Abnormalities among offspring of oral and nonoral contraceptive users HLCTOR
E.
ABELARDO
ORTIZ-PkRE%, FUERTES-DE
ISHVER
S. BANGDIWALA,
CARLOS
A.
Snrr ,Juan,
Purrto
ROURE,
M.D. LA
HABA,
M.D.,
D.P.H.,
PH.D.,
F.A.S.A.
F.A.(:.O.(;.
M.D.
Rico
An analysis of 223 children born between 1961 and 1965 to 5,465 women in a controlled experiment at the University of Puerto Rico School of Medicine, regarding the use of oral and nonoral contraceptives, failed to reveal any statistical differences in birth weight and physical abnormalities between the two contraceptive groups. The mean birth weight for the oral group was 7 pounds, 4.1 ounces, whereas for the nonoral group it was 7 pounds, 5.4 ounces. Abnormal physical findings were 10.7% for the oral group and 16.7% for the nonoral group. A comparison is also made between the two groups with respect to incidence of abnormalities by socioeconomic class and by sex of the child, as well as by the number of pregnancies and age of the mother. No significant differences were noted between the groups as an indication of the effect of oral contraceptives. (AM. J. OBSTET. GYNECOL. 134:512, 1979.)
SIN c E the development of oral contraceptives, many cluestions have appeared, opening the way to research and debate between scientists and lay people. Many sectors of our society wonder about their possible effects on women and their offspring. Suspicions regarding a potentially teratogenic role for “the pill” have been voiced for several years but reports have been conflicting, as may be observed in reviewing the literature up to 1976. At the University of Puerto Rico Medical Sciences Campus, a controlled experiment is being carried out with over 10,000 women, about half of them using oral contraceptives and the remaining using nonoral (vaginal) methods. Several parameters have been studiecl since the beginning of the experiment in 1961 and the results of the comparison between the oral and control groups have been published.‘-” The present report deals with the description of some findings of a study with regard to the presence of some congenital abnormalities in children whose From the Department of Obstetrics
and Gynecology, of Puerto Rico School oj Medicine, and the Ff Graduate Studies, University of Puerto
L’nirwrsity Department Rico. Received
for
Revised
September
publication
Accrpted
Sepkmbrr
June
16, 1978.
5, 1978. 11, 1978.
Reprint requests: Dr. Hector E. O&-P&z, Department of Obstetrics and Gynecology, Medical Sciences Campus, G. P. 0. Box 5067, San Juan, Puerto Rico 00936.
512
mothers have been using two kinds of’ contraceptive methods, oral and nonoral. Birth weights of the cllildren from the two groups of women arc compared. The variables are also compared by sex of-the child and socioeconomic condition of the mother as well as by age at the time of delivery and number of pregnancies ot the mother-.
IiWtwiel and methods The subjects of this study were offspring 01’ won+ en belonging to the University of Puerto Rico Maternal Health Study Program which was designed i~r 1961 to study the incidence of genital artd breast cancer in women who were using progesrationai agents. Women admitted to the study program met basic minimum qualifications such as: age ‘L I to 39 years, at least one nornral pregnancy, and nc) prior, use of oral contraceptives or ot intrauterine contraceptive devices (IUDs). Each candidate beforr% admission to the program agreed to use the contraceptive to be prescribed. Once a woman was found to be eligible and prior LO her physical examination, she was assigned at random to the experimental* (oral contraceptive) or control group (vaginal contraceptive), which she was to follow throughout the experiment. *The oral contraceptive group used norethynodrel, 5 mg, and mestranol, 0.075 rilg (Enovid, C. D. Searle & Co., Chicago, Illinois). The total steroid dosage was 5.75 mg per tablet.
Abnormalities
The 5,465 women of the present study were admitted to one of the clinics in the project between 196 1 and 196.5. Wit11 randomization procedure 2,741 women (50.16%) were assigned to the oral contraceptive group and 2,724 (40.34!%) were assigned to the control group. A comparison of strverai socioeconomic characteristics s11cl1 as age, education, family income, occupation, parity, etc., of the randomly assigned subjects to our two groups ShJWed that both groups were alinost identical and tlierefi)re comparable.” T11e next step was to identify the mothers who had offspring afttlr admission to the study. These were mostly voluntary pregnancies, since there were no cases of contraceplive failure among either of the groups. During rhc period 1!161 to 1965, 229 children were born to these women. Of these 229 children, 223 were included in the study; the remaining six subjects had moved with their families to other communities and therefore were lost IO follow-up. Of the 223 children included in the analysis, 2 10 were alive and I3 had died at the time of the study. Tile subjects of the present study (223) were distributed as follows: 103 (hildren (44 boys and 59 girls) were in the group whose mothers used oral contraceptives and 120 (65 boys and 55 girls) were in that of women using nonoral contraceptives. The average age at the time of’ study was 6.1 years for the 96 living children of the study group and 6.2 years fclr the 114 living children of the control group. Each living child was referred to a pediatrician who performed a complete physical examination and recorded a detailed history including birth weight. For the dead children the data were obtained from autopsy records or death certificates. A comparison between groups was made by variables of the child and mother using appropriate statistical analysis. A 5% level of probability was used as the criterion for significance tests.
Results Birth weight. From the two groups (103 oral and 120 nonoral) only three birth weights for oral and one for nonoral groups were not available for the birth weight study. Thus the analysis included 100 subjects for the oral group and 119 for the nonoral group. The mean weight at birth for the oral group was 7 pounds, 4.1 ounces, and for the nonoral group it was 7 pounds, 5.4 ounces, with a standard deviation of 24.6 ounces for the oral group and 24.3 ounces for the nonoral group (Table I). From these values it can be observed that the difference (1.32 ounces) between the mean birth weights of the two groups is not significant at the 5% level as indicated by the t test. Abnormal physical findings. Table II shows the
among
offspring
of contraceptive
513
users
I. l‘est of significance of difference between mean birth weights of children born to mothers of the oral and nonoral cant raceptive groups
Table
Oral ffouf~
j2’onoral p-ou$
loo*
119*
No. of children Mean
weight
ar birth
116.1 ounces (7 pounds, 4.1 ounces)
117.4 ounces (7 pounds,
24.6 onnces
SD
5.4 ounces)
24.3 ounces
Difference between means not significant at 5% level (t = 0.40). *Birth weights of three children in oral and one child in nonoral
group
were
not
available.
Table II. Comparison of number of children with abnormalities observed between offspring of oral and nonoral groups
Oral
Croup
Normal Abnormal ‘I‘Otdl
Abnormal age
(%) (aver-
92 11 103 10.7
Nonoral
lhtal
100
IY:!
20 120 16.7
31 223
13.9)
x’ = 1.6tN with one degree of freedom. 5% level.
Not significant at
number of abnormalities found during physical examination of children in both groups. In the oral group 11 abnormalities were found among the 103 children whereas in the nonoral group 20 of 120 children showed some abnormalities. The percentages of abnormalities were 10.7% tbr the oral group and 16.7% for the nonoral group. The total chi-square value is 1.660 with one degree of freedom, which indicates that the difference between observed frequency and expected frequency is not significant at the 5% level, that is, the difference between the percentages of abnormal cases in both groups could be considered to have occurred by chance and therefore the incidence is almost the same in both. On an average it was 13.9%. A list of the different abnormalities found in each case study is given in Table III. Table IV shows the abnormal physical findings by socioeconomic groups according to standards previously established for the experimental subjects.3 Data for 210 children were available for this variable. In the upper class no abnormalities were found in either group. The middle-class group included 10 cases from the oral group and 14 cases from the nonoral group, and for the low class one abnormal case was found in the oral group and three in the nonoral group. The percentages of abnormalities for the middle class thus were 13.7% and 15.1% for the oral and nonoral groups,
Ortiz-PBrez et al
514
Table
III. List of abnormal Oral
findings
in study group
group
I 1 I
Nevus
I
of skin*t
Seizures by history*l-
I
Deformed right side of chest*+ Abundant body hair*t Hairy pigmented nevi at neck Earlobe folded forward Umbilical hernia
I 1 I 1 I
Undescended testis Genu varum right leg Peclus excavatutn
I I I
findings findings
IV. Number
in the same in the same
of children
High Middle LO\V Total Abnormal (%), high class Abnormal (%), middle class .4bnormal (%), low class 2~’ = 3.510 with *For I3 subjects,
- \‘o. 01
Nonoral
coW-aceptive
group
( f>.\(‘5
Left inguinal hernia Epilepsy* Vitiligo at neck* Grade 1 syslolic murmur-*+ Hypoplastic mandible Focomelia*
1 I I !I I I
Micrognatia* Microglossia” High-arched palate* Right tibia1 torsion juvenile premature venrricular contractions Right undescended testis*+ Speech defect Endocardial fibroekdstosis Anencephalic monster Cleft palare*+ Inperforate anus*t
I 1 1 I 1 I 1 1 I 1 I
patient patient.
with abnormalities
by socioeconomic
Oral Socioemmmic level
-__--___-.-.-
.Vo. of ( UTC.,
Congeniral d&err of nose High-arched leg Grade I systolic murmur
*Abnormal tAbnormal
Table
contraceptive
physical
level for oral and nonoral
groups
Il’onoral Sgnificancr
Normal
Abnormal
5 63 17 85 -
0 IO I II
-
13.7
-
i.6
6 degrees of freedom-not the socioeconomic level
significant of rhe mother
h’O?-d
4 79 I4 97 .-
Abnormal
Total
ofdiffererrcr
0 I4 3 I7 -
9 166 35 210* -
NS at 5%
(average)
NS at .i%m
15. I
14.5
17.6
I 1.4 (average)
NS al 5’1
al 5% level; NS = IVot significant. could not be obtained
respectively. The low class indicated 5.6% for the oral and 17.674 for the nonoral group. The total chi square for the differences between observed and expected frequencies was 3.510 with six degrees of freedom. The difference between observed frequency and expected frequency is therefore not significant at the 59 level in this case either. Thus the percentages in both cases are considered almost the same with an average of O.% ti)r upper class, 14.5% for middle class, and 1 1.4!1( for low class. The difference between these three groups at individual socioeconomic classes was also insignificant at the 5% level as indicated in Table IV. A comparison between groups was also made with reference to sex. In the oral and nonoral groups there were IO and 13 cases, respectively, with abnormal physical findings in the boys and one and seven cases for the girls. The percentage of abnormal boys in the oral
group was 2 I .7% whereas for the nonoral group it was 20.0%. The difference, however, is not significant at the 5% level, as indicated in Table V. The percentage of ahnormal girls in the oral group was 1.8(X, whereas for the nonoral group it was 12.7% which, as indicated in Table V, is a signifcant difference at the same level. In the two groups under study the distribution of mothers by age, as presented in Table VI, showed that the average age of the mothers of the 103 children in the oral group was 3 1.5 years while that of the mothers of the 120 children in the nonoral group was 32.0 years. The difference between the two averages is not significant. The mean ages of mothers of the normal and ahnormal children in the two groups also failed to show any statistical difference, indicating that age is not an
Abnormalities
Table
V. Number
of children
with abnormalities
by sex for oral and nonoral
Male Female Total Abnormal (%), males Abnormal (%), females
Normal
Abnormal
Normal
Abnormal
36 56 92
10 1 11
52 48 100
13 7 20
VI. Age distribution
20.0
1.8
12.7
7.1 (average)
(%)
of normal
Abnormal
37.0 39.1 20.6 3.3 100.0 92 31.5
NS at 5% Significant at 5%
at 1% level and abnormal
children
in oral and nonoral
groups
Nonoral group
Oral group
25-29 30-34 35-39 40 and over Total % No. Average age (yr.)
Signz$cance of difference
Total
21.7
of mothers
Normal
515
groups
111 112 223 20.7 (average)
Xx’ = 13.64 with 3 degrees of freedom--significant Table
users
Nonoral
Oral Sex of child
among offspring of contraceptive
(%)
Total (%)
45.5 36.4 9.1 9.1 100.0 11 31.6
Normal
37.9 38.8 19.4 3.9 100.0 103 31.5
Abnormal
(%)
37.0 28.0 30.0 5.0 100.0 100 32.1
(%)
40.0 30.0 25.0 5.0 100.0 20 31.8
Total
(%)
37.5 28.3 21.2 5.0 100.0 120 32.0
Common standard error = 4.3 14 (based on 2 19 degrees of freedom in the analysis of variance). Table VII. Distribution in the oral and nonoral
of number groups
of pregnancies Oral
No. of pregnancies as of childbirth
Normal (%)
2 3 4 5 6 7 8 or more Total % Total No.
0.0 14.1 18.5 20.6 .12.0 12.0 22.8 100.00 92”
of mothers
of normal
and abnormal
group
Abnormal
children
Nonoral (%)
9.1 9.1 9.1 27.2 9.1 18.2 18.2 100.0 11*
Total (%)
1.0 13.6 17.5 21.4 11.6 12.6 22.3 100.0 103
Normal
(%)
4.0 13.0 16.0 14.0 14.0 9.0 30.0 100.0 loot
group
Abnormal
0.0 15.0 25.0 0.0 15.0 10.0 35.0 100.0 20*
(%)
Total
(%)
3.3 13.3 17.5 11.7 14.2 9.2 30.8 100.0 120
*x2 = 9.43 (not significant at 5% level). l-x” = 4.59 (nor significant at 5% level). important factor affecting the children of our study with any abnormality. The data were also analyzed for the 223 children as to their position in the family raised by the mother. The rank or the position thus was equivalent to the number of pregnancies incurred by the mother as of this childbirth. Table VII shows the data for the two groups, oral and nonoral, of the mothers of these children. It was observed that the distribution of the mothers according to the number of pregnancies was fairly similar in both groups. When the number of pregnancies of mothers in cases of the normal and ab-
normal children is compared, the distribution in either group is similar, as indicated by the chi-aquare test. Thus the observed frequencies, although apparently different, are not statistically different from their respective expected value. Table VIII shows the 13 dead children with their ages at the time of death and the cause of death as reported in autopsies and death certificates. As can be seen clearly none of the deaths can be attributed to the use of oral contraceptives. Moreover, the three dead children who demonstrated congenital anomalies (vertebral, anal, cardiac, tracheal, esophageal, renal, and
Table
VIII.
and cause
Age
Pnlknl
OF
death
13 children
01‘
iti srud\
groups
Agt
Otol: 11. 11. K. v.
4.5 days 4 y1-.
N. hl. I.. c:. hi:. c:. c;.
2% mo.
(hl(’
oj thth
Pncllmonia, acute gastroenteritia. tieh) dratiotr Acute intoxication with organic phosphorus Pneumonia, acute gastroentcritis, dehydration Abruptio placentae after trauma, no anomalies
of I>. K. M.
SB
Kab) of‘ P. 1). .4.
SB
1.. %I. F. E:. Hat)\ of. H. 1.. B.
I \1.
Premature Pneumonia Unknowtl
2 )r.
Multiple
SB
cardiomegaly. hydrothorax, ~tepatosplenomegal~ I rttrauterine asphyxia secot&cr\ to loops of’ coral around
WAJ)
~l’orror/ll: K. K. II. Bahk Baby Baby
of L). S. F. of‘ hf. G.
0t’K.
M.
E:. G. F,.
SB 24
Baby of M. Q. C:.
SB
Bah)
SB
OF C. 0.
C.
labor, with
body
Anenc.ephalic
hr.
Kernicterus, No anomalies, NC> anomalies,
intrauterine asphyxia, no anomalies asphyxia secondart to aspiration of’ ascaris
trauma,
congenital
heart
tibrt&istosis
disease-elldocardial
of left vrntric
le,
neck
monster
inrperforate
~IILIS,
mother with hypertensive
c lel’t palate
Class A diabetes mellitll\ disortier of pregnanq --
SH = Stillbirth.
litnbs) belonged users.
to the group
of‘
nonoral
contraceptive
Comment By the introduction of‘ contraceptive drugs, a major breakthrough in the probletn of human population control seems to have been achieved. A large sector of the female population is IHJN dependent upon the “pill” as an effective tneans of birth control. There are, however, controversies as to the “pill’s” other effects. Janerich and associates’, J have reported congenital limb reduction defects associated with maternal oral contraceptive exposure with a preponderance in male offspring. Nora and Nora”. ’ have also reported various cases of fetal abnormalities (vertebral. anal, cardiac, tracheal, esophageal, renal and limbs) in the offspring of contraceptive users also with a preponderance among male children. However, these reports associate fetal anomalies with the use of‘ six steroids during early stages of gestation, contrary to out. study in which oral contraceptives were used prior to conception. Although both groups agree in their cottelusions. their studies have been retrospective to the present time and neither can be taken as conclusive. Reports have also been made in the literature of masculiniLation of the female fetus with the use, of prclgestins during the first trimester of fetal life as a test for pregnaticy.“~ !’ Other authors believe that since the great majority of pregnancies preceded by use of oral contraceptives do not result in a defective offspring, some maternal predisposition is probably necessary before malformations occur. Some experimental animals have been used to induce congenital malformation with high doses of estrogeniprogestin. But, on the basis of the effect of
dosage,
it is possible
that
the
use
of’
higher
closes
ot
~on~racepti~~c drugs \\,or~ld produce a higher tr-equency of abnormalities. as has beecAnfiJUlltl wirh othr:1, cstabWed chemical mtttagetis.“. ‘W ” ‘l‘he fact rrmaitts that such high doses 01 c,ontraceptive drugs are not at all in IISC by any human population, and ettijrts haw beet1 made IO minimiz the applied dose of the steroids to the lowest and saf’st possible levels. As stated earlier, our experimenral group at the L’niversitv of Puerto Rico recei\,ed it total daily steroid dose ot .i. 17.5 tug (estrogeli/lJrogestitt) and ranged from one to 29 cvclcs prior to preguatic\. Still other authors like Klinger and associates’” and I’asuda and Millrr” have found no evidence that pliot IIW of’ oral contraceptives alters the risk of’ chrotttosomally abnormal offspring or can be a cause ot “tt,ansposition of t.hc great IFWZ~~” in tilati.‘6. Ii In a study tarried out b) Fuertcs-de la flaba and colleagues, cell culture t or chrt~mosom~ stud& ~3s conducted iti the oral and nonora~ groups. N
E.
ABELARDO
ORTIZ-PkRE%, FUERTES-DE
ISHVER
S. BANGDIWALA,
CARLOS
A.
Snrr ,Juan,
Purrto
ROURE,
M.D. LA
HABA,
M.D.,
D.P.H.,
PH.D.,
F.A.S.A.
F.A.(:.O.(;.
M.D.
Rico
An analysis of 223 children born between 1961 and 1965 to 5,465 women in a controlled experiment at the University of Puerto Rico School of Medicine, regarding the use of oral and nonoral contraceptives, failed to reveal any statistical differences in birth weight and physical abnormalities between the two contraceptive groups. The mean birth weight for the oral group was 7 pounds, 4.1 ounces, whereas for the nonoral group it was 7 pounds, 5.4 ounces. Abnormal physical findings were 10.7% for the oral group and 16.7% for the nonoral group. A comparison is also made between the two groups with respect to incidence of abnormalities by socioeconomic class and by sex of the child, as well as by the number of pregnancies and age of the mother. No significant differences were noted between the groups as an indication of the effect of oral contraceptives. (AM. J. OBSTET. GYNECOL. 134:512, 1979.)
SIN c E the development of oral contraceptives, many cluestions have appeared, opening the way to research and debate between scientists and lay people. Many sectors of our society wonder about their possible effects on women and their offspring. Suspicions regarding a potentially teratogenic role for “the pill” have been voiced for several years but reports have been conflicting, as may be observed in reviewing the literature up to 1976. At the University of Puerto Rico Medical Sciences Campus, a controlled experiment is being carried out with over 10,000 women, about half of them using oral contraceptives and the remaining using nonoral (vaginal) methods. Several parameters have been studiecl since the beginning of the experiment in 1961 and the results of the comparison between the oral and control groups have been published.‘-” The present report deals with the description of some findings of a study with regard to the presence of some congenital abnormalities in children whose From the Department of Obstetrics
and Gynecology, of Puerto Rico School oj Medicine, and the Ff Graduate Studies, University of Puerto
L’nirwrsity Department Rico. Received
for
Revised
September
publication
Accrpted
Sepkmbrr
June
16, 1978.
5, 1978. 11, 1978.
Reprint requests: Dr. Hector E. O&-P&z, Department of Obstetrics and Gynecology, Medical Sciences Campus, G. P. 0. Box 5067, San Juan, Puerto Rico 00936.
512
mothers have been using two kinds of’ contraceptive methods, oral and nonoral. Birth weights of the cllildren from the two groups of women arc compared. The variables are also compared by sex of-the child and socioeconomic condition of the mother as well as by age at the time of delivery and number of pregnancies ot the mother-.
IiWtwiel and methods The subjects of this study were offspring 01’ won+ en belonging to the University of Puerto Rico Maternal Health Study Program which was designed i~r 1961 to study the incidence of genital artd breast cancer in women who were using progesrationai agents. Women admitted to the study program met basic minimum qualifications such as: age ‘L I to 39 years, at least one nornral pregnancy, and nc) prior, use of oral contraceptives or ot intrauterine contraceptive devices (IUDs). Each candidate beforr% admission to the program agreed to use the contraceptive to be prescribed. Once a woman was found to be eligible and prior LO her physical examination, she was assigned at random to the experimental* (oral contraceptive) or control group (vaginal contraceptive), which she was to follow throughout the experiment. *The oral contraceptive group used norethynodrel, 5 mg, and mestranol, 0.075 rilg (Enovid, C. D. Searle & Co., Chicago, Illinois). The total steroid dosage was 5.75 mg per tablet.
Abnormalities
The 5,465 women of the present study were admitted to one of the clinics in the project between 196 1 and 196.5. Wit11 randomization procedure 2,741 women (50.16%) were assigned to the oral contraceptive group and 2,724 (40.34!%) were assigned to the control group. A comparison of strverai socioeconomic characteristics s11cl1 as age, education, family income, occupation, parity, etc., of the randomly assigned subjects to our two groups ShJWed that both groups were alinost identical and tlierefi)re comparable.” T11e next step was to identify the mothers who had offspring afttlr admission to the study. These were mostly voluntary pregnancies, since there were no cases of contraceplive failure among either of the groups. During rhc period 1!161 to 1965, 229 children were born to these women. Of these 229 children, 223 were included in the study; the remaining six subjects had moved with their families to other communities and therefore were lost IO follow-up. Of the 223 children included in the analysis, 2 10 were alive and I3 had died at the time of the study. Tile subjects of the present study (223) were distributed as follows: 103 (hildren (44 boys and 59 girls) were in the group whose mothers used oral contraceptives and 120 (65 boys and 55 girls) were in that of women using nonoral contraceptives. The average age at the time of’ study was 6.1 years for the 96 living children of the study group and 6.2 years fclr the 114 living children of the control group. Each living child was referred to a pediatrician who performed a complete physical examination and recorded a detailed history including birth weight. For the dead children the data were obtained from autopsy records or death certificates. A comparison between groups was made by variables of the child and mother using appropriate statistical analysis. A 5% level of probability was used as the criterion for significance tests.
Results Birth weight. From the two groups (103 oral and 120 nonoral) only three birth weights for oral and one for nonoral groups were not available for the birth weight study. Thus the analysis included 100 subjects for the oral group and 119 for the nonoral group. The mean weight at birth for the oral group was 7 pounds, 4.1 ounces, and for the nonoral group it was 7 pounds, 5.4 ounces, with a standard deviation of 24.6 ounces for the oral group and 24.3 ounces for the nonoral group (Table I). From these values it can be observed that the difference (1.32 ounces) between the mean birth weights of the two groups is not significant at the 5% level as indicated by the t test. Abnormal physical findings. Table II shows the
among
offspring
of contraceptive
513
users
I. l‘est of significance of difference between mean birth weights of children born to mothers of the oral and nonoral cant raceptive groups
Table
Oral ffouf~
j2’onoral p-ou$
loo*
119*
No. of children Mean
weight
ar birth
116.1 ounces (7 pounds, 4.1 ounces)
117.4 ounces (7 pounds,
24.6 onnces
SD
5.4 ounces)
24.3 ounces
Difference between means not significant at 5% level (t = 0.40). *Birth weights of three children in oral and one child in nonoral
group
were
not
available.
Table II. Comparison of number of children with abnormalities observed between offspring of oral and nonoral groups
Oral
Croup
Normal Abnormal ‘I‘Otdl
Abnormal age
(%) (aver-
92 11 103 10.7
Nonoral
lhtal
100
IY:!
20 120 16.7
31 223
13.9)
x’ = 1.6tN with one degree of freedom. 5% level.
Not significant at
number of abnormalities found during physical examination of children in both groups. In the oral group 11 abnormalities were found among the 103 children whereas in the nonoral group 20 of 120 children showed some abnormalities. The percentages of abnormalities were 10.7% tbr the oral group and 16.7% for the nonoral group. The total chi-square value is 1.660 with one degree of freedom, which indicates that the difference between observed frequency and expected frequency is not significant at the 5% level, that is, the difference between the percentages of abnormal cases in both groups could be considered to have occurred by chance and therefore the incidence is almost the same in both. On an average it was 13.9%. A list of the different abnormalities found in each case study is given in Table III. Table IV shows the abnormal physical findings by socioeconomic groups according to standards previously established for the experimental subjects.3 Data for 210 children were available for this variable. In the upper class no abnormalities were found in either group. The middle-class group included 10 cases from the oral group and 14 cases from the nonoral group, and for the low class one abnormal case was found in the oral group and three in the nonoral group. The percentages of abnormalities for the middle class thus were 13.7% and 15.1% for the oral and nonoral groups,
Ortiz-PBrez et al
514
Table
III. List of abnormal Oral
findings
in study group
group
I 1 I
Nevus
I
of skin*t
Seizures by history*l-
I
Deformed right side of chest*+ Abundant body hair*t Hairy pigmented nevi at neck Earlobe folded forward Umbilical hernia
I 1 I 1 I
Undescended testis Genu varum right leg Peclus excavatutn
I I I
findings findings
IV. Number
in the same in the same
of children
High Middle LO\V Total Abnormal (%), high class Abnormal (%), middle class .4bnormal (%), low class 2~’ = 3.510 with *For I3 subjects,
- \‘o. 01
Nonoral
coW-aceptive
group
( f>.\(‘5
Left inguinal hernia Epilepsy* Vitiligo at neck* Grade 1 syslolic murmur-*+ Hypoplastic mandible Focomelia*
1 I I !I I I
Micrognatia* Microglossia” High-arched palate* Right tibia1 torsion juvenile premature venrricular contractions Right undescended testis*+ Speech defect Endocardial fibroekdstosis Anencephalic monster Cleft palare*+ Inperforate anus*t
I 1 1 I 1 I 1 1 I 1 I
patient patient.
with abnormalities
by socioeconomic
Oral Socioemmmic level
-__--___-.-.-
.Vo. of ( UTC.,
Congeniral d&err of nose High-arched leg Grade I systolic murmur
*Abnormal tAbnormal
Table
contraceptive
physical
level for oral and nonoral
groups
Il’onoral Sgnificancr
Normal
Abnormal
5 63 17 85 -
0 IO I II
-
13.7
-
i.6
6 degrees of freedom-not the socioeconomic level
significant of rhe mother
h’O?-d
4 79 I4 97 .-
Abnormal
Total
ofdiffererrcr
0 I4 3 I7 -
9 166 35 210* -
NS at 5%
(average)
NS at .i%m
15. I
14.5
17.6
I 1.4 (average)
NS al 5’1
al 5% level; NS = IVot significant. could not be obtained
respectively. The low class indicated 5.6% for the oral and 17.674 for the nonoral group. The total chi square for the differences between observed and expected frequencies was 3.510 with six degrees of freedom. The difference between observed frequency and expected frequency is therefore not significant at the 59 level in this case either. Thus the percentages in both cases are considered almost the same with an average of O.% ti)r upper class, 14.5% for middle class, and 1 1.4!1( for low class. The difference between these three groups at individual socioeconomic classes was also insignificant at the 5% level as indicated in Table IV. A comparison between groups was also made with reference to sex. In the oral and nonoral groups there were IO and 13 cases, respectively, with abnormal physical findings in the boys and one and seven cases for the girls. The percentage of abnormal boys in the oral
group was 2 I .7% whereas for the nonoral group it was 20.0%. The difference, however, is not significant at the 5% level, as indicated in Table V. The percentage of ahnormal girls in the oral group was 1.8(X, whereas for the nonoral group it was 12.7% which, as indicated in Table V, is a signifcant difference at the same level. In the two groups under study the distribution of mothers by age, as presented in Table VI, showed that the average age of the mothers of the 103 children in the oral group was 3 1.5 years while that of the mothers of the 120 children in the nonoral group was 32.0 years. The difference between the two averages is not significant. The mean ages of mothers of the normal and ahnormal children in the two groups also failed to show any statistical difference, indicating that age is not an
Abnormalities
Table
V. Number
of children
with abnormalities
by sex for oral and nonoral
Male Female Total Abnormal (%), males Abnormal (%), females
Normal
Abnormal
Normal
Abnormal
36 56 92
10 1 11
52 48 100
13 7 20
VI. Age distribution
20.0
1.8
12.7
7.1 (average)
(%)
of normal
Abnormal
37.0 39.1 20.6 3.3 100.0 92 31.5
NS at 5% Significant at 5%
at 1% level and abnormal
children
in oral and nonoral
groups
Nonoral group
Oral group
25-29 30-34 35-39 40 and over Total % No. Average age (yr.)
Signz$cance of difference
Total
21.7
of mothers
Normal
515
groups
111 112 223 20.7 (average)
Xx’ = 13.64 with 3 degrees of freedom--significant Table
users
Nonoral
Oral Sex of child
among offspring of contraceptive
(%)
Total (%)
45.5 36.4 9.1 9.1 100.0 11 31.6
Normal
37.9 38.8 19.4 3.9 100.0 103 31.5
Abnormal
(%)
37.0 28.0 30.0 5.0 100.0 100 32.1
(%)
40.0 30.0 25.0 5.0 100.0 20 31.8
Total
(%)
37.5 28.3 21.2 5.0 100.0 120 32.0
Common standard error = 4.3 14 (based on 2 19 degrees of freedom in the analysis of variance). Table VII. Distribution in the oral and nonoral
of number groups
of pregnancies Oral
No. of pregnancies as of childbirth
Normal (%)
2 3 4 5 6 7 8 or more Total % Total No.
0.0 14.1 18.5 20.6 .12.0 12.0 22.8 100.00 92”
of mothers
of normal
and abnormal
group
Abnormal
children
Nonoral (%)
9.1 9.1 9.1 27.2 9.1 18.2 18.2 100.0 11*
Total (%)
1.0 13.6 17.5 21.4 11.6 12.6 22.3 100.0 103
Normal
(%)
4.0 13.0 16.0 14.0 14.0 9.0 30.0 100.0 loot
group
Abnormal
0.0 15.0 25.0 0.0 15.0 10.0 35.0 100.0 20*
(%)
Total
(%)
3.3 13.3 17.5 11.7 14.2 9.2 30.8 100.0 120
*x2 = 9.43 (not significant at 5% level). l-x” = 4.59 (nor significant at 5% level). important factor affecting the children of our study with any abnormality. The data were also analyzed for the 223 children as to their position in the family raised by the mother. The rank or the position thus was equivalent to the number of pregnancies incurred by the mother as of this childbirth. Table VII shows the data for the two groups, oral and nonoral, of the mothers of these children. It was observed that the distribution of the mothers according to the number of pregnancies was fairly similar in both groups. When the number of pregnancies of mothers in cases of the normal and ab-
normal children is compared, the distribution in either group is similar, as indicated by the chi-aquare test. Thus the observed frequencies, although apparently different, are not statistically different from their respective expected value. Table VIII shows the 13 dead children with their ages at the time of death and the cause of death as reported in autopsies and death certificates. As can be seen clearly none of the deaths can be attributed to the use of oral contraceptives. Moreover, the three dead children who demonstrated congenital anomalies (vertebral, anal, cardiac, tracheal, esophageal, renal, and
Table
VIII.
and cause
Age
Pnlknl
OF
death
13 children
01‘
iti srud\
groups
Agt
Otol: 11. 11. K. v.
4.5 days 4 y1-.
N. hl. I.. c:. hi:. c:. c;.
2% mo.
(hl(’
oj thth
Pncllmonia, acute gastroenteritia. tieh) dratiotr Acute intoxication with organic phosphorus Pneumonia, acute gastroentcritis, dehydration Abruptio placentae after trauma, no anomalies
of I>. K. M.
SB
Kab) of‘ P. 1). .4.
SB
1.. %I. F. E:. Hat)\ of. H. 1.. B.
I \1.
Premature Pneumonia Unknowtl
2 )r.
Multiple
SB
cardiomegaly. hydrothorax, ~tepatosplenomegal~ I rttrauterine asphyxia secot&cr\ to loops of’ coral around
WAJ)
~l’orror/ll: K. K. II. Bahk Baby Baby
of L). S. F. of‘ hf. G.
0t’K.
M.
E:. G. F,.
SB 24
Baby of M. Q. C:.
SB
Bah)
SB
OF C. 0.
C.
labor, with
body
Anenc.ephalic
hr.
Kernicterus, No anomalies, NC> anomalies,
intrauterine asphyxia, no anomalies asphyxia secondart to aspiration of’ ascaris
trauma,
congenital
heart
tibrt&istosis
disease-elldocardial
of left vrntric
le,
neck
monster
inrperforate
~IILIS,
mother with hypertensive
c lel’t palate
Class A diabetes mellitll\ disortier of pregnanq --
SH = Stillbirth.
litnbs) belonged users.
to the group
of‘
nonoral
contraceptive
Comment By the introduction of‘ contraceptive drugs, a major breakthrough in the probletn of human population control seems to have been achieved. A large sector of the female population is IHJN dependent upon the “pill” as an effective tneans of birth control. There are, however, controversies as to the “pill’s” other effects. Janerich and associates’, J have reported congenital limb reduction defects associated with maternal oral contraceptive exposure with a preponderance in male offspring. Nora and Nora”. ’ have also reported various cases of fetal abnormalities (vertebral. anal, cardiac, tracheal, esophageal, renal and limbs) in the offspring of contraceptive users also with a preponderance among male children. However, these reports associate fetal anomalies with the use of‘ six steroids during early stages of gestation, contrary to out. study in which oral contraceptives were used prior to conception. Although both groups agree in their cottelusions. their studies have been retrospective to the present time and neither can be taken as conclusive. Reports have also been made in the literature of masculiniLation of the female fetus with the use, of prclgestins during the first trimester of fetal life as a test for pregnaticy.“~ !’ Other authors believe that since the great majority of pregnancies preceded by use of oral contraceptives do not result in a defective offspring, some maternal predisposition is probably necessary before malformations occur. Some experimental animals have been used to induce congenital malformation with high doses of estrogeniprogestin. But, on the basis of the effect of
dosage,
it is possible
that
the
use
of’
higher
closes
ot
~on~racepti~~c drugs \\,or~ld produce a higher tr-equency of abnormalities. as has beecAnfiJUlltl wirh othr:1, cstabWed chemical mtttagetis.“. ‘W ” ‘l‘he fact rrmaitts that such high doses 01 c,ontraceptive drugs are not at all in IISC by any human population, and ettijrts haw beet1 made IO minimiz the applied dose of the steroids to the lowest and saf’st possible levels. As stated earlier, our experimenral group at the L’niversitv of Puerto Rico recei\,ed it total daily steroid dose ot .i. 17.5 tug (estrogeli/lJrogestitt) and ranged from one to 29 cvclcs prior to preguatic\. Still other authors like Klinger and associates’” and I’asuda and Millrr” have found no evidence that pliot IIW of’ oral contraceptives alters the risk of’ chrotttosomally abnormal offspring or can be a cause ot “tt,ansposition of t.hc great IFWZ~~” in tilati.‘6. Ii In a study tarried out b) Fuertcs-de la flaba and colleagues, cell culture t or chrt~mosom~ stud& ~3s conducted iti the oral and nonora~ groups. N
