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Actu
Psychiatr
Scand
1997:
96:
260-264
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in
UK
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all
right.? reserved
Copvright
0
Munksgaard
1997
ACTA PSYCHIATRICA
SCANDINAVICA
ISSN
0001
-690X
Fertility and schizophrenia: evidence for
increased fertility in
schizophrenic patients
the relatives
of
Srinivasan
TN,
Padmavati
R.
Fertility and schizophrenia: evidence for
increased fertility in the relatives of schizophrenic patients.
Acta Psychiatr Scand 1997: 96: 260-264.
0
Munksgaard
1997.
Fertility has been observed to be reduced in patients with schizophrenia,
although the disorder was seen to occur at a steady rate in the general
population. The hypothesis of increased fertility in the healthy relatives of
the patients, which maintained the genetic contribution to the disorder has
been proposed but has not received much support. The present study reports
the fertility rate in 100 schizophrenic patients and their relatives
(grandparents, parents, uncles, aunts and siblings). The fertility of the
different family members was compared, taking into account the completion
of
age
of
maximum reproductivity, i.e. up to
50
years of age. The trends in
fertility rates over three generations of patients’ families were compared
with those in the general population of India over a corresponding period
from 1950 to 2000 AD. The patients were observed to be hypofertile, but
their parents showed
a
higher fertility than all other relatives, as well as the
general population. The siblings of the patients also tended to have higher
fertility rates than the general population. This increased fertility in parents
and sibs, who are the probable carriers
of
the abnormal gene, could
compensate for the reduction in genetic contribution to morbid risk for
schizophrenia due to reduced reproductivity of the patients themselves.
Introduction
The genetic contribution to the origin
of
schizo-
phrenia is now well accepted. Reproductive beha-
viour is an important variable in the epidemiological
studies of the disorder, and needs to be taken into
consideration when attempting to clarify the gene-
tic contribution to the disease
(1).
The fertility
of
patients with schizophrenia has been repeatedly
shown to be lower than that
of
patients with other
psychiatric disorders, as well as of the general
population
(1-5).
On the other hand, schizo-
phrenia has been observed to occur at a steady rate
in populations of different regions over a long
period of time
(6).
Hence some explanation is
required for this apparently stable occurrence of
the disorder in the face
of
reduced reproductivity
of the patients. Lane et al.
(5)
suggested that there
could be an increase in the role
of
environmental
factors over time in the aetiology
of
the disorder,
which would overcome the reduction in genetic
contribution due to reduced fertility.
A
high rate
T.
N.
Srinivasan,
R.
Padmavati
Schizophrenia Research Foundation (India). Anna
Nagar (East). Madras, India
Key
words:
schizophrenia, fertility; India
T.N. Srinivasan. Schizophrenia Research Foundation
(India).
C-46.
13th Street, Anna Nagar (East),
Madras
-
600
102, India
Accepted for publication January
4,
1997
of
genetic mutation which could compensate for
the low reproductivity has also been cited as an
explanation
(1).
The studies on reproductivity of schizophrenic
patients have offered other explanations for the
steady occurrence
of
the disorder. It was suggested
that a subgroup of patients produced greater
numbers of offspring, thus maintaining the morbid
risk for developing the disorder in a larger number
of individuals
(5).
In this context an increase in
fertility has been observed in married male patients
compared to married female patients
(5).
Yet
another explanation that has been offered is that,
following widespread deinstitutionalization and out-
patient treatment in recent decades, more patients
have had an opportunity to marry and reproduce,
so
contributing to the morbid risk for the disorder
Several references have been made to the fact
that if the healthy relatives of the patient, some of
(3,
7-9).
260
Fertility
and
schizophrenia
whom are presumed to be carriers of the abnormal
gene in the heterozygous state, show increased
fertility, this would explain the perpetuation of the
disorder despite the low fertility of the patients
(1,
3,
5,
7,
10-13).
A
few studies on the fertility
of
relatives of the patient have supported this view.
A
study comparing schizophrenic patients with
normal controls showed that the parents and pa-
ternal
grandparents of the patient were more fertile
than
the patient, a trend which was not observed
in
normal healthy subjects
(4).
In another study,
the
parents of male patients with a high familial-
genetic loading were shown to be more repro-
ductive than the parents of patients without such a
family history
(14).
This increased fertility among
relatives who are putative carriers of the abnormal
gene for schizophrenia
is
comparable to the
increased fertility of the relatives of patients with
cystic
fibrosis, which is also associated with reduced
reproductivity of the affected individuals (10).
One important factor that needs to be taken into
account in understanding the changes in fertility
from generation to generation in the families of
patients is the changes in the fertility rate of the
general population which occur worldwide. The
fertility rate has been reported to be declining in
many parts
of
the world over time, but at different
rates. For example, in India, the population had
shown a minimal decrease in the total fertility rate
from the mid-1950s to 1970s, followed by a more
steady fall until the mid-1990s
(15).
Against this background, the present study was
conducted with the aim
of
measuring and comparing
the fertility rate among schizophrenic patients and
their relatives across three generations (grand-
parents, parents and siblings of the parents, and
patients and their siblings). The study also aimed
to compare the changes in fertility in the families
of the patients with fertility changes in the general
population. For the purposes
of
such a comparison,
the general population rates (measured for women),
recorded (and projected) for the period 1950 to
2000
in the World Development Report
(15),
was
used. This period was considered to be representa-
tive of the reproductive period
of
the three gene-
rations of the patients’ families
(1950
with that of
the grandparents, 1970 with that of the parents,
uncles and aunts, and
2000
with that of patients and
their siblings).
Material and methods
The study was conducted on 100 patients with
schizophrenia (according
to
DSM-IV criteria) who
attended the out-patient centre of the Schizophrenia
Research Foundation (India), in the city of Madras
in
southern India.
All
of the patients had been ill
for a minimum period of 3 years. There were 60
male and
40
female patients, and 48 patients were
married. The mean age of the married patients was
36.2 years; five
of
them were over
50
years of age.
They were all from the urban and suburban com-
munities of Madras,
84%
of them belonging to the
Hindu religion,
30%
of them belonging to higher-
and middle-income group families, and the rest
from families of lower socio-economic status. The
interview was conducted with the patient, his or
her parents and/or other older relatives who were
readily available for the enquiry. The following
details were recorded: the age of the parents and
the number of their children (parental fertility);
the number of siblings of the father and mother
(fertility of paternal and maternal grandparents);
the age, marital status and number
of
children
of the siblings of the father and mother (fertility of
paternal and maternal uncles and aunts); the age,
marital status and number of children of the
siblings
of
the patient (fertility of the siblings
of patients); the age, marital status and number of
children of the patient (fertility of patients).
For the purposes of this study, fertility rate was
defined as the number
of
live children born to the
individuals as in other studies
(4,
14).
Reports on
fertility rates for women in the population gener-
ally considered
50
years of age to be the end-point
of maximum reproductive activity (15). In this
study the same age limit was applied for both sexes.
The fertility rates of all of the married subjects and
for those
a50
years of age among them were
measured. The fertility of all female subjects who
had reached
50
years of age was also measured
separately. The reproductivity of the patients and
their siblings, the parents and their siblings and the
grandparents was compared. The rates measured
for those over 50 years of age were only taken for
this comparison, except in the case of patients for
reasons described below. The fertility rate
of
women who completed their reproductive activity
were compared with the reported trends in total
fertility rate of the Indian women
(15).
Results
The fertility rates measured are shown in Table 1.
There were only
5
patients, including one female
subject over
50
years of age. Among the relatives
there was no gross difference between the fertility
of those who were
50
years of age or over and that
of
their respective total group, except in the siblings
of the patient. The older siblings had a fertility
rate
49%
higher than that
of
the total group. The
older female siblings had a rate 13% higher than
that of the total older group.
As
very few of the
patients had passed the end-point of maximum
26
1
Srinivasan and Padmavati
Table
1.
Fertility rate in three generations
of
the family of patients
Mean number of children
(SD)
In)
All
married Married females
above
50
years
above
50
years
Generation Family members
All
married of age
of
age
Paternal grandparents
Maternal grandparents
Parents
Paternal uncles and aunts
Maternal uncles and aunts
Patients
Patients' siblings
5.06
(2.39) (1
00)
5.06
(2.39) (100)
5.06
(2.391 (100)
4.87 (2.63) (100) 4.87 (2.63) (100) 4.87 (2.63) (100)
5.16 (2.36) (100)
5.56
(2.39) (77) 5.22 (2.39) (94)
3.41 (2.14) (353) 3.63 (2.13) (295) 3.59 (2.24) (133)
3.05
(2.13) (331) 3.27 (2.22) (259) 3.64 (2.48) (128)
1.31 (1.85) (48) 1.40 (1.04) (5) 1.11 (1.43) (17)"
1.83 (1.41) (271) 2.73 (2.14) (44) 3.09 (2.16)
(22)
a
Includes
all
married patients.
reproductive activity, the fertility rate of the total
patient group was taken for comparison with the
relatives. If it was assumed that all of the married
patients were
50
years
of
age or over and were
comparable with their siblings with regard to
fertility, then the fertility rate
of
the patients would
be 1.9 instead of 1.31 (i.e. 49% higher), and the
fertility rate of the female patients would be 1.58
instead of 1.40 (i.e. 13% higher).
The comparison
of
fertility rates among the
patients and relatives using the Z-statistic is shown
in Table
2.
It was seen that the reproductivity
of
the parents was highest by comparison with that of
the grandparents, and significantly higher than that
of their own siblings (uncles and aunts of the
patient) and children. The fertility of the siblings
of the patient was significantly lower than that of
all other relatives, except for maternal aunts and
uncles and the patient. The patients were the least
fertile subjects. Although they were not signifi-
cantly different from their siblings, the latter had
more children. The trend towards a decline in the
Table
2.
Comparison of fertility of patients and relatives: z-values
Paternal Maternal
Relationship Father Mother siblings siblings Patient
Paternal
Maternal
Fathers
Mothers
Patient's siblings
Patients"
grandparents
grandparents
1 38
5 62"
NS
1
82
4
65
NS
6
45" 7
50"
670" 670"
260""
154
NS
185
NS
1081" 1081" 724"
6
0"
a
Includes all married patients
(n=48)
NS.
non-significant.
*
P<O.OOl.
**
PiO.01.
fertility of the patients and their families is shown
in Fig.
1.
The changes in fertility of the female subjects
in
the general population in India, and in the families
studied, are plotted in Fig. 1. The overall trend in
the fertility of Indian women is seen as a steady
decline from
5.8
during 1950-1970 to 3.9 during
1970-1990, to a projected rate of
2.5
in
2000~~.
Comparison of this trend with the two lineages
of
the patient's families showed two patterns. In the
lineage
of
grandparents-parents-patient
(female),
the fertility of parents
(5.2)
is much higher than
that of the general population for the correspond-
ing period (1970-1990), whereas that of the female
patient (1.1) fell well below that of the average
female in 2000
AD.
In the other lineage of grandparents-aunts-
sisters, the fertility of aunts (3.6) is similar to that
of the general population for the period 1970-1990,
but the fertility
of
the sisters
of
the patients (3.1)
is above that
of
an average Indian women in
In summary, the results indicate the following:
2000
AD.
(i) increased fertility of the parents of the patient,
higher than that of other relatives and the
general population;
(ii) a trend toward increased fertility of the siblings
of the patient;
(iii)a decline in the fertility of uncles and aunts
following the trends in fertility of the general
population;
(iv) lowest fertility in the patients, lower than that
of
the general population.
Discussion
There are several issues which need considera-
tion in studies on fertility in schizophrenia. It
is
262
Fertility
and
schizophrenia
1950-1970 1971 -1990 1991-2000
Year
-
general population
--C-
patients
+
siblings
Fig.
1.
Change
in
fertility rates.
necessary to consider the low marriage rates
reported in affected individuals, as this has been
attributed to the low productivity in schizophrenia
(16,
17).
Other factors include divorce, childbearing,
termination of pregnancies, pre-marital and extra-
marital pregnancies, and the use of artificial repro-
duction methods which can affect the measurement
of
fertility. Studies also need to consider the age of
the
subject and their family members, in order to
establish whether all of them have passed their
period of maximum reproductivity. As indicated
earlier, one should be aware of the trends of change
in
the fertility of the general population of the
region from which the study subjects originated.
This study has taken into account most of these
issues. The Indian population of the type studied
here provided a specific opportunity to study
fertility in a setting with high rates of marriage,
most of which are stable over a long period of time
(18),
and in the absence of extramarital pregnan-
cies and the use of artificial methods of repro-
duction. As only the live births were included in
the study, terminated pregnancies did not confound
the observations.
Methodology
This study has taken into consideration some
aspects that have not featured in similar studies.
One of these was the estimation of fertility of sub-
jects who had completed their period of maximum
reproductivity. Although this issue was examined
in
one study
(l),
most other recent studies have not
addressed it (4,
5,
9). The present study compared
fertility among individuals who had completed
their reproductive activity. Although it could not
be applied to the patients, the fertility rate calcu-
lated for patients comparable with the fertility of
their siblings did not appear to be grossly different.
The mean age of the patients was 36.2 years. The
maximum reproductivity of the Indian population
was estimated to occur between the ages of
15
and
29 years, which accounted for
75%
of the total
reproduction rate (19). Hence the patients in the
study, although younger than their other relatives,
could be considered to have completed their period
of
maximum reproductive activity. For these two
reasons we feel that the comparison of fertility of
all the patients as a group with their older relatives
would be quite appropriate. Even if the absolute
values are different, the trend in the fertility
observed would still hold good.
The second issue concerned the number and nature
of the relatives studied. Previous studies have
examined fertility of the parents, siblings (14) and
grandparents (4), but not all of these have featured
in the same study. Our measurement of fertility
in aunts, uncles and siblings of the patients did
yield results which influenced the inference that
there was an increased fertility among parents and
siblings
of
the patients.
The comparison of national trends in fertility
with trends at the family level was a unique feature
of this report. Although the general population’s
fertility rate was considered by Lane et al.
(5),
the
trend in fertility over a period of time was not
studied. The comparison was made only among the
female subjects, as the national trends in the World
Development Report
(15)
measured the total fertility
rates of female members of the general population.
A comparison over time, as was made in the
present study, could help to aid our understanding
of changes in fertility in schizophrenia with refer-
ence to changes occurring over time in the general
population.
This study does have limitations in that its find-
ings relate specifically to individuals with chronic
schizophrenia who were receiving treatment as out-
patients. Fertility has been related to severity of
illness (l), and also to the familial genetic loading
for schizophrenia (14). These two issues have not
been addressed here.
Fertility
and
schizophrenia
This study has shown that, although the patients
with schizophrenia tended to be hypofertile, their
parents produced more children than any other
relative, and than the general population. The
siblings
of
the patient also tended to be more fertile
than the general population. These observations
lend support to the hypothesis of increased fertility
among the relatives of schizophrenics compen-
sating for the lowered reproductivity of the patients
themselves.
There are several possible genetic mechanisms
which could underlie such an increase in fertility
among the relatives. The alleles for schizophrenia are
possibly maintained in the population by positive
263
Srinivasan and Padmavati
rather than negative selection
of
heterozygous
healthy individuals
(1,
10).
The genes for the
disorder could also be influenced by positive selec-
tion by being closely linked to other genes whose
alleles are favoured by selection or by an epistatic
reaction with an unlinked gene
(20).
Gottesman
and Shields
(12)
proposed that the penetrance of
the schizophrenia genotype in healthy relatives
could be suppressed by other genes which also
enhance fertility in these individuals. In this study,
maximally increased fertility was found in the
healthy parents of the patients, who were obvious
carriers of the gene for schizophrenia. Any of the
genetic mechanisms proposed above could explain
the underlying process.
In conclusion, this study has shown that the
schizophrenic patients displayed lower fertility
than of all their close relatives, as well as compared
to the general population. The patients’ parents
had more increased fertility than any other rela-
tives, and than the general population. The fertility
rate of the siblings of the patient was also higher
than the national rates for the population over
the same time period. Although the patients in this
study were young and had not completed the
reproductive phase of their life, there is a clear
trend in fertility rate over the three generations of
patients’ families. The increased fertility among the
parents and siblings of the patient, the most prob-
able carriers of the abnormal gene, could be the
mechanism whereby the genetic contribution to
the morbid risk for schizophrenia is maintained in
the face of reduced reproductivity
of
the patients
themselves.
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264
