BrifishJournal of Obstetrics and Gynaccology August 1976. VOI 83. pp 621-627
MATERNAL FACTORS ASSOCIATED WITH FETAL CHROMOSOMAL ANOMALIES IN SPONTANEOUS ABORTIONS BY
EVAALBERMAN M. CREASY
MAUREEN ELLIOTT Paediatric Research Unit Guy’s Hospital Medical School AND
C . SPICER Division of Medical Computing Northwick Park Hospital
Summary The effect is described of maternal factors on the proportion of fetal chromosomal anomalies in a series of 2620 spontaneous abortions, of which 992 specimens were karyotyped. Maternal age was the most important factor associated with a rise in the proportion abnormal, followed by Social Class I or I1 and the use of oral contraception before conception. The problem of extrapolating from the proportion abnormal to absolute incidence of anomalies is discussed. In the case of increasing maternal age, the evidence suggests that the rise in incidence of spontaneous abortions with age is accounted for by an increased incidence of chromosomally abnormal fetuses. In the case of high social class and a history of oral contraception, the evidence on incidence is scanty and the rise in the proportion abnormal may either reflect a decrease in the abortion rate of chromosomally normal fetuses, or a small increase in the incidence of lethal chromosomal anomalies. OVER90 per cent of recognized pregnancies of abnormal karyotypes are spontaneously aborted (Polani, 1970). Those anomalies which are most likely to be compatible with survival, such as trisomy 21 (Down’s syndrome) are of major clinical importance. Those which are invariably lethal early in pregnancy are equally important from the point of view of the causes of chromosoma1 anomalies. The study of spontaneously aborted fetuses does, however, present considerable methodological problems. A substantial proportion are lost unbeknown even to the mother, and many abortions that are recognized never come to medical attention. Such abortions as are reported are selected for gestational age (the later they
occur the more likely they are to require medical treatment) and by the mother’s demand for medical care (which is influenced by factors such as cultural background, home circumstances, age and previous obstetric history). It follows that data on spontaneous abortions are nearly always collected without a full knowledge of the population from which they are derived. We can, however, determine the ratio of chromosomally abnormal to normal fetuses in a sample, and look at factors influencing this ratio. Provided that we have some knowledge of the effects such factors have on the overall incidence of reported spontaneous abortions, we can make some judgement on their probable relationship with chromosome anomalies. In this 621
622
ALBERMAN, CREASY, ELLIOTT AND SPICER
paper we are concerned particularly with the effects of maternal age, smoking, and previous oral contraceptive history.
PATIENTS AND METHODS With the co-operation of the medical and nursing staff of certain gynaecological units in and around London, we obtained information from 2620 mothers who had been admitted with spontaneous abortions between 1971 and 1974. Wherever possible, fetal products of conception were collected, examined macroscopically, and cultured for chromosome analysis. The data regarding maternal history were collected by interview in 91 per cent of all cases included; in the remaining 9 per cent, available information was abstracted from the hospital records. An account of previous obstetric history in these mothers has already been published (Alberman et al, 1975). A full description of the cytogenetic and pathological findings are given elsewhere (Creasy et al, 1976). The laboratory outcomes were classified into four main groups: no fetal tissue received, no or insufficient growth, chromosomes normal, and chromosomes abnormal (Table I). Other definitions used are usually selfexplanatory but two need to be amplified. The use of oral contraception is usually presented in groups of ‘ever’ users and ‘never’ users. Included in the ‘ever’ users are a proportion who have used hormones for therapeutic reasons. The latter indication often overlapped with their use for contraception, and it was difficult to distinguish clearly between the two. However, on analyzing the data for the last pill used, it appeared that 14 per cent of all takers had used it for therapeutic purposes. Overall this proportion would be lower, since women who had used several different types of ‘pills’ nearly always took them for contraceptive purposes. Smoking history is presented both as smoking habit in pregnancy or, where relevant, as those who had ever or never smoked. This is specified where it occurs. FINDINGS Products of conception received Table I shows the number of specimens received, their chromosome constitution, and whether the pregnancy had been single or
TABLEI Chromosomal constitution of pregnancies in series No tissue Tissue culture culture Normal normal Abset failed UP* Singleton Twins Total abortuses
Total
778 16
854 18
661 42
289 0
2582 76
794
872
703
289
2658
* Includes 777 with no fetal tissue in specimens received and 17 where no tissue was received at all.
multiple. Because each of the pair of twins were sometimes in different ‘outcome’ groups, most subsequent Tables in this account are based on the number of specimens, and not mothers. This means that the 38 mothers of twin pregnancies are counted twice. Ratio of chromosomally abnormal to normal abortions Figure 1 shows how the proportion chromosomally abnormal varied with maternal age, parity, smoking in the presenting pregnancy, social class and history of previous oral contraception. The proportion of abnormals can be presented as either a proportion of the total specimens collected, or of only those of known karyotype. Both proportions are presented for the sake of completeness although they show similar trends. This is because the failure of fetal cell culture or the absence of fetal tissue in the specimen was not influenced by the maternal variables under consideration, the individual proportions showing no significant difference from the average (xz = 110 on 91 d.f.; p>O-I). The clearest findings relate to the variation of the proportion abnormal with maternal age. There is a steep rise with maternal age, so that the proportion known to be abnormal out of the whole sample doubles from the under-20 age group to the over-40 age group. None of the other factors studied had an effect as large as this. Taking each of the factors individually, the proportion abnormal increased with the number of previous surviving livebirths, with rising social class, and a previous
-
65
CHROMOSOMAL ANOMALIES IN ABORTIONS
623
% out of known karyotype
0 % out of all cases
,---
G
55
E
Y
N
al u
&
- Ever - Never
45
d
5
2
35
I C)
-
x
2
; 5
25
15
b
if; 5
V this preg. Maternal age
Oral contraception FIG.
Smoking
Social class
1
Per cent of chromosomally abnormal abortions by maternal age, oral contraception, smoking this pregnancy and social class.
history of oral contraception. The proportion tended to fall with the number of cigarettes smoked in the presenting pregnancy.
8o
1
mSmoking 0 Not smoking
70 ’
60
$
50
5
40
B
,
)
I
this pregnancy
u 0
E
30
&
20 10
Age Social class
MATERNAL FACTORS ASSOCIATED WITH FETAL CHROMOSOMAL ANOMALIES IN SPONTANEOUS ABORTIONS BY
EVAALBERMAN M. CREASY
MAUREEN ELLIOTT Paediatric Research Unit Guy’s Hospital Medical School AND
C . SPICER Division of Medical Computing Northwick Park Hospital
Summary The effect is described of maternal factors on the proportion of fetal chromosomal anomalies in a series of 2620 spontaneous abortions, of which 992 specimens were karyotyped. Maternal age was the most important factor associated with a rise in the proportion abnormal, followed by Social Class I or I1 and the use of oral contraception before conception. The problem of extrapolating from the proportion abnormal to absolute incidence of anomalies is discussed. In the case of increasing maternal age, the evidence suggests that the rise in incidence of spontaneous abortions with age is accounted for by an increased incidence of chromosomally abnormal fetuses. In the case of high social class and a history of oral contraception, the evidence on incidence is scanty and the rise in the proportion abnormal may either reflect a decrease in the abortion rate of chromosomally normal fetuses, or a small increase in the incidence of lethal chromosomal anomalies. OVER90 per cent of recognized pregnancies of abnormal karyotypes are spontaneously aborted (Polani, 1970). Those anomalies which are most likely to be compatible with survival, such as trisomy 21 (Down’s syndrome) are of major clinical importance. Those which are invariably lethal early in pregnancy are equally important from the point of view of the causes of chromosoma1 anomalies. The study of spontaneously aborted fetuses does, however, present considerable methodological problems. A substantial proportion are lost unbeknown even to the mother, and many abortions that are recognized never come to medical attention. Such abortions as are reported are selected for gestational age (the later they
occur the more likely they are to require medical treatment) and by the mother’s demand for medical care (which is influenced by factors such as cultural background, home circumstances, age and previous obstetric history). It follows that data on spontaneous abortions are nearly always collected without a full knowledge of the population from which they are derived. We can, however, determine the ratio of chromosomally abnormal to normal fetuses in a sample, and look at factors influencing this ratio. Provided that we have some knowledge of the effects such factors have on the overall incidence of reported spontaneous abortions, we can make some judgement on their probable relationship with chromosome anomalies. In this 621
622
ALBERMAN, CREASY, ELLIOTT AND SPICER
paper we are concerned particularly with the effects of maternal age, smoking, and previous oral contraceptive history.
PATIENTS AND METHODS With the co-operation of the medical and nursing staff of certain gynaecological units in and around London, we obtained information from 2620 mothers who had been admitted with spontaneous abortions between 1971 and 1974. Wherever possible, fetal products of conception were collected, examined macroscopically, and cultured for chromosome analysis. The data regarding maternal history were collected by interview in 91 per cent of all cases included; in the remaining 9 per cent, available information was abstracted from the hospital records. An account of previous obstetric history in these mothers has already been published (Alberman et al, 1975). A full description of the cytogenetic and pathological findings are given elsewhere (Creasy et al, 1976). The laboratory outcomes were classified into four main groups: no fetal tissue received, no or insufficient growth, chromosomes normal, and chromosomes abnormal (Table I). Other definitions used are usually selfexplanatory but two need to be amplified. The use of oral contraception is usually presented in groups of ‘ever’ users and ‘never’ users. Included in the ‘ever’ users are a proportion who have used hormones for therapeutic reasons. The latter indication often overlapped with their use for contraception, and it was difficult to distinguish clearly between the two. However, on analyzing the data for the last pill used, it appeared that 14 per cent of all takers had used it for therapeutic purposes. Overall this proportion would be lower, since women who had used several different types of ‘pills’ nearly always took them for contraceptive purposes. Smoking history is presented both as smoking habit in pregnancy or, where relevant, as those who had ever or never smoked. This is specified where it occurs. FINDINGS Products of conception received Table I shows the number of specimens received, their chromosome constitution, and whether the pregnancy had been single or
TABLEI Chromosomal constitution of pregnancies in series No tissue Tissue culture culture Normal normal Abset failed UP* Singleton Twins Total abortuses
Total
778 16
854 18
661 42
289 0
2582 76
794
872
703
289
2658
* Includes 777 with no fetal tissue in specimens received and 17 where no tissue was received at all.
multiple. Because each of the pair of twins were sometimes in different ‘outcome’ groups, most subsequent Tables in this account are based on the number of specimens, and not mothers. This means that the 38 mothers of twin pregnancies are counted twice. Ratio of chromosomally abnormal to normal abortions Figure 1 shows how the proportion chromosomally abnormal varied with maternal age, parity, smoking in the presenting pregnancy, social class and history of previous oral contraception. The proportion of abnormals can be presented as either a proportion of the total specimens collected, or of only those of known karyotype. Both proportions are presented for the sake of completeness although they show similar trends. This is because the failure of fetal cell culture or the absence of fetal tissue in the specimen was not influenced by the maternal variables under consideration, the individual proportions showing no significant difference from the average (xz = 110 on 91 d.f.; p>O-I). The clearest findings relate to the variation of the proportion abnormal with maternal age. There is a steep rise with maternal age, so that the proportion known to be abnormal out of the whole sample doubles from the under-20 age group to the over-40 age group. None of the other factors studied had an effect as large as this. Taking each of the factors individually, the proportion abnormal increased with the number of previous surviving livebirths, with rising social class, and a previous
-
65
CHROMOSOMAL ANOMALIES IN ABORTIONS
623
% out of known karyotype
0 % out of all cases
,---
G
55
E
Y
N
al u
&
- Ever - Never
45
d
5
2
35
I C)
-
x
2
; 5
25
15
b
if; 5
V this preg. Maternal age
Oral contraception FIG.
Smoking
Social class
1
Per cent of chromosomally abnormal abortions by maternal age, oral contraception, smoking this pregnancy and social class.
history of oral contraception. The proportion tended to fall with the number of cigarettes smoked in the presenting pregnancy.
8o
1
mSmoking 0 Not smoking
70 ’
60
$
50
5
40
B
,
)
I
this pregnancy
u 0
E
30
&
20 10
Age Social class
