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Discussion
The incidence of congenital malformations in the newborns of Goa
is found to be 19.4/1000 births and is comparable to the reports of similar
studies from various parts of the country such as Trivandrum (Sugunabi,
1982), Agra (Ajay et al., 1983), Davangere (Thomas, 1992) and Simla
(Neelam, 2000). However, this is much lower as compared to some of the
reports in other parts of India (Hemrajani et al., 1971; Tiberwal et al., 1974;
Verma et al., 1983; Mishra et al., 1989 and Swain et al., 1994.). Further the
incidence reported from Michigan was 34/1000 births (Evan et al., 1963)
while that in Afganisthan was 55/1000 births (Singh et al., 1982) and are
much higher than that observed in the present study.
The low incidence in the present study may be because the
malformations were studied only in the live births and no autopsies were
carried out due to the ethical sentiments of the parents. The incidence of
malformations reported at the global level, thus varies from 9/1000 to 55/
1000 births and is seen to be differing from country to country and from
region to region within the same country. However, the relative difference
in occurrence of malformations might also reflect some geographic and
racial differences.
Present study reveals that the most frequent malformation in Goa is
that of the musculoskeletal system (25.0% of the total malformations),
followed by the central nervous system and cardiovascular system. This
159
Discussion
observation is consistent with the findings of Ghosh et al. (1963), Mathur et
al. (1975), Chaturvedi et al. (1989) and Datta et al. (2000). Studies of
Khrouf et al. (1989) in Tunis, also reveals a high incidence of
malformations of the musculoskeletal system.
The incidence of central nervous system abnormalities, in the
present study is 22.17 % and is the second most common malformation
seen in the newborns of Goa. But some studies in other parts of India,
have reported malformations of the central nervous system as the most
common malformation (Purundara et al., 1966; Hemrajani et al., 1971; Puri
et al., 1979 and Neelam, 2000). So in most of the regions in our country,
the most frequent malformation seen is either that of the musculoskeletal
system or of the central nervous system. The high incidence of
malformations of the CNS in some regions may be because all those
studies included both live and still births. The incidence of the CNS
malformations in the present study is slightly lower than that of the MSS.
So the incidence of the malformations of the different systems is also seen
to be varying from region to region. This variation can be attributed to
various factors including the lifestyles, food habits and different cultures.
This study also reveals that the frequency of the malformation is
slightly higher in the females (51.20%) as compared to the males (48.8%),
but the difference was found to be statistically insignificant. Leck et al.
(1992), Temtany et al. (1998) and Datta et al. (2000) also reported such
160
Discussion
findings of insignificant difference in the number of malformations in the
males and the females.
But sexwise distribution of the malformations of the different
systems, in the present study showed preponderance in one sex. The
frequencies of the malformations of the MSS, CNS and the CVS were
higher in the females while those of GIT, GUS and RES were higher in the
male newborns. Our findings of preponderance of malformations are in
agreement with the observations of Potter (1964), Someshwar et al. (1973)
and Thomas (1992).
The present study shows a high incidence of malformations among
the Muslims (10.0%) as compared to the Hindus (2.14%) and Christians
(1.46 %) [X=7.59, p<0.01]. This may be on account of the higher rate of
consanguineous marriages among the Muslims. Present study also reveals
significantly high incidence of malformations among the offspring of the
consanguineous marriages (X=10.401, p<0.001). This indicates that
consanguinity may be one of the causation factor of congenital
malformations. Similar observations are reported earlier in many studies
(Stevenson et al., 1967; Someshwar, 1973; Mathur et al., 1975; Sugunabi
et al., 1982; Temtany et al., 1998 and Rider et al., 2001). Further, the
frequency of the malformations is significantly higher in the offspring of
second degree consanguinity as compared to the offspring of the third
degree consanguinity. Therefore, homozygosity of some recessive
161
Discussion
genes on account of consanguinity, may be another factor which can
cause malformations.
Parental age is seen to be associated with the increase in the
frequency of malformations, in the present study. The risk of having an
offspring with congenital malformation is seen to be significantly increasing
with the increase in the maternal age [X=23.91, p<0.0011. In the present
study, the malformations seen to be associated with the increased
maternal age are those of the GIT, CVS and CNS. These malformations
included cleft lip and/or cleft palate, hydrocephalus and ventricular septal
defect. The syndromes associated with the advanced maternal age are
trisomies of the 13 th, 18th and 21 st chromosomes. In most of the newborns
showing trisomies the maternal age was advanced (>30 years).
Malformations associated with the advanced maternal age may be on
account of the error in the cell division, which may occur on account of
genetic predisposition of the ova to nondisjunction during meiotic division I
or II. This error may occur during the early meiotic division of the
embryonic development or during the I or II meiotic division. However,
there was no chromosomal abnormality in the lymphocytes of the parents
and hence the error must have occurred during the meiotic division of the
ova.
These observations are in agreement with the observations of
Ghosh et al. (1963), Carter (1970), Tiberwal (1974), Sugunabi et al.
162
Discussion
(1982) and Jyothy et al. (2000). The rise in the rate of malformations with
rise in the paternal age in the present study may be because the males
were always older than their female counterparts. No association was
observed between congenital malformations in the offspring of couples,
when paternal age was >30 and maternal age <30 and so also in couples
were paternal age is <30. This indicates that paternal age may not be
contributing to the rise in the frequency of congenital malformations.
The present observation of a significant rise in the incidence of
congenital malformations in the offspring born to mothers who had
previous history of abortions indicates genetic origin of some congenital
abnormalities. In such couples, one partner may be a carrier of a
chromosomal rearrangement, which predisposes them to severe
imbalance through mal-segregation at meiosis.
The frequency of congenital malformations in those with a positive
sibling and family history of malformations in the present study is slightly
higher than those without. However the difference is found to be
statistically insignificant. This may indicate a sporadic nature of occurrence
of most malformations. Therefore many malformations may be occurring
de novo due to nondisjunction during parental gametogenesis.
Rise in the frequency of congenital malformations (X=10.9, p<
0.001) observed in the present study, in those newborns exposed to
163
Discussion
hyperthermia on account of maternal fever during pregnancy indicates that
maternal gestational fever may be one of the causes of congenital
malformations. The malformations seen to be associated with maternal
fever are those of the CNS (hydrocephaly, microcephaly, anencephaly and
meningomyelocele), CVS (patent ductus arteriosus and ventriculoseptal
defect) and limb abnormalities. These malformations may be on account of
the hyperthermia, which alters the tissue growth or interferes with the
cellular differentiation. The failure of hyperthermia to induce malformations
in all the mothers who had a history of gestational fever, may be because
only some conceptus have genetic predisposition, which again is
determined by the genotype of the conceptus. Therefore, this study shows
that hyperthermia on account of maternal fever during the first trimester
may be having a teratogenic effect on the developing organs of the CNS,
CVS and the limbs of the human embryo.
Association between the hyperthermia and the CNS malformations
in the human population is reported earlier, in the epidemiological studies
of Edwards (1972), Miller (1978), Smith et al. (1978), Leck (1978), Chance
et al. (1978), Loyde et al. (1980), Shiota (1982), Cristo et al. (1987),
Peterka et al. (1994) and Edwards et al. (1995). Animal studies (Skreb et
al., 1963; Edwards, 1968 and Shiota et al., 1989) also report an
association of the CNS malformations with hyperthermia. CVS
malformations are also reported by Pearson and Skelton (1978) and
164
Discussion
Tikkanen et al. (1991). Limb abnormalities were noted by Martinez et al.
(2001). Numerous studies suggest that hyperthermia during pregnancy is
associated with malformations. The present study is yet another additional
case supporting the hypothesis that hyperthermia may be an extremely
potent teratogen causing malformations of the CNS, CVS and limb
abnormalities.
The frequency of malformations is higher in the offspring of the
mothers who had consumed paracetamol during pregnancy (X=5.27,
p<0.05). The genotoxicity of paracetamol was assessed through the
micronucleus test. The insignificant increase in the micronuclei in the mice
treated with paracetamol doses (0.030 and 0.060 grams/ Kg bodyweight/
day) indicates that paracetamol is not genotoxic at the normal prescribed
doses. But the treatment of the same doses of paracetamol to the female
mice during pregnancy resulted in the termination of the pregnancies in all
the treated mice. Though the therapeutic doses are non-genotoxic, the
repeated abortions of the fetuses of the treated mice in the present study
indicates that paracetamol may cause reproductive toxicity and may
therefore act as a teratogen.
The present study also shows that the frequency of occurrence of
malformations is significantly higher in the offspring of the fathers who were
habitual alcohol consumers (X=7.79, p<0.001). The malformations
observed in the offspring of such fathers are that of the MSS, which
165
included hypermovable joints, knee contractures, elastic skin and
congenital talipes equinovarus. Other malformations seen are
hypertelorism, tonguetie, protruding tongue and ventriculoseptal defect.
Animal experiments of paternal alcohol consumption in the present study
also shows a significant increase in the frequency of malformations in the
offspring of the male mice who were treated with alcohol doses. There is
decrease in the litter size and increase in the fetal weight. Malformations
observed in the fetus are hypertelorism, protruding tongue, polydactyly,
laxed skin, short limbs, hydrocephalus and hyperflexible joints. Because of
similar malformations observed in the human population and in the
experiments on mice, it can be postulated that paternal alcohol
consumption may be resulting in malformations, especially of the
musculoskeletal system in the offspring.
Effect of paternal alcohol exposure, on the human offspring was
studied earlier by Cake (1985), Friedler (1988), Hamesmaki et al. (1989),
Abel (1992) and Cicero (1994). Further, animal studies (especially on the
male rats and mice) have also shown to effect the offspring (Leichter,
1986; Abel and Moore, 1987 and Abel, 1995).
Chromosomal abnormalities are observed in 24.1% of the
newborns. All the newborns with malformations were subjected to
cytogenetic analysis in the present study, unlike several other studies
where cytogenetic analysis was carried out only in suspected cases of
166
chromosomal abnormalities or of multiple congenital abnormalities of
unknown cause. Although the theoretical selection criteria are generally the
same, the ability to exclude "known or recognizable" syndromes varies
from one service to another. There are reports of children referred for
cytogenetic examination for multiple congenital anomalies excluding
Down's, with frequencies of chromosomal abnormalities ranging from
11.9% to 27.6% (Winter et al., 1980; Verma and Dosik, 1980; Mehes and
Bajn'oczky, 1981; Coco and Penchaszadeh, 1982; Billerbeck, 1986). Yet in
these reports, there is no way of knowing the total number of births
screened and they do not deal only with the newborn infants. Other studies
on congenital malformations in the newborn infants including the stillbirths
and the malformed fetuses, report the number of cases with chrOmosomal
abnormalities but do not always mention the number of infants referred for
cytogenetic examination (Van Regemorter et al., 1984; Stoll et al., 1986;
Farhud et al., 1986).
The present study can be compared to the study of Bochkov et al.
(1974) and Borovik et al. (1989). Excluding the Down's syndrome,
abnormal chromosome constitution is found in 13.65% cases in the study
of Bochkov et al. (1974) and 28.4% in the study of Borovik et al. (1989). In
the present study, it is 15.06% and is lower as compared to the study of
Borovik et al. (1r9). This can be becat4§9, 9f t of only conventional 141P 1,1
techniques in th9 present stwAy to cletect.t4 chromosomal abnormalities,
167
which must have overlooked some submicroscopic microdeletions, which
encompass multiple genes that contribute to the phenotype. Use of modern
techniques such as FISH would have probably resulted in the increase in
the frequency.
The rate of the chromosomal abnormality of trisomy 21 is found to
be 1/658 births in the present study. This can be compared to the rates
found by Borovik et al., 1989 (1/741); Farhud et al., 1986 (1/813) and Van
Regemorter et al., 1984 (1/476). The rate reported by Stoll et al. (1986) is
slightly lower (1/971) as compared to the present study (Table 3.40). The
high rate in the present study may be attributed to the advanced maternal
age in most of the cases.
Trisomy 18 shows a rate of 1/2857 in the present study. This is
comparable to the rates reported by Van Regemorter et al., 1984 (1/2500).
However Borovik et al., 1989 and Stoll et al., 1986 reported intermediate
rates of 1/6099 and 1/4990 respectively. The rates reported by Bochkov et
al., 1974 (1/15,944) and Farhud et al., 1986 (1/13,037) are much lower.
The rate of trisomy 13 in the present study is 1/8333 and is lower
than the rate reported by Stoll et al., 1986 (1/4990), but higher than the
rates reported by Bochkov et al., 1974 (1/15,944); Farhud et al., 1986
(1/13,037) and Borovik et al., 1989 (1/24,397).
168
Discussion
Monosomy X is seen in 1/ 4348 births in the present study and is
almost comparable to Stoll et al., 1986 (1/6654), but higher than the rates
of Bochkov et al., 1974 (1/31,888); Van Regemorter et al., 1984 (1/10,000)
and Borovik et al., 1989 (1/24,397).
Table- 3.40: Comparison of the rate of numerical abnormalities in the present study compared to other studies.
Authors Births
Trlsomy 21 Trisomy 18 Trisomy 13 Monosomy X
No Rate No Rate No Rate No Rate
1 31,888 - 2 1/15,944 2 1/15,944 1 1/31,888
2 10,000 17 1/476 4 1/2500 1 1/10,000
3 39,924 41 1/971 8 1/4990 8 1/4990 8 1/6654
4 13,037 16 1/813 1 1/13,037 1 1/13,037 -
5 73,192 99 1/741 13 1/6099 3 1/24,397 3 1/24,397
*6 8551 13 1/658 3 1/2857 1 1/8333 2 1/4348
(1 )-Bochkov et al. (1974). (2)- Van Regemorter et al. (1984). (3) Stoll et al.(1986). (4)- Farhud et al. (1986). (6)- Borovik et al. (1989).
*(6)- Present study.
The high rate of trisomies 21, 18 and 13 and the monosomy X in the
present study can be attributed to the advanced maternal age. The
maternal age was above 30 in 76.9% (10/13) of trisomy 21, 66.7% (2/3) of
trisomy 18, 100% of trisomy 13 (1/1) and 100% of monosomy X (2/2). This
shows a genetic predisposition of the ova to nondisjunction with increased
maternal age. Therefore, it can be postulated that advanced maternal age
may be leading to the rise in the chromosomal abnormalities such as
169
Discussion
trisomy 13, 18, 21 and monosomy X on account of gametic non-
disjunction.
Mosaics encountered in the present study includes 46,XX/45,X0
and 46,XX/XY / 47XX/XY +21. The proportion of 46,XX and 47,XX+21 cell
lines are almost equal, indicating a very early nondisjunction event, as
early as the second mitotic division. In case of the 46,XX/45,X0 mosaic the
proportion of the two cell lines is unequal, suggesting that nondisjunction
event has occurred at a much later point of development (late morula or
early blastula).
Critical regions, in the form of gaps and breaks are observed on the
1 St, 2nd , 4th and 13th chromosome. A break is observed on the 'q' arm of the
chromosome I in a case having ventriculo septal defect associated with
dysmorphic facies. So it may be assumed that some genes controlling the
normal development of the cardiovascular system may be present on 1 q.
A break in the 'q' arm of chromosome 2 is seen to be associated
with meningomyelocele and congenital talipes equinovarus. Therefore, it
may be assumed that the some genes on 2q controls the development of
the CNS and MSS.
Critical regions in the form of breaks are observed on the 'q' arm of
the 4th chromosome in many cases. In almost all these cases, the major
- malformations observed are that of the musculoskeletal system. This
170
Discussion
includes unilateral ectrodactyly of the right-hand and foot, absence of
fibula, congenital talipes equinovarus, advanced bone age, prominent
frontal bone and flat nasal bridge.
Deletions of the q arm of the chromosome 4 at the terminal or
interstitial regions are reported earlier by Davis et al. (1981); Back et al.
(1983); Campbell et al.(1986); Butler et al. (1987) and Angela et al.(1988)
and are mostly seen to be associated with malformations of the limbs.
Malformations associated with deletions of 4q are also reported by Ockey
et al. (1967); Serville et al. (1977); Schroff et al. (1981); Yu Cw et al.
(1981); Mitchell et al. (1981); Del Valle Torando (1982); Lech et al. (1982)
and Lipson et al. (1982).
Thus, from the observations in the present study and the earlier
reports, it can be postulated that some of the genes required for normal
development of the skeletal system may be present on the 'q' arm of the 4 th
chromosome.
A break in the 'q' arm of the chromosome 13 is observed in a case
with a large posterior encephalocele, cyclops, hypoplastic forearms,
abnormal genitalia and absence of nose and thumb. It can be assumed
that some missing genes on one chromatid of the chromosome may be the
cause of the expression of such a phenotypic character.
171
Discussion
Partial deletion of the 13' arm of both the homologous pair of the X
chromosome is associated with skeletal deformities including joint
contractures at the knees, rib deformity, restricted movement of the
shoulders and the hip and wasting of the thigh muscles.
In an unusual case, which had all the features assigned to trisomy
13, the cytogenetic study revealed a normal chromosome constitution of
46, XX. Similar cases were reported earlier by Young and Madders (1987);
Shiota and Tanimura (1988); Cohen et al. (1989) and Moerman et al.
(1988). It was suggested that such cases be called Pseudotrisomy 13. The
present study agrees with these earlier reports. Thus it can be postulated
that the presence of an entire chromosome 13 may not be essential for
manifestation of the phenotypic characters in Patau's syndrome. The
characteristic phenotype is on account of presence of a few genes of the
13th chromosome in triplicate, which may be translocated on any other
chromosome thus giving a normal constitution of 46XX.
In the same case, the chromosomes showed a characteristic
separation of the chromatids with puffing and splitting of the chromosomes
at the centromere. This abnormality termed as 'Premature centromeric
separation' (PCS) was reported earlier by Judge (1973); Tomkins et al.
(1979); German (1979); Davis et al. (1989) and is seen to be associated
with Roberts-SC- phocomelia. PCS is also reported by Anguilar et al.
(1988) and was seen to be associated with Dyskeratosis Congenita. In
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the present study PCS is seen in 48% of the metaphase plates. PCS is
thought to reflect a generalized disturbance in cell division correlating with
numerous congenital anomalies and stunted growth (Tomkins and Sisken,
1984).
Based on the results and analyses of the present study the following
management strategies can be recommended to prevent, diagnose or treat
the congenital malformations in Goa:
MANAGEMENT OF CONGENITAL MALFORMATIONS IN GOA.
The birth of a child with a malformation places severe stress on the
parents and on the other family members. This stress imposed on the
parents may be helped considerably by understanding the causes of the
malformations. The present study shows that many human malformations
arise because of the interplay of both genetic and environmental factors,
though some of them may be solely genetically determined. Based on the
findings of this study, the following management strategies can be outlined
for the prevention or reduction of congenital malformations in Goa.
(1) PRECONCEPTUAL COUNCELLING:
> To prevent the birth of a malformed child preconceptual counseling is
recommended to make the couples aware of the potential sources
resulting in congenital malformations.
173
> It is advisable for the women to avoid drug intake around the time of
possible conception and throughout early pregnancy, unless there is a
strong medical reason for its use.
> It is advisable for the women to avoid potential sources of infections
which might lead to malformations in the developing embryo, or which
might result in hyperthermia in the mother.
> It is prudent to be cautious during diagnostic examinations of the pelvic
region in the pregnant women, especially diagnosis involving the use of
X-radiations.
> Exogenous lifestyle factors including smoking and alcohol consumption
and endogenous factors viz. age and gender etc should also be
considered during counseling.
> It is advisable for the prospective fathers to refrain from alcohol
consumption at least three months in advance before attempting to
have children.
> Premarital genetic counseling is also advised, especially in the
presence of parental consanguinity and positive sibling and family
history of congenital malformations.
> A genetic counseling session is of great benefit not only from the point
174
of view of arriving at a diagnosis, but because it also offers an
opportunity to obtain further information of the condition and for the
parents to get educated about the accurate circumstances.
(2) PRENATAL DIAGNOSIS:
➢ Prenatal diagnosis for malformations using ultra-sonography at around
16 weeks of pregnancy should be a routine procedure.
➢ Cytogenetic prenatal diagnosis of Down's syndrome and other
chromosomal abnormalities should be done in high risk cases.
(3) POSTNATAL MEDICAL SURGERY:
➢ Malformed children have fewer social contacts and therefore,
intervention to improve or correct the malformation by medical surgery
wherever possible may have a dramatical effect on a child's self
esteem.
(4) POSTNATAL CYTOGENETIC STUDIES:
➢ Chromosomal studies should be undertaken for every child with
congenital abnormality.
• Establishing a chromosomal diagnosis will prevent further potentially
unpleasant investigations being undertaken.
175
• Information about the prognosis can be provided along with the
details of the relevant lay society and an offer of contact with other
families.
• A chromosomal diagnosis should facilitate the provision of accurate
information about the recurrence risk for future siblings.
> In case of a birth of a child with ambiguous genitalia, a chromosomal
analysis should be amongst the first investigations undertaken, to
assign the gender of the newborn and for easing the inevitable parents
anxiety.
> From this study we emphasize the accurate and early diagnosis of,
congenital malformations is the key to proper management of cases.
> Taking into consideration the importance of cytogenetic analysis, in
diagnosis and management of congenital malformation, establishment
of a 'Genetic Centre' in Goa is recommended.
These management strategies will help to prevent, diagnose or treat
the congenital malformations in Goa thereby reducing the stress imposed
on the parents of the malformed children.
* * *
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