-AN- MJBA-330305.
-TI- Original Articles: Absence of An Environmental Effect on the Recurrence of
Facial-Cleft Defects.
-AU- Christensen, Kaare; Schmidt, Marianne M.; Vaeth, Michael; Olsen, Jorn.
-SO- The New England Journal of Medicine. 1995 Jul 20. 333 (3). pp 161-164.
-IS- 0028-4793.
-PD- 950720.
-PT- Original Articles
-PU- Copyright 1995 by the Massachusetts Medical Society.
-IN- From the Danish Epidemiology Science Center research unit at the Steno
Institute of Public Health, Department of Epidemiology and Social Medicine,
Aarhus (K.C., M.M.S., J.O.); the Odense University Medical School, Odense
(K.C.); and the Department of Biostatistics, Aarhus University, Aarhus (M.V.) --
all in Denmark. Address reprint requests to Dr. Christensen at the Steno
Institute of Public Health, Department of Epidemiology and Social Medicine,
Norrebrogade 44, Bygning 2C, 8000 Aarhus C, Denmark.
Supported by the Egmont Foundation, Frode V. Nyegaard and Wife's
Foundation, Lily Benthine Lund's Foundation, Torkil Steenbeck's Foundation, and
Ville Heise's Foundation, and by a grant (JN12-1663-1) from the Danish Medical
Research Council.
-AB- Abstract
Background: The rate of recurrence of a broad range of birth defects may
decrease among women who change residence after the birth of their first infant.
The aim of the present study was to determine the effect of changing residence
on the recurrence of congenital facial-cleft defects.
Methods: We identified 4189 women who had had infants with facial-cleft
defects by linking a data base comprising the records of children with facial
clefts born between 1952 and 1987 with the Central Person Registry in Denmark.
Among the 4189 mothers, 1902 each had additional children after the first child
with a facial-cleft defect. A total of 2692 younger siblings were identified. We
compared the proportion of infants with facial-cleft defects among the younger
siblings between mothers who had changed municipalities or sexual partners and
those who had not.
Results: Changing the municipality of residence did not decrease the
frequency with which facial-cleft defects recurred in younger siblings. Among
the 907 infants of mothers who changed municipalities but not partners, 29 (3.2
percent) had facial-cleft defects, as compared with 48 (3.4 percent) of 1425
infants of mothers who changed neither municipality nor partner (relative risk,
0.9; 95 percent confidence interval, 0.6 to 1.5). However, a change of partner
reduced the recurrence risk significantly. Among 236 infants of mothers who
changed partners, 1 (0.4 percent) had a facial-cleft defect, as compared with 77
(3.3 percent) of 2350 infants of mothers who did not change partners (relative
risk, 0.1; 95 percent confidence interval, 0.02 to 0.9).
Conclusions: Recurrence of facial-cleft defects is not linked to the
residence of the mother, but having a different partner reduced a woman's risk
of having a second child with this defect. (N Engl J Med 1995;333:161-4.)
-TEXT-
The search for genetic factors that influence the occurrence of birth
defects has been more successful than the search for environmental factors,
particularly with regard to malformation syndromes. Specific DNA deletions
associated with specific malformation syndromes have been identified, and a
number of positive genetic-linkage and genetic-association studies have been
published in recent years. *RF 1-4* More indirect methods, such as segregation
analyses and twin studies, also indicate that genetic factors have a major role
in the pathogenesis of some of the major birth defects. *RF 5-7*
Since thalidomide was recognized as a potent teratogen, substantial
effort has been directed toward identifying environmental factors that play a
part in causing birth defects. Except for the recognition that folic acid
protects against neural-tube defects, *RF 8* such efforts have been
disappointing. A number of risk factors have been identified for some birth
defects -- for example, smoking, *RF 9* alcohol, *RF 10* and various drugs *RF
11* -- but the associations are usually weak.
Last year in the Journal, Lie et al. *RF 12* reported a reduction in
the risk of the same birth defect's occurring in two siblings born to women in
Norway who moved from one municipality to another between the two births; there
was no significant reduction in risk among women who changed sexual partners.
The study considered 24 groups of birth defects, including 2 groups of
facial-cleft defects. The finding was particularly unexpected in a country such
as Norway, which has homogeneous social conditions and high environmental
standards. This study may have been vulnerable to detection bias in the routine
malformation-registration system, because more than half of the birth defects
considered belong to categories of malformations whose recognition may be
difficult. *RF 13* The aim of the present study was to estimate the effect of a
change in partner or residence on the recurrence of cleft lip, with or without
cleft palate, and isolated cleft palate, which are among the most common birth
defects that are well defined and easily diagnosed.
Methods
We obtained the data for this study from the Danish Central Person Registry
and from a data base on all children with facial-cleft defects born in Denmark
between 1936 and 1987. The Danish Central Person Registry, which was established
in 1968, registers all persons residing in Denmark on April 1, 1968, or later
with a unique 10-digit identification number. The identification number of any
person born before April 1, 1968, can be traced in the registry through his or
her name and the date and place of birth. The registry includes the
identification numbers of the mothers of virtually all infants with facial-cleft
defects born after 1960. For infants born before 1952, the mother's
identification number is available for less than 10 percent, and the proportion
increases from 43 percent in the 1952 cohort to 96 percent in the 1959 cohort.
The father is identified slightly less often, peaking at a 99 percent level in
the 1970s. For births before January 1, 1978, the registry contains data only on
the place of birth and not the home address. Both the place of birth and the
home address (when it is given) are identified as to parish; the approximately
2200 parishes can be pooled to form 276 municipalities, which is still a fairly
extensive division of a country of 44,000 km(sup 2) and 5 million inhabitants.
The registry does not contain information on the biologic parents of adopted
children, but in the Danish birth cohorts considered (1952 to 1987), only about
1.2 percent of children born in Denmark were adopted, according to official
statistics.
The Danish facial-cleft data base has previously been described in
detail. *RF 14,15* In brief, the identification of cases has been based on data
from two sources. The first, the Deaconess Hospital and University Hospital of
Copenhagen, has been responsible for all surgical treatment of facial-cleft
defects in Denmark since the 1930s. Throughout this period, lip operations have
been performed on infants at about two months of age and palate operations at
about two years of age. The surgical files contain information on major
associated malformations or syndromes known at the time of surgery. The second
source of data, the National Institute for Defects of Speech, coordinates
multidisciplinary treatment for children with facial-cleft defects. Since 1954,
midwives in Denmark have been obliged to report any newborn with a cleft lip or
cleft palate to the institute. Facial cleft defects recognized later in a
child's life (e.g., submucous cleft palate diagnosed after the development of
speech difficulties) are also reported to the institute. Reported cases dating
back to 1939 are registered, and information about major associated
malformations is included. Both of these sources of data contain the names and
dates of birth of the children with facial-cleft defects and, in nearly all
cases, their places of birth. Other sources have been used, including a national
registry of congenital malformations, a national death registry, and local
registers, and capture-recapture methods have indicated that nearly all cases
(99 percent) of liveborn infants with facial-cleft defects without associated
anomalies have been identified, except for cases of submucous cleft palate,
which often remains asymptomatic or nearly asymptomatic. *RF 14,15*
The facial-cleft data base includes information about 7290 live-born
infants, of whom 89 percent have unique identification numbers, 6 percent died
before the introduction of identification numbers in 1968, and 5 percent could
not be identified further than by name and date of birth. For the period from
1952 to 1987, 92 percent of the children in the facial-cleft data base have
identification numbers.
The Danish facial-cleft data base and the Central Person Registry were
linked by identification numbers in the following manner. The identification
numbers of children with facial-cleft defects who were born between 1952 and
1987 were obtained through the facial-cleft data base. The parental
identification numbers as well as the places of birth were obtained for these
children from the Central Person Registry. The identification number of a mother
was used to obtain from the Central Person Registry the identification numbers
of children born after her first infant with a facial-cleft defect. Through the
identification numbers of these younger siblings, the fathers and the places of
birth could be identified in the Central Person Registry. Finally, these
children were linked, by their identification numbers, to the facial-cleft data
base to identify affected younger siblings. Only siblings born in Denmark
between 1952 and 1987 were included, without reference to birth order. All
multiple births were excluded.
Only infants with facial-cleft defects and no associated major or
minor defects were considered in the study. Major defects included anomalies
such as neural-tube defects, monogenic traits (Van der Woude's syndrome), and
other disorders (trisomy and Pierre Robin's syndrome). Anomalies such as
polydactyly and clubfoot were considered minor defects. Minimal anomalies such
as nevi and undescended testes were not considered to be associated defects.
The risk of recurrence was estimated as the proportion of younger
siblings with facial-cleft defects stratified according to the mothers' change
of municipality and change of partner. Since a change of partner and a change of
municipality are not independent events, a Mantel-Haenszel test was used to
assess the effect of a change of municipality after stratification according to
whether there was a change of partner, and vice versa.
Results
We obtained information about 4189 mothers, each of whom had at least one
infant with a facial-cleft defect born between 1952 and 1987. This total
included 4108 mothers each with one infant having a facial-cleft defect, 74
mothers each with two infants having a facial-cleft defect, and 3 mothers each
with three infants having this defect. The first affected infant was not
necessarily the mother's first-born child. Four mothers who each had one infant
with a cleft lip and one infant with an isolated cleft palate were not
considered to have two infants with the same birth defect, because these two
birth defects are etiologically distinct. *RF 16* Among the 4189 mothers, 1902
had additional children after the first infant with a facial-cleft defect. A
total of 2692 such younger siblings were identified (the infants with
facial-cleft defects and their siblings were all born in the period 1952 to
1987) (Table 1). On the basis of the Danish facial-cleft data base, the
prevalence of facial clefts at birth was estimated to be 0.2 percent during the
period 1952 to 1987 (unpublished data).
*Table 1.-Effect of Changes in Municipality or Sexual Partner on
the Risk of Facial-Cleft Defects in Younger Infants of 1902
Mothers Who Had Already Had Infants with Such Defects *.
-------------------------------------------------------------------
NO. OF YOUNGER
SIBLINGS WITH
NO. OF YOUNGER FACIAL-CLEFT
PARTNER/MUNICIPALITY* SIBLINGS DEFECTS (%)
-------------------------------------------------------------------
Same/same 1425 48 (3.4)
Same/different 907 29 (3.2)
Different/same 97 0
Different/different 138 1 (0.7)
One or both unknown 125 2 (1.6)
Total 2692 80 (3.0)
-------------------------------------------------------------------
* Municipality is the actual place of birth before January 1,
1978, and the mother's home address from that date on. The risk of recurrence of facial-cleft defects among younger siblings
did not depend on whether the mothers moved to a new municipality (Table 1).
Among the 907 infants of mothers who changed municipalities but not sexual
partners, 29 (3.2 percent) had facial-cleft defects, as compared with 48 (3.4
percent) of 1425 infants of mothers who changed neither municipality nor partner
(relative risk, 0.9; 95 percent confidence interval, 0.6 to 1.5). Change of
partner and change of municipality are not independent events, but stratifying
the results according to whether there was a change of partner did not alter the
relative risk (0.9; 95 percent confidence interval, 0.6 to 1.5). A change of
partner reduced the risk of recurrence. Among the 236 infants of mothers who
changed partners, 1 (0.4 percent) had a facial-cleft defect, as compared with 77
(3.3 percent) of 2350 infants of mothers who did not change partners (relative
risk, 0.1; 95 percent confidence interval, 0.02 to 0.9). When the effect of a
change of partner was stratified according to whether there was a change of
municipality, the results were similar (relative risk, 0.1; 95 percent
confidence interval, 0.02 to 0.7). The results of analyses of subgroups based on
the type of defect -- cleft lip with or without cleft palate and isolated cleft
palate -- were similar, but the numbers of affected infants were small.
The results were similar if the analysis was restricted to the period
after 1977 or if only the mothers' first and second pregnancies were considered
(the latter analysis included 1290 mothers). An analysis identical in approach
to that of the Norwegian study *RF 12* (restricted to first and second
pregnancies in the period after 1977 and using residence at the municipality
level) had similar results, but the numbers were small. Among 29 infants of
mothers who changed municipalities but not partners, 1 (3.4 percent) had a
facial-cleft defect, as compared with 3 (2.1 percent) of 143 infants of mothers
who changed neither municipality nor partner (relative risk, 1.7; 95 percent
confidence interval, 0.2 to 16.7). Among the 19 siblings of affected infants
with different fathers, none had facial-cleft defects.
Discussion
Our study focused on two well-defined birth defects -- cleft lip with or
without cleft palate and isolated cleft palate -- although there probably is
etiologic heterogeneity even within these categories. If an adverse outcome of
pregnancy (such as the presence of a facial-cleft defect) decreases the
probability of another pregnancy, the risk of recurrence will be underestimated
if older siblings are included in the analysis, *RF 17* because families having
an affected infant might be less likely to have more children. Therefore, we
considered recurrence among younger siblings only. Since parental age is not
related to the occurrence of facial-cleft defects, the analysis included all
younger siblings. *RF 18* Separate analyses were performed that were restricted
in various ways (considering only the first and second child or only the period
after 1977). The restriction of the time period minimized the number of siblings
who could not be linked to parents in the Central Person Registry and eliminated
the possibility that there would be only a hospital address at birth for a child
instead of a home address. The results of the main and the restricted analyses
were similar.
Recurrence rates were probably somewhat underestimated in this study
because of the missing identification numbers in the Danish facial-cleft data
base. However, because only 8 percent of the cases in the data base of infants
born between 1952 and 1987 were missing identification numbers and because the
identification of cases of facial cleft by capture-recapture methods has been
estimated to be nearly complete, *RF 14* it seems likely that the fraction of
facial-cleft cases that were not identified in this study was considerably
smaller than the estimated 20 percent not identified in the Norwegian study. *RF
12* The estimates of the risk of recurrence of facial-cleft defects in the two
studies were, however, very similar (3.6 percent in the Norwegian study and 3.0
percent in this study). Despite the probable underreporting of facial-cleft
defects in the Norwegian study, it is likely that the recurrence of birth
defects was reported accurately, since the mothers were undoubtedly aware of the
possibility of a similar defect in their second children and therefore the
likelihood of registration of the defect would be greater.
Both our study and the Norwegian study provide evidence that a change
of sexual partner reduces the risk of recurrence of birth defects, a finding
that emphasizes the importance of genetic factors in the causation of birth
defects. The intriguing finding that a mother's change of residence between
pregnancies protects against the recurrence of birth defects could not, however,
be corroborated for facial-cleft defects in Denmark. The effect of change of a
mother's municipality in the Norwegian study was due as much to changes in the
reference groups as to changes in the index-case group. Among couples who had
healthy first children, the risk of having second children with birth defects
was 47 percent higher for those who changed residences between the two births
than for those who did not, *RF 12* possibly because of a detection bias induced
by movement from rural to urban areas with an associated increase in the
availability of diagnostic expertise and facilities. Similarly, when a woman had
had one infant with a birth defect, she and those providing her health care were
undoubtedly aware of the possibility of a similar defect in the second child. If
the second child did not in fact have the defect in question, he or she was more
likely to be classified correctly in a specialized setting, whereas the high a
priori probability of the defect might cause a false positive diagnosis in a
healthy second child in a hospital with poorer diagnostic facilities. Such a
detection bias would lead to lower recurrence rates among women who moved from
rural to urban areas than among those who did not.
The study by Lie et al. *RF 12* was based on a routine registration
system (using birth certificates). Danish studies have shown that only about 75
percent of the birth certificates of children with facial-cleft defects contain
any reference to the defect, although this defect is among the most easily
diagnosed. *RF 19* Differences in the frequency of a defect determined by such
systems could therefore reflect differences in rates of diagnosis and
registration among hospitals more than true differences in the frequency of the
defect.
The use of a Danish population reference group was not feasible in the
present study, but a reanalysis of the Norwegian data *RF 12* with a reference
group similar to the one we used showed results similar to those obtained with
the use of a population reference group. The present study did not include all
the types of birth defects considered in the Norwegian study, but the
facial-cleft defect is a good candidate for a defect caused by a
gene-environment interaction. Our results show that the recurrence of
facial-cleft defects is not linked to the residence of the mother but that
having a different partner reduces a woman's risk of having a second infant with
the same defect.
We are indebted to the University Hospital of Copenhagen and the
National Institute for Defects of Speech in Copenhagen and Aarhus for their
cooperation.
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