costa Rica
5.5
TOTAL
2.7
5.2"
567
573
N
10.4':
TABLE
PERCENTAGE
OF WOMEN
IV
REPORTING
CHLOASMA
Norinyl
Ovral
Trinidad
0.7
1.0
Costa Rica
4.4
12.5+::
TOTAL
2.5
6.8%:
567
573
N
"P < .05 **p
A RANDOMIZED
DOUBLE BLIND
STUDY
OF TWO ORAL CONTRACEPTIVES
Herr&
Regional Western
2.
Associate,
3.
Project Director, Columbia, Maryland.
4.
Former Western
5.
Advisor, San Jo&,
6.
Former Medical Port-of-Spain,
Accepted
JULY
Director, Hemisphere The
Sivin
Sushi I
Kumar Kessler
Armando
Carrasco,
Yee,
’
3
Marjorie
4 M.D.5
6
M.D.
International Planned Parenthood Region, New York, New York.
Population
Council,
Westinghouse
Research Assistant, Hemisphere Region, Family Costa
M.D.
2
Irving
Joyce
1.
Sanhueza,
Planning Rica. Director, Trinidad.
for publication
1979 VOL. 20 NO. 1
New York,
Electric
New York.
Corporation,
lnternat ional Planned New York, New York. Program,
Family
June
Costa
Federation/
Rican
Planning
Health
Parenthood
Social
Association,
Security
Trinidad
Systems,
Federation/
Institute,
& Tobago,
6, 1979
29
CONTRACEPTION
ABSTRACT
To study the question of whether one brand of oral contraceptives may be as acceptable as another for use in publiclyassisted family planning programs, a double blind study of two well-known brands, Ovral and Norinyl, was undertaken in Costa Rica and Trinidad. The pills were randomly assigned to 1,200 women. Common side effects - nausea, dizziness, vomiting, headaches Differences in event were associated with both Norinyl and Ovral. rates for these conditions were much more marked by country than by the pill used. Ovral was associated with increases in A higher percentage skin problems, notably chloasma, in Costa Rica. of women using Norinyl reported intermenstrual bleeding and spotting in both countries. In Costa Rica continuation rates for Norinyl were adversely affected by this. With these exceptions there appear to be no important differences between the brands that would affect their use in family planning programs.
30
JULY
1979 VOL. 20 NO. 1
CONTRACEPTION
INTRODUCTION
Publicly recipients of
assisted specific
or funded brands of
family pills,
planning clinics IUDs, condoms or
often other
are
contraceptive methods which represent the choice or requirements of a central health agency or a foreign donor agency, but are not Within the Western Hemisphere the choices of the clinic directors. Region (WHR) of the International Planned Parenthood Federation (IPPF), the exigencies of the supply system led to the use of a single brand of pill in several countries of the region, in place of the Clinic medical directors in some previously locally used brands. countries reported increased side effects attendant upon the use Concerned about widespread complaints, of the newly-supplied brand. yet uncertain that the reported side effects of the new brand differed from the old in frequency or intensity or in effect on continuation rates, IPPF/WHR decided to undertake a rigorous double blind study of the newly-supplied brand and of one which had been widely supplied. Two (2) IPPF affiliates in the region agreed to participate in the study of the brands, the results of which are presented below.
MATERIALS
AND METHODS
Between March, 1976, and April, 1977, 1,197 out of a planned 1200 women enrolled at four IPPF-associated clinics in Trinidad and at Enrollment was equally four clinics in Costa Rica. divided between the two countries. Women participating in the study had to be between the ages of and 39, not currently pregnant nor breast-feeding, and had to have had at least menses subsequent to termination of their one last pregnancy. Use of oral contraceptives in the three months preceding screening for the study was a contraindication to acceptance, Excluded from the as was previous use of injectables. study were women with a history of and/or clinical evidence of cardiovascular disease and other standard contraindications.
18
Women agreeing to participate and having no contraindications were assigned at random to the use of Norinyl 1+50 or of Ovral. Norinyl 1+50 contains 0.05 mg of mestranol, the estrogen, and Ovral contains 1 mg of norethindrone, the progestational agent. the estrogen, and 0.5 mg of 0.05 mg of ethinyl estradiol, norgestrel, the progest in. Materials were supplied by the manufacturers. Tablets for each compound were manufactured to be
JULY
1979 VOL. 20 NO. 1
31
CONTRACEPTION identical also free identical contents letters and the
in shape and color. from indications of
The containers brand name, and
carrying the pills were also made
were
for the two types of pill. ldent if icat ion of the of individual packets was made by central assignment of the “A” and “B” to Norinyl and Ovral, respectively, in Trinidad, letters “C” and “D” to Norinyl and Ovral in Costa Rica.
The clinical staff did not know which particular contained in the variously lettered packets; to 597 women and Ovral to 600. Prior to entry, women agreed to return examinations at months 1, 3, 6, 9 and 12. drug was to be discontinued.
formulation was Nor inyl was assigned
for After
During the course of each follow-up visit,a symptoms commonly associated with the use of The initial and final visits included was made. and a standard gynecological examination. and
supplies and one year, the
study
recording of signs oral contraceptives a general physical
Analysis of the clinical and socio-demographic data is by The life table first -- t, z, F, and X2 tests. standard techniques as amended by segment2rates use the actuarial method of estimation’ Tietze, for oral contraception, and by Jain and Sivin.3 Of particular importance is the treatment of those women lost to Tietze’s recommendation for pill use is that the women follow-up. lost carry after
to follow-up be considered as having terminated this recommendation forward to include those intial enrollment.
use. who are
We never
seen
Statistical analysis of multiple decrement life table rates fol lows the procedures4recommended by Potter. The “log-rank” method was adapted by R. Taylor of the International as used by Azen s & Fertility Research Program to monthly ratherthan daily computations, was used for significance tests for single decrement life table rates. Estimates of characteristics and of life table rates have been made by treating the two countries as strata with equal weights rather than regarding the sample as a simple random sample from a larger universe. The cut-off date for this study was 1 January, 1978.
CHARACTERISTICS
and
OF ACCEPTORS
two study sites differ substantially in their heritages, The Virtually all the and social characteristics. ethnic compositions, study subjects in Costa Rica were white (Table I), whereas in Trinidad 71.6 percent were black and 9.2 percent were of mixed ethnic Women of East Indian origin accounted for 17.7 percent of the origin.
32
JULY
1979 VOL. 20 NO. 1
CONTRACEPTION
enrolled
group
in
Trinidad.
had never been married, married in Trinidad.
In
Costa
which contrasts Ovral was assigned
Rica,
22
percent
of
with the 62 percent to a significantly
the
women
never higher
proportion of never married women (PC.05) and to a significantly lower proportion of currently married women than was Norinyl. This difference may have been an artifact of the way in which some women reported marital status. There was no significant difference between drugs in the proportion ever pregnant. The average age of the acceptors was 22.9 in Trinidad similar, 23.6, in Costa Rica. There was no difference in age of the women using the two varieties of pill.
and was the mean
Educational attainment of the acceptors in Trinidad was somewhat higher than in Costa Rica (years). Forty-five percent of the Trinidadian women had completed eleven or more years of schooling as compared to 12 percent of the Costa Rican acceptors. A very large majority cigarettes at all (Table 80 percent reported they
of the participants did not smoke I), and among women who did smoke, more had fewer than five cigarettes per day.
than
Past experiences with contraception, and especially with the pill, was notably different in the two countries, reflecting the differences in percentages in current martial status and never having been pregnant. Three-fifths of the participants in Costa Rica and five-sixths of the women in Trinidad had never previously used the pill.
JULY
1979 VOL. 20 NO. 1
33
CONTRACEPTION TABLE
CHARACTERISTICS
CHARACTERISTIC
Trinidad
% White
1.3
b. % Black
71.6
a.
BY COUNTRY
Costa
AND
R.
BY DRUG
Norinyl
Ovral
50.0
50.2
1.5
37.0
35.7
98.5
C.
% Never
Married
62.3
22.1
38.9
45.3*
d.
% Never
Pregnant
30.5
10.4
18.3
22.5
1.1
1.5
1.3
1.3
22.9
23.7
23.4
23.2
8.4
6.4
7.6
7.3
93.2
78.6
85.6
86.1
53.1
53.0
52.9
53.3
84.0
59.9
72.0
71.8
597
600
597
600
e. Mean No. of Living Children f. Mean
Age
g. Mean No. Schooling
Years of Completed
h. % Do Not
Smoke
i. Mean J.
Weight
% Never
Used
No. of Women
34
OF ACCEPTORS
I
(Kg) Pill
JULY 1979VOL.20NO.l
CONTRACEPTION RESULTS
Four results are reported. First we report types of the verbal statements of the acceptors concerning common side This is followed by results of effects of oral contraceptives. Next are descriptions by physical examinations and measurements. the acceptors of their menstrual patterns since beginning the study. Fourth are the termination and continuation rates. There were some differences between drugs in the participants’ reports of the occurrence of moderate or severe nausea, vomiting, dizziness and headache, but differences between drugs were not significant for any of these four commonly recorded effects associated with the use of orals (Table II). Women using Ovral in Costa Rica reported acne and chloasma in significantly greater numbers than did women using Norinyl. Participants in the Trinidad study were virtually free of such complaints (Tables I II and IV). Physical examinations conducted at termination substantiated these different ial reports, particularly Ovral affected significantly for chloasma among Costa Rican women. more users both with regard to chloasma, and with regard to all skin conditions, than did Norinyl (Table V). Physical examination also revealed a moderate excess of cervicitis and cervical erosion among Ovral users in Trinidad, In Costa Rica, although the differences were not significant. cervical erosion was noted in 13 percent of the users of either drug white cervicitis was noted in three percent of each group (Table VI). Average blood pressure readings rose somewhat in both countries and for both drugs. The percentages of women with high readings showed an upward but not a significant rise (Table VI I). Both brands of orals reduced the average number of days of menstrual bleeding in the two countries, and both pills effected a reduction in the percentage of women reporting relatively heavy menstrual flow (Table VIII). On the other hand, intermenstrual spotting or bleeding was strongly associated with use of Norinyl. In both countries the percentage of women using Norinyl who reported intermenstrual bleeding events was at least twice that of the Ovral users. The differences in the percentages were highly significant (Table IX).
JULY
1979 VOL. 20 NO. 1
35
CONTRACEPTION
TABLE
PERCENTAGE
OF WOMEN
MODERATE
OR SEVERE
WHILE
CONDITION
Vomiting
Headache
Dizziness
N
Ovral 12.2
16.8
TOTAL
12.2
14.5
1.7
2.4
Rica
4.7
5.4
TOTAL
3.2
3.9
9.5
5.4
Rica
24.1
26.5
TOTAL
16.8
16.0
6.1
2.0
Rica
14.6
15.0
TOTAL
10.4
8.5
567
573
Trinidad Costa
Nor inyl
16.8
Trinidad Costa
REGIMEN
Rica
Trinidad Costa
REPORTING CONDITIONS
7.5
Trinidad Costa
36
USING
Country
Nausea
II
JULY
1979 VOL. 20 NO. 1
CONTRACEPTION
TABLE
PERCENTAGE
OF WOMEN
III
REPORTING
INCREASED ACNE
Norinyl
Ovral
Trinidad
0.0
0.0
Costa Rica
5.5
TOTAL
2.7
5.2"
567
573
N
10.4':
TABLE
PERCENTAGE
OF WOMEN
IV
REPORTING
CHLOASMA
Norinyl
Ovral
Trinidad
0.7
1.0
Costa Rica
4.4
12.5+::
TOTAL
2.5
6.8%:
567
573
N
"P < .05 **p
