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Chapter 6
Congenital anomalies
6.1 Introduction
Now that a hypothetical cohort has been constructed in Chapter 5, the results for this cohort (in the absence of induced abortion) can be used to assess the relative importance of the selected adverse pregnancy and birth outcomes in the EME region. In achieving this, the current chapter focuses on the relative importance of congenital anomalies, in particular chromosomal aberrations, neural tubes defects, and congenital heart disease (see also Chapter 3, Section 3.4.1). The next chapter, Chapter 7, deals with low birth weight, preterm birth and intrauterine growth retardation/small-for-gestational-age, and birth asphyxia. The relative importance of the selected risk factors at the individual level is assessed on the basis of incidence of loss/death and the relative risk of loss/death. The relative importance at the population level is based on the prevalence of the risk factor in the population, the attributable risk among the exposed, and the etiologic fraction (see Chapter 4). The relative risk (RR) indicates how many times more likely persons with the risk factor will experience the outcome (i.e. loss or death) as compared to persons without the risk factor. The attributable risk among the exposed, AR(E), indicates the proportion of cases of the outcome (i.e. loss or death) in the exposed population which is attributable to, or due to, the exposure or risk factor of interest. Lastly, the etiologic fraction (EF) is the proportion of all cases of the outcome in the total population that can be attributed to exposure to the risk factor. In the present chapter, the values of these measures come from secondary sources, or are estimated by combining assumptions derived from these sources with the hypothetical cohort. For a more detailed discussion of the methods and equations used, please refer to Section 4.2.4. Overall, it is important to note that the results represent educated guesses and are not absolute, ‘true’, figures. Indeed, they frequently consist of ranges of estimates. The sections in the present chapter deal with: congenital anomalies (Section 6.2), chromosomal aberrations (Section 6.3), neural tube defects (Section 6.4), and congenital heart disease (Section 6.5). Each of these sections presents and discusses antepartum and birth data (i.e. about induced abortion and selective abortion, spontaneous loss and stillbirth, live birth and all births, and the in-utero prevalence) and neonatal data (i.e. about neonatal death). Subsequently, Section 6.6 gives attention to associations between the subcategories of anomalies, and the combination of several anomalies in an individual. Finally, the results of the chapter are summarised and discussed in Section 6.7. Throughout the chapter, ‘SA’ refers to spontaneous abortion, ‘SB’ to stillbirth, ‘LB’ to live birth, and ‘B’ to all births (live and stillbirths combined). All antepartum figures refer to, or are assumed to refer to, the situation in which induced abortion (IA) is absent.
EARLY LIFE CHANGES
150
6.2 Congenital anomalies (all)
6.2.1 ANTEPARTUM AND BIRTH DATA
Incidence of anomalies Intrinsic to their definition, congenital anomalies arise before birth. However, information on the antepartum incidence of anomalies is not readily available. Close monitoring of in-utero human development throughout the gestation period is complicated, and ordinarily the exact onset of an anomaly remains inaccessible to observation. As a result, most of the information available on the incidence of anomalies is based on knowledge about the timing of the development of organs. Congenital anomalies not only arise in different ways (see Chapter 3), they also arise at different times (Kline et al. 1989). Timing of development (cf. occurrence) is generally related to the causal mechanism that produces a specific anomaly. For example, chromosomal aberrations and other genetic anomalies are likely to develop around the time of conception or even earlier. More specifically, chromosomal abnormalities may come into being at three developmental stages: gametogenesis, fertilisation, and embryogenesis (Delhanty and Handyside 1995). In general, the embryonic period including organogenesis (i.e. the process during which the majority of organs are formed) is the most critical period in terms of the development of anomalies (Moore 1986; Cunningham et al. 1993). Neural tube defects, for instance, are believed to result from the failure of tubal closure by the 6th gestational week (embryonic age 26 to 28 days) (Cunningham et al. 1993). Similarly, the critical period during which congenital heart anomalies can develop is between 14 and 60 days gestational age (Nora and Hart-Nora 1984 cited by Van der Veen 2001). Exposure to teratogens later in pregnancy is likely to have less harmful effects (Moore 1986). However, some congenital anomalies that are multifactorial in origin arise later in gestation. For example, Nishimura (1970), who studied embryos and early foetuses recovered after induced abortion and hysterectomy, noticed that certain malformations such as dislocation of the hip and talipes equinovarus (clubfoot) were found only in specimens obtained after the 5th month of pregnancy. The above indicates that some anomalies are already present at conception. For these abnormalities, incidence during gestation is therefore an inappropriate concept. For the other congenital anomalies, incidence appears to be highest early in gestation and is likely to decrease once most organs have been formed. It should be noted that recovery from an anomaly is highly unlikely, and that the development of an anomaly can be regarded as irreversible.
Hysterectomy and induced abortion The in-utero prevalence of congenital anomalies may be approximated by the prevalence proportions among induced abortions and hysterectomies (see Chapter 4). Perhaps the most famous study in this respect is the one by Hertig et al. (1959). They examined fertilised ova
CHAPTER 6: CONGENITAL ANOMALIES
151
recovered following hysterectomies during the first 17 days of development. Maternal age was relatively high, ranging from 26 to 42 years, with the mean age between 33 and 34 years. Out of the total of 34 fertilised ova, 10 specimens or 29.4% were found to be ‘abnormal’ and the prevalence rose to 38.2% (13 cases) when ‘minor’ abnormalities were included. Nishimura (1970) studied external malformations in a Japanese population of embryos and early foetuses aged about 3-18 weeks from fertilisation (i.e. gestational weeks 5-20) that were obtained by induced abortion or hysterectomy. In total, 90 out of 3,718 (2.4%) were found to be externally malformed. Prevalence was highest in the final embryonic stage at 4.7% around 8 weeks from fertilisation, but declined again afterwards to about 3.9%. In line with the information on incidence (see the previous subsection), the author explained this by saying that, as the process of organogenesis proceeds, new types of defects can be found. Finally, Blanch et al. (1998) studied pregnancies that were artificially terminated with mifepristone and misoprostol before 9 weeks of gestation. Average maternal age was 25 years, ranging from 16 to 41 years. In about 42% of cases where the products of conception could be examined, the pregnancy turned out to be non-viable (e.g. ruptured sac without embryo) or the products showed structural abnormalities. In those cases that appeared to be viable, 15% had structural abnormalities. Table 6.1 summarises the results of these three studies. In these studies, selective abortion on the basis of prenatal diagnostic tests, is likely to have played no, or only a minor, role. The prevalence of anomalies in induced abortion seems to be relatively high (30-40%) during the first 2-3 weeks after fertilisation, which suggests that the general prevalence in utero will also be of this order. However, later in gestation the prevalence appears to fall to about 2 to 15%. Table 6.1: Prevalence of congenital anomalies in hysterectomies and/or induced abortions
Source Country Gestational period % Type(s) of Remarksanomalies
Hertig et al. 1959 USA first 17 days of development* 29 I excl. "minor abnormalities"first 17 days of development* 38 I incl. "minor abnormalities"
Nishimura 1969 Japan 3-18 weeks [a] 2 II -embryo CRL 3-6 mm 3 II -embryo CRL 6-10 mm 1 II -embryo CRL 10-17 mm 4 II -embryo CRL 17-30 mm 5 II -foetus CRL 30-60 mm 4 II -foetus CRL 60-120 mm 4 II -
Blanch et al. 1998 UK < 9 weeks gestation 42 I incl. "non-viable pregnancies"**< 9 weeks gestation 15 III apparently viable pregnancies
Notes: CRL - crown-rump length; I - "abnormal"; II - "external malformations"; III - structural abnormalities"*expressed in time since fertilisation (not in LMP); **includes: anembryonic, intact gestation sacs; ruptured sac (noembryo present); resorbing (disproportionately small compared to sac and containing necrotic tissue).
EARLY LIFE CHANGES
152
Selective abortion Prenatal diagnosis and selective abortion are quite recent phenomena. Congenital anomalies such as chromosomal aberrations and neural tube defects can be detected antenatally by prenatal diagnostic tests. A woman whose baby has been diagnosed prenatally as anomalous, may opt for an induced abortion. In 1990, about 65% of such women in the Netherlands opted for pregnancy termination (Werkgroep voor Prenatale Diagnostiek 1993). However, this amounted to only 1.3% of all induced abortions in the country during the same year (based on data from Werkgroep voor Prenatale Diagnostiek 1993 and Rademakers 1995). In Europe, EUROCAT (European Registration of Congenital Anomalies) carries out an epidemiologic surveillance of congenital anomalies. EUROCAT is a network of population-based registries for children with congenital anomalies in various countries and regions of Europe (EUROCAT 2002). According to EUROCAT data, the proportion of cases that are prenatally diagnosed has been increasing over the years, as the utilisation of screening programmes and diagnostic technologies has become more widespread. As a result, the proportion of cases terminated by selective abortion has also been increasing. However, the proportion of diagnosed cases that are followed by induced abortion shows variation and fluctuation: for some anomalies the proportion has increased, while for others it has decreased or remained stable (EUROCAT 1993; EUROCAT 1995). For example, on the basis of 12 combined EUROCAT registries, the percentage of Down’s syndrome cases that were prenatally diagnosed increased from 16.0% in 1980-1985 to 40.1% in 1989-1990. During the same period, the percentage of all Down’s syndrome cases ending in induced abortion increased from 14.2% to 34.5%, while induced abortion among prenatally diagnosed cases decreased slightly from 88.8 to 86.1% (EUROCAT 1993). In Europe, induced abortion following prenatal diagnosis of an anomaly is most frequent in anomalies of the nervous system (anencephaly) and in chromosomal anomalies (Down’s syndrome) (EUROCAT 1993; EUROCAT 1995). Overall, of all the detected anomalous cases that were registered in one of 25 EUROCAT registries between 1990 and 1996, 85.9% ended in live birth, 2.4% in foetal death, and 11.8% in induced abortion (EUROCAT 2001).
Spontaneous loss and stillbirth For anomalous embryos and foetuses, the risks of spontaneous loss and stillbirth are higher than for their normal counterparts. This is not only reflected in the higher incidences of spontaneous abortions and stillbirths for anomalous cases but also in the high prevalence of anomalies among losses and stillbirths. On the basis of a literature review, Roman and Stevenson (1983) estimated that at least half of conceptuses that end in spontaneous abortion have anatomic and/or chromosomal abnormalities which, in the majority of cases, are incompatible with survival. Table 6.2 presents an overview of prevalence proportions of anomalies found in both spontaneous losses and stillbirths. For spontaneous loss, the proportions vary from only 7.4% (Creasy and Alberman 1976) to as high as 58.3% of intrauterine deaths in the period 5-8 weeks after fertilisation (Shiota 1993). Overall, prevalence seems to decline with increasing
Tab
le 6
.2: P
reva
lenc
e of
con
geni
tal a
nom
alie
s in
spon
tane
ous a
bort
ions
and
still
birt
hs
In sp
onta
neou
s em
bryo
nic
and
foet
al a
bort
ions
Sour
ceR
egio
nPe
riod
Popu
latio
n sa
mpl
e%
Type
(s) o
f ano
mal
ies
Rem
arks
Cre
asy
and
Alb
erm
an 1
976
UK
1971
-197
499
5 sp
onta
neou
s abo
rtion
s7.
4"m
alfo
rmat
ion"
in c
ompl
ete,
org
aniz
ed
foet
uses
Shio
ta 1
993
Japa
nN
S19
9 in
traut
erin
e de
aths
in e
mbr
yos
58.3
"ext
erna
l maj
or m
alfo
rmat
ions
"fo
und
in in
duce
d ab
ortio
ns a
ged
5-8
wks
*Sh
iota
199
3Ja
pan
NS
95 in
traut
erin
e de
aths
in fo
etus
es17
.9"e
xter
nal m
ajor
mal
form
atio
ns"
foun
d in
indu
ced
abor
tions
(w
eek
9 to
term
)*H
ollie
r et a
l. 20
00U
SA19
88-1
994
701
sing
leto
n 2n
d tri
m. a
borti
ons
16"n
onch
rom
. inf
ant a
nom
aly"
hosp
ital-b
ased
(>
13 w
ks a
nd <
500
g)
an
d "a
bnor
mal
kar
yoty
pe"
In st
illbi
rths
Sour
ceR
egio
nPe
riod
Popu
latio
n sa
mpl
e%
Type
(s) o
f ano
mal
ies
Rem
arks
Kal
ter 1
991
Euro
pe19
80s
still
birth
s18
.3"c
onge
nita
l mal
form
atio
ns"
base
d on
revi
ew o
f (
>= 1
,000
g)
lit
erat
ure
Kal
ter 1
991
USA
&19
80s
still
birth
s11
.8"c
onge
nita
l mal
form
atio
ns"
base
d on
revi
ew o
f C
anad
a (
>= 1
,000
g)
lit
erat
ure
Kat
o an
d Fu
jiki 1
996
Japa
n19
79-1
993
1,78
6 st
illbi
rths
9.0
"gro
ss p
hysi
cal o
r ana
tom
ical
hosp
ital-b
ased
; det
ecte
d(T
okyo
) (
> 16
wks
)
deve
lopm
enta
l mal
form
atio
ns"
w
ithin
7 d
ays o
f birt
hD
e G
alan
-Roo
sen
et a
l. 19
98N
ethe
rland
s19
83-1
992
155
still
birth
s + in
trapa
rtum
dea
ths
25.2
"maj
or a
nd m
inor
con
geni
tal
base
d on
var
ious
link
ed(w
est)
(>=
28
wks
)**
m
alfo
rmat
ions
"
regi
stra
tion
syst
ems
Sam
rén
et a
l. 19
99N
ethe
rland
s19
81-1
997
1,43
2 st
illbi
rths
10.8
"con
geni
tal a
nom
alie
s"as
repo
rted
to E
UR
OC
AT
(nor
th)
(>=
24
wks
)
regi
stry
Hol
lier e
t al.
2000
USA
1988
-199
482
9 si
ngle
ton
still
birth
s14
"non
chro
m. i
nfan
t ano
mal
y"ho
spita
l-bas
ed(D
alla
s) (
>= 5
00 g
)
and
"abn
orm
al k
aryo
type
"
Not
es: N
S - n
ot st
ated
; non
chro
m. -
non
chro
mos
omal
*exp
ress
ed in
tim
e si
nce
ferti
lisat
ion
(not
in L
MP)
; **i
nclu
des t
hose
who
die
d po
stna
tally
with
in 3
0 m
inut
es.
Tab
le 6
.3: P
reva
lenc
e of
con
geni
tal a
nom
alie
s in
birt
hs a
nd li
ve b
irth
s
In b
irth
s*
Sour
ceR
egio
nPe
riod
Popu
latio
n sa
mpl
e%
Type
(s) o
f ano
mal
ies
Rem
arks
PDC
U (n
.d.)
Aus
tralia
1983
-199
476
1,33
6 bi
rths
3.0
"con
geni
tal m
alfo
rmat
ions
"-
(Vic
toria
) a
t 20
wks
and
late
rLi
lienf
eld
1970
--
-1.
0-12
.3"c
onge
nita
l mal
form
atio
ns"
base
d on
revi
ew o
f lite
ratu
reK
alte
r and
War
kany
198
3a-
--
3"m
ajor
con
geni
tal m
alfo
rmat
ions
"ge
nera
l; de
tect
ed in
neo
nata
l per
iod
Kal
ter a
nd W
arka
ny 1
983a
--
-6
"maj
or c
onge
nita
l mal
form
atio
ns"
gene
ral;
dete
cted
up
to y
rs a
fter b
irth
Mod
ell a
nd B
ulyz
henk
ov 1
988
[a]-
--
1.4-
4.3
"sev
ere
cong
enita
l dis
orde
rs"
gene
ral e
stim
ate
Cor
nel e
t al.
1993
bEu
rope
1981
-198
6-
2.2
"con
geni
tal a
nom
alie
s"av
erag
e fo
r 19
EUR
OC
AT
regi
strie
sM
aruy
ama
et a
l. 19
93 [b
]Ja
pan
1991
114,
785
birth
s1.
0"m
alfo
rmed
"ho
spita
l-bas
edR
ober
ts e
t al.
1993
New
Zea
land
1988
-198
912
,909
birt
hs1.
7"c
onge
nita
l abn
orm
aliti
es"
hosp
ital-b
ased
(Auc
klan
d)K
ato
and
Fujik
i 199
6Ja
pan
1979
-199
313
8,54
4 bi
rths,
incl
.1.
5"g
ross
phy
sica
l or a
nato
mic
alho
spita
l-bas
ed; d
etec
ted
(Tok
yo)
stil
lbirt
hs >
16
wks
de
velo
pmen
tal m
alfo
rmat
ions
"w
ithin
7 d
ays o
f birt
hW
HO
Sci
entif
ic G
roup
199
6de
velo
ped
--
7.8
"gen
etic
and
non
gene
ticge
nera
l; de
tect
ed u
p to
coun
tries
co
ngen
ital a
nom
alie
s"
age
of 3
0 ye
ars
Sam
rén
et a
l. 19
99N
ethe
rland
s19
81-1
997
247,
996
live
2.4
"con
geni
tal a
nom
alie
s"as
repo
rted
to E
UR
OC
AT
regi
stry
(nor
th)
and
still
birth
sV
an d
er V
een
2001
--
-2-
10"c
onge
nita
l ano
mal
ies"
base
d on
revi
ew o
f lite
ratu
re
In li
ve b
irth
s
Sour
ceR
egio
nPe
riod
Popu
latio
n sa
mpl
e%
Type
(s) o
f ano
mal
ies
Rem
arks
Shio
ta 1
993
Japa
n-
new
born
s1.
0"m
alfo
rmed
"ba
sed
on re
view
of l
itera
ture
Kat
o an
d Fu
jiki 1
996
Japa
n19
79-1
993
136,
758
live
birth
s1.
4"g
ross
phy
sica
l or a
nato
mic
alho
spita
l-bas
ed; d
etec
ted
with
in(T
okyo
)
deve
lopm
enta
l mal
form
atio
ns"
7
days
of b
irth
Shib
uya
and
Mur
ray
1998
--
-2-
6"c
onge
nita
l dis
orde
rs",
gene
ral e
stim
atio
n
excl
. "m
inor
ano
mal
ies"
Sam
rén
et a
l. 19
99N
ethe
rland
s19
81-1
997
246,
564
live
birth
s2.
3"c
onge
nita
l ano
mal
ies"
as re
porte
d to
EU
RO
CA
T re
gist
ry(n
orth
)H
ollie
r et a
l. 20
00U
SA19
88-1
994
101,
198
sing
leto
n3.
2"n
onch
rom
. inf
ant a
nom
aly"
hosp
ital-b
ased
(Dal
las)
liv
e bi
rths >
500
g
and
"abn
orm
al k
aryo
type
"
Not
es: *
incl
udes
thos
e ca
ses u
nkno
wn
to re
fer t
o al
l birt
hs o
r onl
y liv
e bi
rths;
PD
CU
- Pe
rinat
al D
ata
Col
lect
ion
Uni
t; n.
d. -
do d
ate
(yea
r of p
ublic
atio
n un
know
n).
[a]
cite
d by
Shi
buya
and
Mur
ray
1998
; [b]
cite
d by
Kat
o an
d Fu
jiki 1
996
CHAPTER 6: CONGENITAL ANOMALIES
155
gestational age. In stillbirths, the prevalence of anomalies appears to range between 9% (Kato and Fujiki 1996) and 25% (De Galan-Roosen et al. 1998) (Table 6.2). However, the relatively high prevalence found by the latter authors is likely to be due to the inclusion of minor malformations. After exclusion of this category, the prevalence of major congenital malformations in stillbirths around the Dutch city of Delft was found to be 12.9% (De Galan-Roosen et al. 1998). With regard to the incidence of spontaneous abortion and/or stillbirth, Blanch et al. (1998) concluded that the potential loss for embryos with structural abnormalities or other non-viable conditions is 34%. They compared their results to the risk of spontaneous miscarriage in all (both normal and abnormal) clinical pregnancies for which they found a figure of 15% (Kline and Stein 1990 cited by Blanch et al. 1998). However, it would be more relevant to compare the figure to that for normal foetuses, thereby enabling the opportunity to estimate the relative risk. In Japan, Shiota (1993) examined 7,358 embryos and foetuses taken from a large collection of human conceptuses, most of which were obtained after induced abortion. Cases referred after antenatal diagnosis were not included, and the embryo population was assumed to be representative of the total intrauterine population in Japan. Shiota (1993) studied the proportion of spontaneous intrauterine deaths encountered in the sample and concluded that 92.7% of malformed conceptuses end in spontaneous loss before birth. Intrauterine mortality in phenotypically normal conceptuses after 5 weeks appeared to occur in only 17.6% of cases. Consequently, the risk of spontaneous loss among malformed conceptuses is about five times the risk of spontaneous loss in normal conceptuses (i.e. RR = 92.7 / 17.6 = 5.3).
Live birth and all births Table 6.3 shows how estimates of the prevalence of congenital anomalies at birth vary widely. Figures seem to range between 1 and 12%. Part of this variation can be explained by differences in study design, such as criteria for inclusion and exclusion (Van der Veen 2001) (also see Chapter 4). For example, Kalter and Warkany (1983) estimate that prevalence at birth is about 3% when only those abnormalities detected during the neonatal period are included in the results. However, they believe the figure would double after inclusion of cases that are detected months, or even years, after birth. In addition to the proportion of all births, Table 6.3 also presents data on the prevalence of congenital anomalies in live births, which ranges from 1 to 6%. Shibuya and Murray (1998c) suggest a prevalence range of 2 to 6%. However, they assume an average birth prevalence, across all regions of the world, of approximately 3%. One should also note that some of the prevalence figures for ‘all births’ in Table 6.3 may in fact refer only to ‘live births’ since several authors failed to specify their populations and findings. However, because stillbirth rates are low in the EME region, differences between the two figures are likely to be small. With regard to the sex of the newborn, the prevalence of congenital anomalies appears to be higher among males than among females. For example, in a Japanese hospital-based study in 1979-1993 (Kato and Fujiki 1996), prevalence was slightly, yet significantly, higher among males. In total, 1.6% of male births had a congenital malformation compared to 1.4%
EARLY LIFE CHANGES
156
of females (p < 0.01). In live births, the prevalence figures were 1.5% and 1.3% respectively. EUROCAT data from Reefhuis et al. (1998) for the region of the Southwestern Netherlands appear to support these Japanese findings. In the period 1990-1996, 57.1% of anomalous cases (SA, SB, IA, and LB) of known sex reported to EUROCAT were males whereas the proportion of males within the total population of liveborn children was only 51.3%. However, the data for the Southwestern Netherlands may have been affected by underascertainment and underregistration. Moreover, in the EUROCAT region of the Northern Netherlands, males did not appear to be overrepresented among anomalous cases during 1981-1996: 51.5% of anomalous cases compared to 51.2% within the total liveborn population (Reefhuis et al. 1998).
Prevalence in utero The prevalence of congenital anomalies among all embryos or foetuses in utero at a specific gestational age is difficult to assess directly through observation. However, a combination of data, such as the information presented in the previous subsections, may be used to make a reasonable estimate. Shiota (1993), for instance, combined data on the risk of spontaneous loss with the prevalence of malformations among those lost in order to estimate prevalence among all in-utero foetuses. According to the resulting estimates, prevalence declines from 10.3% at the beginning of week 5 to 9.7% at week 6, 8.6% at week 7, 6.9% at week 8, and finally to only 2.4% at the beginning of week 9 (weeks since fertilisation). Similarly, it is possible to establish estimates for the hypothetical cohort that was constructed in Chapter 5. In the absence of induced abortion, the 100,000 pregnancies in this cohort that are present at the beginning of gestational week 5 end in: 11,157 spontaneous losses (SA) < 28 weeks of gestation, 434 stillbirths (SB) ≥ 28 weeks, and 88,410 live births (LB). If one assumes, on the basis of the data presented in the previous subsections, that the prevalences of anomalies among each of these outcome groups are 40%, 14%, and 3% respectively, then the total number of abnormal embryos is 7,176 (4,463 SA + 61 SB + 2,652 LB) which is 7.2% of the entire cohort of 100,000 embryos. Using the simple assumption that all anomalies were already present at the start of gestation, this proportion equals the prevalence of anomalies at the beginning of gestational week 5 (LMP). The prevalence proportion of 7.2% is somewhat lower than Shiota’s (1993) estimate of 10.3% at 5 weeks after fertilisation (i.e. 7 weeks LMP). The difference is likely to be explained by the choices of data on pregnancy outcome as well as data on prevalence of anomalies.
Relative risk and attributable risk: foetal loss As noted earlier, Shiota (1993) estimated the risk of SA/SB in anomalous embryos/foetuses to be about five times the risk for non-anomalous ones, i.e. RR = 5.3. Consequently, the attributable risk among the exposed, AR(E), is: (5.3 – 1) / 5.3 = 0.811 which means that 81.1% of spontaneous losses and stillbirths among anomalous embryos/foetuses can be attributed to the anomalies. In addition, the etiologic fraction (EF) is calculated as: [0.103 * (5.3 – 1)] / [0.103 * (5.3 – 1) + 1] = 0.307
CHAPTER 6: CONGENITAL ANOMALIES
157
Gestational interval* Malformed (%) RR AR(E) EF
Week 5 10.3 4 0.750 0.236Week 6 9.7 18 0.944 0.622Week 7 8.6 11 0.909 0.462Week 8 6.9 10 0.900 0.383
Foetal period (wk 9) 2.4 9 0.889 0.161
Total 10.3 5.3 0.811 0.307
Note: *in weeks since fertilisationBased on data from Shiota 1993
Table 6.4: Estimated RR, AR(E) and EF of SA/SB in malformed andpotentially malformed embryos/foetuses, by gestational interval*
based on the assumption that, in total, 10.3% of conceptuses have an anomaly. This indicates that 30.7% of all spontaneous losses and stillbirths within the population are attributable to anomalies. Shiota (1993) presented his estimates by week since fertilisation, and therefore RR, AR(E) and EF can also be calculated by gestational age as shown in Table 6.4. It would seem that the RR, AR(E) and EF vary with gestational duration. All three measures show a sharp increase early in gestation at week 6 (weeks since fertilisation), but from then onwards they all decline gradually. Shiota’s (1993) estimates – i.e. an initial prevalence of 10.3% and an incidence of SA/SB of 92.7% in anomalous conceptuses – can also be applied to the hypothetical cohort. Then, 10,300 embryos (10.3% of 100,000) at the beginning of week 5 are potentially malformed and 9,548 of these (92.7% of 10,300) are lost due to spontaneous abortion or stillbirth. This implies that the incidence of SA/SB in their non-anomalous peers is only 2.3% (2,042 out of 89,700) whereas Shiota (1993) estimated it to be 17.6%. Subsequently, the RR, AR(E) and EF are much higher than the estimates above: namely 40.3, 97.5%, and 80.2% respectively. In the above subsection on prevalence in utero, the total percentage of abnormal embryos in the hypothetical cohort was estimated as 7.2%. This was based on the assumptions that 40% of SA, 14% of SB, and 3% of LB have anomalies. As a consequence, 63% of all anomalous embryos end in either spontaneous loss or stillbirth. For non-anomalous embryos, the resultant incidence of SA/SB is 7.6%, and the RR is thus 8.3, which is much lower than 40.3 but more comparable with Shiota’s (1993) estimate of 5.3. Subsequently, AR(E) is 7.3 divided by 8.3 (88%) and EF is: [0.072 * (8.3 – 1)] / [0.072 * (8.3 – 1) + 1] = 0.345 or 34.5%. Table 6.5 summarises the assumptions and the resultant estimates for the hypothetical cohort. Any minor differences to the calculations above are due to rounding. In addition, the table specifies the previous assumptions and results to obtain separate estimates for spontaneous loss (SA) and stillbirth (SB). This requires an additional assumption on the prevalence of anomalies among foetuses remaining in utero at the end of the second trimester. In the hypothetical cohort, 88,614 foetuses are still in utero at the beginning of gestational week 28 (see Table 5.6), and Table 6.5 assumes that 3% of these have anomalies since the
EARLY LIFE CHANGES
158
prevalence of congenital anomalies is generally believed to be about 3 per 100 births (live and stillbirths). A combination of the prevalence proportions with the total numbers then yields the incidence proportions for SA and SB shown in Table 6.5, for both the abnormal and the normal populations. Ultimately, the RR, AR(E) and EF of spontaneous abortion are 8.6, 88.4%, and 35.4% respectively. In the case of stillbirth, the effect of congenital anomalies appears to be less strong: the RR is 5.3, the AR(E) is 81.0%, and the EF is 11.3%.
6.2.2 NEONATAL DATA
Neonatal death Unfortunately, the data available on congenital anomalies in relation to neonatal mortality are limited. Moreover, the majority of publications only discuss anomalies as causes of death. However, Riley and Halliday (1999) have published mortality figures for Victoria (Australia) including “all birth defect cases, including those where the cause of death may not be directly related to the birth defect” (p. 109). According to their figures, 6.0% of live births with birth defects between 1983-1998 died during the neonatal period. In comparison, the incidence of neonatal death was only 0.4% among all live births within the population. Overall, 43.3% of neonatal deaths had a birth defect (Riley and Halliday 1999). Table 6.6 presents data on congenital anomalies in general as the cause of neonatal mortality. The figures from the WHO in this table were presented earlier in Table 2.6a. It appears that around 23 to 51% of neonatal deaths in EME countries are caused by congenital anomalies. Since these figures only refer to those cases where death was caused by the anomaly, the total proportion of anomalous deaths is likely to be higher. In addition, it is important to note that the proportion of neonatal deaths due to congenital anomalies has increased during the epidemiologic transition. This is because other causes (such as infectious diseases) and deaths due to these other causes have been increasingly prevented. Some data are available that specifically relate to the early neonatal period, i.e. the first week of life. Kalter (1991) reviewed hospital- and medical personnel-based reports to study trends in perinatal mortality. In his article, he noted that it is important to divide perinatal death into its two components: stillbirth and early neonatal death. His findings for stillbirth have already been presented above in Table 6.2. With regard to the early neonatal period, he concluded that the prevalence of congenital malformations in deaths during the 1980s was about 36% in Europe and 31% in America (USA and Canada). In the Dutch Delft-Westland-Oostland region, De Galan-Roosen et al. (1998) found that 47% of early neonatal deaths between 1983 and 1992 had at least one congenital malformation.
Relative risk and attributable risk: neonatal death The data for Victoria (Australia) by Riley and Halliday (1999) suggest that the RR of neonatal death for anomalous cases is at least 15 (6.0 divided by 0.4). In addition, the hypothetical cohort and the data discussed in the above subsections provide a basis for further estimates. In the hypothetical cohort, 88,410 live births occur of whom 383 die during the neonatal period. If one assumes: (1) prevalence of congenital anomalies in live births (pB
1) is 3%, (2) incidence
T
able
6.5
: Est
imat
ed o
f RR
, AR
(E) a
nd E
F of
SA
and
SB
in a
nom
alou
s em
bryo
s/fo
etus
es, h
ypot
hetic
al c
ohor
t
Inpu
tO
utpu
tB
pB1
SASB
pSA
1pS
B1
I1I0
RR
AR
(E)
EF
SA/S
B10
0,00
00.
072
11,1
5743
40.
400
0.14
00.
630
0.07
68.
30.
879
0.34
3SA
100,
000
0.07
211
,157
-0.
400
-0.
622
0.07
28.
60.
884
0.35
4SB
88,6
140.
030
-43
4-
0.14
00.
023
0.00
45.
30.
810
0.11
3
Not
es: B
- to
tal n
o. o
f em
bryo
s or f
oetu
ses i
n ut
ero
at th
e be
ginn
ing
of th
e in
terv
al; p
B1
- pre
vale
nce
of a
nom
alie
s am
ong
B; S
A -
tota
l no.
of S
A;
SB -
tota
l no.
of S
B; p
SA1
- pre
vale
nce
of a
nom
alie
s am
ong
SA; p
SB1
- pre
vale
nce
of a
nom
alie
s am
ong
SB; I
1 - i
ncid
ence
of S
A a
nd/o
r SB
am
ong
anom
alou
s em
bryo
s/fo
etus
es; I
0 - i
ncid
ence
of S
A a
nd/o
r SB
am
ong
non-
anom
alou
s em
bryo
s/fo
etus
es.
See
Cha
pter
4 fo
r equ
atio
ns. B
ased
on
the
hypo
thet
ical
coh
ort.
Tab
le 6
.6: P
ropo
rtio
n of
neo
nata
l dea
ths w
ith c
onge
nita
l ano
mal
ies (
all)
as c
ause
of d
eath
Sour
ceC
ount
ryPe
riod
%D
escr
iptio
n
Gol
denb
erg
et a
l. 19
83U
SA (A
laba
ma)
NS
23"a
ttrib
uted
to le
thal
con
geni
tal a
nom
alie
s"H
ein
and
Lath
rop
1986
[a]
USA
(Iow
a)19
82-1
983
31"a
ttrib
utab
le to
mal
form
atio
ns"
Teno
vuo
et a
l. 19
86[a
]Fi
nlan
d19
78-1
982
37"d
ied
from
leth
al m
alfo
rmat
ions
"C
artli
dge
and
Stew
art 1
995
UK
(Wal
es)
1993
28.9
caus
e of
dea
th; c
linic
opat
holo
gica
l cla
ssifi
catio
nFi
nan
et a
l. 19
99Ir
elan
d19
91-1
996
51"d
ue to
con
geni
tal m
alfo
rmat
ions
"; W
iggl
esw
orth
cla
ssifi
catio
nW
HO
[b]
Net
herla
nds
1990
36.0
caus
e of
dea
th, I
CD
-9W
HO
[b]
Italy
1992
23.5
caus
e of
dea
th, I
CD
-9W
HO
[b]
Spai
n19
9232
.4ca
use
of d
eath
, IC
D-9
WH
O[b
]U
SA19
9224
.6ca
use
of d
eath
, IC
D-9
WH
O[b
]Ja
pan
1993
37.7
caus
e of
dea
th, I
CD
-9W
HO
[b]
Swed
en19
9341
.3ca
use
of d
eath
, IC
D-9
Not
es:[
a] c
ited
by P
hilip
199
5; [b
] Wor
ld H
ealth
Sta
tistic
s Ann
ual (
vario
us y
ears
); se
e al
so C
hapt
er 2
.
EARLY LIFE CHANGES
160
of neonatal death in anomalous live births (I1) is 6% (cf. Riley and Halliday 1999), and/or (3) prevalence of anomalies in neonatal deaths (pD
1) is 38% then, subsequently, RR, AR(E), and EF can be estimated using equations (4.18) and (4.19). Table 6.7 presents the resultant RRs which range between 19.8 and 23.0. The proportion of deaths in anomalous neonates that can be attributed to the congenital anomalies is reflected in the AR(E) and is as high as 95.0-95.6%. Within the total population, 36.1 to 39.7% of neonatal deaths appear to be attributable to congenital anomalies (i.e. EF). In the final column of the table, the one measure that is missing from the input data – either pB
1, I1, or pD1 – is calculated to check whether the
combination of input data and the resultant estimates are plausible (see equations (4.22), (4.23), and (4.24)). Fortunately, all the values are similar to those in the assumptions made above which implies that all the series of estimates of RR, AR(E) and EF in the table are at least credible. The lower part of Table 6.7 presents the assumptions and estimates for early neonatal mortality. Again, it is assumed that the prevalence of congenital anomalies in live births is 3% and that the prevalence of anomalies in early neonatal deaths is 38%. However, the incidence proportion of early neonatal death among anomalous live births is assumed to be slightly lower than the incidence of total neonatal death, i.e. 5%. It is known that 299 neonates in the hypothetical cohort will die during the early neonatal period (see Table 5.9). As a result, estimates for the RR, AR(E) and EF of early neonatal death are slightly higher than those of total neonatal death. The RR ranges between 19.8 and 25.8, the AR(E) between 95.0 and 96.1%, and the EF between 36.1 and 42.8%. Again, all estimates appear to be plausible (checks compared with assumptions).
6.3 Chromosomal aberrations
6.3.1 ANTEPARTUM AND BIRTH DATA
Induced abortion Several authors have studied the prevalence of chromosomal abnormalities in induced abortuses. Table 6.8 presents the results of such studies. The studies are all somewhat old and therefore unlikely to include selective abortion. In the table, the prevalence of chromosomal aberrations in induced abortions ranges from zero to 6.4%. Differences between the results may have been caused by a multitude of factors, including the number of undetected spontaneous abortions, the method applied to retrieve conceptuses, and the techniques used for karyotyping1 (Kajii 1973; Van der Veen 2001). In addition, maternal age and gestational age of the embryo/foetus may affect the findings. Specimens obtained from older women, terminating their pregnancies at an earlier stage of gestation, are likely to result in a higher prevalence of chromosomal aberrations (Yamamoto and Watanabe 1979). Therefore, Table
1 Karyotyping: assessment of chromosomal constitution or karyotype of a cell (Kline et al. 1989).
T
able
6.7
: Est
imat
ed R
R, A
R(E
) and
EF
of n
eona
tal d
eath
in a
nom
alou
s liv
e bi
rths
, hyp
othe
tical
coh
ort
Inpu
tRe
sults
BD
pB1
I1pD
1R
RA
R(E
)EF
chec
k*
nn88
,410
383
0.03
00.
060
-23
.00.
956
0.39
7pD
1 =
0.41
688
,410
383
0.03
0-
0.38
019
.80.
950
0.36
1I1
= 0
.055
88,4
1038
3-
0.06
00.
380
21.7
0.95
40.
363
pB1
= 0.
027
early
nn
88,4
1029
90.
030
0.05
0-
25.8
0.96
10.
426
pD1
= 0.
444
88,4
1029
90.
030
-0.
380
19.8
0.95
00.
361
I1 =
0.0
4388
,410
299
-0.
050
0.38
023
.20.
957
0.36
4pB
1 =
0.02
6
Not
es: B
- to
tal n
o. o
f liv
e bi
rths;
D -
tota
l no.
of n
eona
tal d
eath
s; p
B1
- pre
vale
nce
of a
nom
alie
s am
ong
live
birth
s; I1
- in
cide
nce
of n
eona
tal
deat
hs a
mon
g an
omal
ous l
ive
birth
s; p
D1
- pre
vale
nce
of a
nom
alie
s in
neon
atal
dea
ths.
*Che
ck: c
alcu
latio
n of
eith
er p
B1,
I1, o
r pD
1 on
the
basi
s of t
he in
put a
ssum
ptio
ns.
See
Cha
pter
4 fo
r equ
atio
ns. B
ased
on
the
hypo
thet
ical
coh
ort.
T
able
6.8
: Pre
vale
nce
of c
hrom
osom
al a
berr
atio
ns in
indu
ced
abor
tions
Sour
ceC
ount
rySa
mpl
e si
ze%
Mea
n ge
stat
iona
lM
ean
mat
erna
l W
omen
age
(day
s)ag
e (y
ears
)41
+ yr
s (%
)
Sasa
ki, M
akin
o et
al.
1961
, '62
, '63
, '67
, '71
, '72
[a]
Japa
n1,
060
1.3
5326
.62.
6To
nom
ura,
Sas
aki e
t al.
1969
, '72
[a]
Japa
n60
91.
840
27.1
3.1
Yas
uda
et a
l. 19
67, '
72[a
]Ja
pan
188
2.7
40.9
29.0
NS
Ford
et a
l. [a
]U
K30
70.
065
27.7
4.8
Kaj
ii 19
73Sw
itzer
land
618
2.9
63.6
29.4
4.2
Hah
nem
ann
1973
[b]
NS
NS
3.5
8726
.56.
4Y
amam
oto
and
Wat
anab
e 19
79Ja
pan
(Niig
ata)
1,25
0*6
.459
28.0
3.2
Kaj
ii et
al.
1978
[c]
Switz
erla
nd (G
enev
a)91
02.
6N
SN
SN
SZh
ou e
t al.
1989
[c]
Chi
na (B
eijin
g)1,
186
4.5
NS
NS
NS
Bur
goyn
e et
al.
1991
[c]
UK
(Lon
don)
260
4.6
NS
NS
NS
Not
es: *
"gr
oss c
hrom
osom
al a
nom
alie
s"; N
S - n
ot st
ated
.[a
] ci
ted
by K
ajii
1973
; [b]
cite
d by
Yam
amot
o an
d W
atan
abe
1979
; [c]
cite
d by
Hof
fman
199
5b.
EARLY LIFE CHANGES
162
6.8 also provides information about the mean maternal age and the mean gestational age in the studies. However, these factors do not seem to explain the observed differences in prevalence. Kajii et al. (1978 cited by Van der Veen 2001) studied induced abortions in Switzerland and published prevalence data by gestational age. Their results were as follows: 5.9% were abnormal in gestational age interval 6-7 weeks, 4.4% in the interval 8-11 weeks, and 0.5% in the interval 12-13 weeks. However, women under 20 years of age and women aged 35 years or over were overrepresented as compared to Swiss live-birth data and, therefore, the results are believed to be biased and to be slightly high (Hook 1985 cited by Van der Veen 2001). Nevertheless, the results are consistently lower than the findings of Yamamoto and Watanabe (1979) with aberrations found in: 9.3% of induced abortions at 5-6 weeks, 6.5% at 7-8 weeks, 6.4% at 9-10 weeks, and 5.4% at 11-12 weeks. Both studies show a decline in the prevalence of chromosomal aberrations by gestational age. This decline is likely due to spontaneous loss.
Spontaneous loss and stillbirth Numerous studies have been published on the prevalence of chromosomal anomalies in spontaneous abortuses. The results, however, show wide variations. In Table 6.9, the percentages of chromosomal abnormalities range between 22 and 77% with an average of 50%. Again, these variations are likely to be related to factors such as sample population and study methods and design, including gestational age and method applied to assess gestational age. In general, the proportions ‘abnormal’ are higher in studies based on developmental age (e.g. Boué et al. 1975, see Van der Veen 2001), inferred from an observed state of development, when compared to studies based on gestational age at expulsion. Also in studies based on chorionic material and in more recent studies, the prevalence is comparatively high (Van der Veen 2001). In general, the chromosomal disorders that are most frequently observed in spontaneous losses are autosomal trisomy (48.6-62.1% of cases), monosomy X (9.0-23.7%), and triploidy2 (9.0-20.3%) (Kline et al. 1989; Van der Veen 2001). The risk of spontaneous loss is said to vary by type of chromosomal anomaly. For some chromosomal aberrations, e.g. trisomy 16 and polyploidy3, the risk approaches 100% and as a result, these anomalies are hardly ever observed in live births. For most other chromosomal anomalies the risk is above 90%. Only for a few types of chromosomal aberrations, such as trisomy 21 and sex chromosomal trisomy, is the incidence of loss below 90% (Van der Veen 2001). Some authors have presented their prevalence data by gestational age, although length of age interval varies between publications. Kline and Stein (1987) presented data in one-week intervals from studies by Creasy et al. (1976), Ohama (1978), Hassold (1982), and
2 For an explanation of the terms, please refer to Section 3.4.1. 3 Polyploidy: the presence of extra, complete set(s) of chromosomes in a cell.
Tab
le 6
.9: P
reva
lenc
e of
chr
omos
omal
abe
rrat
ions
in sp
onta
neou
s los
ses
Sour
ceC
ount
ryM
ater
ial
%G
esta
tiona
l age
Sam
ple
size
Rem
arks
Car
r 196
7[a
, b]
Can
ada
(Lon
don)
embr
yoni
c/fe
tal
22<
22 w
ks22
7<
500
gD
hadi
al e
t al.
1970
[a, b
]U
K (L
ondo
n)em
bryo
nic/
feta
l24
=< 2
4 w
ks42
3-
Bou
é et
al.
1975
[a, b
]Fr
ance
(Par
is)
embr
yoni
c/fe
tal
61<
12 w
ks p
ostc
once
ptio
n1,
498
-La
urits
en 1
976
[a, b
]D
enm
ark
(Aar
hus)
embr
yoni
c/fe
tal
55=<
18
wee
ks25
5-
Cre
asy
et a
l. 19
76[a
, b]
UK
(Lon
don)
embr
yoni
c/fe
tal
30<
28 w
ks94
1si
ngle
tons
Taka
hara
et a
l. 19
77, O
ham
a[b
]Ja
pan
(Hiro
shim
a)N
S47
< 20
wks
505
-K
ajii
et a
l. 19
80Sw
itzer
land
(Gen
eva)
mix
ed53
.5<
31 w
ks40
2C
RL
< 10
0 m
mH
asso
ld e
t al.
198
0[a
, b]
Haw
aii (
Hon
olul
u)em
bryo
nic/
feta
l49
NS
1,63
9<
500
gB
yrne
et a
l. 19
85[c
]N
SN
S39
.8N
S1,
356
-G
uern
eri e
t al.
1987
Italy
chor
ioni
c76
.71s
t trim
este
r18
9-
Eibe
n et
al.
1990
Ger
man
ych
orio
nic
50.1
5th-
25th
wk
750
-St
rom
et a
l. 19
92[a
]N
Sch
orio
nic
83N
SN
S-
Gar
dó a
nd B
ajnó
czky
199
2H
unga
rych
orio
nic
51.3
1st t
rimes
ter
224
-Si
mps
on a
nd C
arso
n 19
93[a
]N
Sem
bryo
nic/
feta
l46
NS
NS
-Sc
hmid
t-Sar
osi e
t al.
1998
USA
chor
ioni
c69
.21s
t trim
este
r52
in in
ferti
le w
omen
Klin
e, K
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EARLY LIFE CHANGES
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Table 6.10: Prevalence of chromosomal aberrations in spontaneous losses, by gestational age
Gestation UK, London [a] Japan, Hiroshima [b] Hawaii, Honolulu [c] USA, NY City [d](weeks) % N % N % N % N
=< 7 - 0 13.6 44 36.6 82 28.8 1608 50.0 4 35.3 51 39.0 77 46.2 1199 31.2 16 44.8 29 48.1 133 52.1 171
10 41.4 36 35.1 37 54.7 170 59.1 31311 60.0 65 50.0 50 60.2 261 57.0 41912 46.1 115 56.6 76 56.9 225 57.0 37213 47.6 124 55.2 58 53.4 178 43.6 23614 43.3 90 52.4 42 43.3 127 42.0 20015 34.0 47 61.8 34 36.7 90 37.7 13816 28.6 56 54.5 22 33.3 66 34.5 11617 28.9 45 91.7 12 44.8 67 26.7 12018 19.4 36 72.7 11 45.5 33 20.0 9019 0.0 31 66.7 6 37.2 43 14.3 9820 15.6 32 50.0 4 39.1 23 10.3 11721 16.5 37 - 0 36.4 11 13.3 9822 5.0 40 - 0 40.0 15 10.0 8023 5.6 36 0.0 1 83.3 6 7.5 6724 0.0 28 - 0 75.0 4 11.1 4525 0.0 19 - 0 I I 13.6 4426 0.0 23 - 0 41.7 24 10.3 2927 0.0 13 - 0 I I 22.2 9
Total 31.1 893 48.2 477 49.2 1635 40.2 3041Unknown 18.8 48 25.0 28 50.0 4 31.1 273
Gestation in 4-week intervals
=< 7 - 0 13.6 44 36.6 82 28.8 1608-11 50.4 121 41.3 167 53.7 641 55.6 1022
12-15 44.1 376 56.2 210 50.2 620 47.7 94616-19 21.4 168 68.6 51 39.7 209 24.5 42420-23 10.3 145 40.0 5 43.6 55 10.5 36224-27 0.0 83 - 0 46.4 28 12.6 127
Total 31.1 893 48.2 477 49.2 1635 40.2 3041Unknown 18.8 48 25.0 28 50.0 4 31.1 273
Sources: [a] Creasy et al. 1976 cited by Kline and Stein 1987, table 3.1, p.30; [b] Ohama 1978, personal communication citedby Kline and Stein 1987, table 3.1, p.30; [c] Hassold 1982, personal communication cited by Kline and Stein 1987, table 3.1,p.30; [d] J. Kline, A. Kinney, and D. Warburton, personal communication in 2000. Warburton et al. (1983; additional data from Kline, Kinney, and Warburton, personal communication in 2000). Table 6.10 presents the outcomes of these four large series of karyotyped miscarriages. During the first few intervals, the results of the four studies lie relatively close together. The proportion of chromosomal anomalies is low early in gestation but increases to about 55-60% around gestational week 11. The low proportion below 7 weeks of gestation is likely to be an underestimation that could be explained by a tendency of chromosomally aberrant embryos to be retained in utero for several weeks after implantation,
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i.e. missed abortion (Warburton et al. 1980). Later in pregnancy, the patterns in the four studies diverge. While the percentage of chromosomally aberrant seems to decline in London and New York City, it continues to increase in Honolulu and Hiroshima. The disparities between the outcomes are partly to be explained by differences in study design but, of course, genuine geographic or ethnic differences may also underlie the differences (Kline et al. 1989). In stillbirths, the prevalence of chromosomal aberrations is much lower than in spontaneous losses. According to data from Warburton et al. (1980, 1982 cited by Simpson and Bombard 1987), about 5% of abortuses after 28 weeks have chromosomal abnormalities. On the basis of these data and other perinatal data, Simpson and Bombard (1987) estimated the prevalence of chromosomal abnormalities in stillbirths at 5-7%. Kline et al. (1989) combined data from Machin and Crolla (1974), Sutherland et al. (1974), and Kuleshov (1976) resulting in a sample of 452 stillbirths of whom 5.8% had chromosomal aberrations. Hollier et al. (2000) also presented data on the prevalence of chromosomal abnormalities in stillbirths. Out of 829 stillbirths, only 16 (1.9%) had an abnormal karyotype. However, this comparatively low proportion is likely to be a result of the study design and methodology since their estimate of prevalence in second trimester abortions was also extremely low (2.4%). It thus seems likely that several cases of chromosomal aberrations were undetected in the hospital-based study by Hollier et al. (2000). Finally, in an analysis of data from the USSR (N.B. not part of the EME region), Kuleshov (1976 cited by Simpson and Bombard 1987) distinguished between antepartum and intrapartum deaths. The prevalence of chromosomal abnormalities was as high as 13.6% in antepartum deaths while only 4.9% in intrapartum deaths. Similarly, in a study by Machin (1974 cited by Roberts and Lowe 1975), 9% of macerated stillbirths but only 4% of fresh stillbirths were chromosomally abnormal.
Live birth and all births Chromosomal anomalies seem to be present in between 0.3 and 2.0% of live births (see Table 6.11). A lower figure comes from Hollier et al. (2000) who encountered only 155 abnormal karyotypes among 101,198 singleton live births (> 500 g), i.e. 0.15%. This figure is likely to be an underestimation since their prevalence figures among spontaneous losses and stillbirths, as noted above, were also relatively low. Nevertheless, in a hospital-based study in Tokyo (Japan), only 0.14% of births (including stillbirths > 16 weeks) between 1979-1993 were diagnosed as having a chromosomal anomaly (Kato and Fujiki 1996). However, in this study, only cases were included that were detected within seven days of birth. Generally, the prevalence of chromosomal abnormalities among live births is estimated to be about 0.6%. Prevalence data on chromosomal abnormalities at birth are often presented by type of anomaly, e.g. for Down’s syndrome (trisomy 21), and for Turner’s syndrome (45,X). According to Hook (1985 cited by Van der Veen 2001), this prevalence of 0.6% in live births is made up as follows: autosomal numerical anomalies (0.15%), sex chromosome disorders (0.18%), and structural chromosomal anomalies (0.26%). The most frequent single chromosomal anomaly is trisomy 21 (Down’s syndrome) which occurs in 0.13% of live births.
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Source Country Period % Remarks
Jacobs et al. 1974 [a] NS NS 0.6 based on 6 studiesSimpson and Bombard 1987 - - 0.5 general estimateHoffman 1995b * NS 0.30-2.02 based on 8 studiesHoffman 1995b * NS 0.71 combination of 8 studiesWHO Scientific Working Group 1996 developed - 0.35 general estimateVan der Veen 2001 [b] - - 0.6 general estimate
Notes: *based on studies in Canada, Denmark, UK, and USA; NS - not stated.[a] cited by Cunningham et al. 1993; [b] based on Nielsen 1975, Hook and Hamerton 1977, and Hook 1981.
Table 6.11: Prevalence of chromosomal aberrations in live births
Prevalence in utero Some estimates are available on the prevalence of chromosomal aberrations among all embryos and foetuses in utero at a specific gestational age. Some of these estimates are derived from studies based on prenatal diagnosis. However, caution is required because of possible biases in the sample population. Drugan et al. (1992b) studied a sample of 3,194 chorionic villus sampling procedures. The majority of patients were referred due to their advanced maternal age and the procedure was generally performed between 9 to 13 weeks of gestation. The prevalence of chromosome anomalies in the sample was 1.9%. Similarly, Eiben et al. (1994) examined the results of early amniocenteses between weeks 11 and 14 of gestation. Their result was an overall prevalence of 2.8%. In his dissertation, Van der Veen (2001) combined the results of various studies to obtain a schedule for the in-utero prevalence of chromosomal anomalies by stage of reproduction (see Table 6.12). In the schedule, the prevalences of chromosomal aberrations prior to implantation were derived from several in-vitro studies. The estimates by Hook (1981), in the table, were obtained by combining live birth and miscarriage prevalence data with life table estimates of spontaneous abortion taken from Harlap et al. (1980). Apart from the results in Table 6.12, Van der Veen (2001) also mentioned an estimation by Plachot et al. (1987) that 8 to 10% of clinical first trimester pregnancies are chromosomally abnormal. In addition, estimates can be made for the hypothetical cohort. Out of the 100,000 embryos in the hypothetical cohort, 11,157 end in spontaneous loss (< 28 weeks), 434 in stillbirth (≥ 28 weeks), and 88,410 in live birth (see Table 5.6). We can suppose, on the basis of the data in the subsections above, the following outcome-based prevalences for chromosomal anomalies: 50% in spontaneous losses (< 28 weeks), 6% in stillbirths (≥ 28 weeks), and 0.6% in live births. Let us further assume that chromosomal anomalies only arise before gestational week 5 and that recovery is not possible. These assumptions imply that 6,135 (5,579 SA + 26 SB + 530 LB) of the hypothetical embryos, 6.1% are chromosomally aberrant. A prevalence of 6.1% at the beginning of gestational week 5 appears plausible. In Table 6.12, Hook (1981 cited by Van der Veen 2001) estimates average prevalence between gestational weeks 5-7 at 5.0%.
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Table 6.12: Prevalence of chromosomal anomalies by stage of reproduction
Stage % References
Gametogenesis, oocytes 32 Plachot et al. 1987Gametogenesis, spermatozoa 8-9 Martin et al. 19832-4 cell embryos 55 Almeida and Bolton 19965-8 cell embryos 27 Almeida and Bolton 1996Pre-implantation embryos 21 Plachot et al. 1987Embryos gestational age 5-7 5.0 Hook 1981Foetuses gestational age 8-11 4.2 Hook 1981Foetuses gestational age 12-15 2.4 Hook 1981Foetuses gestational age 16-19 1.1 Hook 1981Foetuses gestational age 20-27 0.8 Hook 1981Live births 0.6 Nielsen 1975, Hook and Hamerton 1977, Hook 1981
Source: Van der Veen 2001, table 20, p.109 However, the assumption that 50% of spontaneous losses are chromosomally abnormal does not agree with the estimate made above in Section 6.2.1 that only 40% of spontaneous losses have a congenital anomaly (all types combined). Moreover, Kline et al. (1989) also estimate that “about 40% of miscarriages are chromosomally aberrant, about 6% of stillbirths, and less than 1% of live births” (p.83). Combining of these figures (N.B. using a prevalence of 0.6% in live births) with the hypothetical cohort yields the following outcome: of the 100,000 hypothetical embryos, 5,019 (4,463 SA + 26 SB + 530 LB), or 5.0% have chromosomal anomalies. This is the same as the estimate by Hook (1981 cited by Van der Veen 2001) in Table 6.12 for gestational weeks 5-7.
Relative risk and attributable risk: foetal loss For further calculations on risk, we will continue to use the second set of assumptions in which prevalence of chromosomal aberrations among SA is 40%, among SB 6%, and among LB 0.6%. Table 6.13 presents these assumptions in combination with total numbers from the hypothetical cohort. Furthermore, the table assumes that the total percentages of abnormal embryos/foetuses at the beginning of gestational week 5 and 28 are 5.0% and 0.6% respectively. The resultant relative risks of SA, SB, and SA/SB combined are 12.7, 10.6, and 12.0 respectively. This means, for example, that chromosomally aberrant foetuses are nearly 13 times as likely as chromosomally normal foetuses to end in spontaneous abortion. The attributable risks among the exposed population are 92.1%, 90.5%, and 91.7% respectively. In other words, 92% of spontaneous abortions, 91% of stillbirths, and 92% of SA/SB in chromosomally abnormal foetuses can be attributed to their chromosomal aberration. Lastly, the etiologic fractions of SA, SB, and SA/SB, are 36.8%, 5.4%, and 35.5% respectively. The comparatively low proportion of stillbirths in the total population that are attributable to chromosomal aberrations (i.e. 5.4%) is explained by the low prevalence of chromosomal abnormalities in the population of foetuses at 28 gestational weeks.
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Table 6.13: Estimated RR, AR(E) and EF of SA and SB in embryos/foetuses with chromosomalanomalies, hypothetical cohort
B pB1 SA SB pSA1 pSB1 I1 I0 RR AR(E) EF
SA/SB 100,000 0.050 11,157 434 0.400 0.060 0.898 0.075 12.0 0.917 0.355SA 100,000 0.050 11,157 - 0.400 - 0.893 0.070 12.7 0.921 0.368SB 88,614 0.006 - 434 - 0.060 0.049 0.005 10.6 0.905 0.054
Notes: B - total no. of embryos or foetuses in utero at the beginning of the interval; pB1 - prevalence of anomalies among B;SA - total no. of SA; SB - total no. of SB; pSA1 - prevalence of anomalies among SA; pSB1 - prevalence of anomaliesamong SB; I1 - incidence of SA and/or SB among anomalous embryos/foetuses; I0 - incidence of SA and/or SB amongnon-anomalous embryos/foetuses.See Chapter 4 for equations. Based on the hypothetical cohort.
Prevalence in utero, by gestational age Table 6.10, which contains data on prevalence of chromosomal aberrations in spontaneous losses by gestational week, provides an opportunity to estimate prevalence among all embryos/foetuses in utero by gestational age. The findings for the karyotyped series by Kline, Kinney, and Warburton (personal communication in 2000) will be applied below to the hypothetical cohort. Additional assumptions about live and stillbirth do not take gestational age into account and are kept simple: the prevalences in live and stillbirths are 0.6 and 6% respectively, at all gestational ages. It should be noted that these additional assumptions are not in accordance with reality. In general, the unhealthy foetus (e.g. anomalous) is more prone to experience intrauterine death and/or to be expelled early in gestation, either as live or stillbirth (also see Section 7.6). Table 6.14 presents the combined estimates and the outcomes. Columns (3) and (6) are copied from the foetal life table for the hypothetical cohort (Table 5.6). In the table, prevalence proportions of chromosomal aberrations are combined with the total numbers of type-specific attritions in order to obtain the numbers of attritions, by type, that have a chromosomal anomaly. The table shows that in total 4,968 (42.9%) of spontaneous losses and stillbirths and 530 (0.6%) of live births are chromosomally aberrant. Column (9) sums the number of chromosomally aberrant attritions. The total of 5,498 in this column equals the total number of chromosomally aberrant embryos alive and in utero at the beginning of gestational week 5 (in column 10). Next, column (10) presents the total numbers of chromosomally aberrant embryos/foetuses still in utero at specific gestational weeks. Finally, the prevalence of chromosomal anomalies within the entire population in utero is calculated by gestational age in column (11). The resultant prevalence develops as follows: 5.5% at the beginning of gestational week 5, 3.3 to 5.1% in weeks 8-11, 1.2 to 2.5% in weeks 12-15, 0.7 to 1.0% in weeks 16-19, 0.7% in weeks 20-25, and 0.6% in the following weeks. These results seem slightly lower than the estimates in the schedule of Table 6.12. Columns (12) through (14) in Table 6.14 are discussed in the subsection below.
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Relative risk and attributable risk, by gestational age In Table 6.14, 4,968 of the 5,498 chromosomally aberrant embryos are eventually lost to spontaneous abortion or stillbirth which means that the incidence of SA/SB is 90.4%. Risk is considerably lower for those without chromosomal anomalies (7.0%) and the RR is thus 12.9 (90.4 divided by 7.0). Consequently, AR(E) is 11.9 divided by 12.9, or 92.2%. The initial prevalence of chromosomal anomalies in the total population of 100,000 embryos is 5.5% and therefore, EF is: [0.055 * (12.9 – 1)] / [0.055 * (12.9 – 1) + 1] = 0.395 or 39.5%. Table 6.14 has been extended to include estimates for RR, AR(E), and EF by gestational week. In column (12), the relative risk (RR) of spontaneous loss/stillbirth is calculated as:
RR = [d'1x / l'x] / [(d1x – d'1x) / (lx – l'x)]
where d'1x is presented in column (5), l'x in column (10), d1x in column (3), and lx in column
(2). Overall, the relative risk is 12.9 but it fluctuates between 6.9 and 53.1 throughout gestation. The RR is lowest early in gestation (weeks 5 through 7) and highest in weeks 12 to 17. For stillbirth (≥ 28 weeks), the RR varies between 10.1 and 10.5. However, when interpreting the results, one should not overlook the problems related to data on early gestation. Early spontaneous losses, both chromosomally normal and abnormal, are often unobserved. Moreover, missed abortion or delayed expulsion can distort findings. Kline et al. (1989) even posed the hypothesis that “chromosomally aberrant conceptuses in which development ceased at 2 to 3 weeks after fertilisation may miscarry later in gestation than chromosomally normal conceptions of the same developmental age” (p.110). Estimates in Table 6.14 of the proportion of losses and stillbirths that can be attributed to chromosomal aberrations are based on RR. Column (13) presents AR(E), the attributable risk among the abnormal, as [RR – 1] / RR or [column (12) – 1] / column (12). The percentages of spontaneous losses among those chromosomally aberrant that can be attributed to chromosomal aberration ranges from 85.6% to as much as 98.1%. For stillbirths, the AR(E) is also high, ranging from 90.1 to 90.4%. Finally, column (14) presents the etiologic fraction (EF) which is calculated with help of the prevalences in column (11) and the RRs in column (12). Within the total population of embryos/foetuses, the percentage of spontaneous losses that can be attributed to chromosomal anomalies ranges from 6.9% (week 23) to 57.4% (week 10). For stillbirths, the EF is lower at only 5.4%. The results seem to be in agreement with the estimates in Table 6.13.
6.3.2 NEONATAL DATA
Neonatal death Information on the neonatal survival chances of newborns with chromosomal anomalies is very limited. Many sources present figures for longer periods of time stretching over infancy and childhood. Sutherland et al. (1978 cited by Van der Veen 2001) estimated the percentages
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Table 6.14: Estimated prevalence of chromosomal aberrations and estimated RR,AR(E) and EF of SA and SB, by gestational age, hypothetical cohort
Gestational In utero Spontaneous loss and stillbirth Live birthweeks total total chrom.ano. chrom.ano. total chrom.ano. chrom.ano.
x lx d1,x % d'1,x d2,x % d'2,x(1) (2) (3) (4) (5) (6) (7) (8)
5 100,000 437 28.8 126 0 0.6 06 99,563 397 28.8 114 0 0.6 07 99,166 682 28.8 196 0 0.6 08 98,484 1,053 46.2 486 0 0.6 09 97,431 1,210 52.1 630 0 0.6 0
10 96,221 1,456 59.1 861 0 0.6 011 94,765 1,318 57.0 751 0 0.6 012 93,447 1,326 57.0 756 0 0.6 013 92,121 752 43.6 328 0 0.6 014 91,369 477 42.0 200 0 0.6 015 90,892 427 37.7 161 0 0.6 016 90,465 383 34.5 132 0 0.6 017 90,082 203 26.7 54 0 0.6 018 89,879 200 20.0 40 0 0.6 019 89,680 242 14.3 35 15 0.6 020 89,423 149 10.3 15 15 0.6 021 89,259 118 13.3 16 0 0.6 022 89,141 102 10.0 10 15 0.6 023 89,025 14 7.5 1 43 0.6 024 88,968 29 11.1 3 29 0.6 025 88,911 113 13.6 15 43 0.6 026 88,755 42 10.3 4 42 0.6 027 88,670 28 22.2 6 28 0.6 028 88,614 56 6.0 3 70 0.6 029 88,489 0 6.0 0 97 0.6 130 88,392 55 6.0 3 96 0.6 131 88,241 27 6.0 2 192 0.6 132 88,021 41 6.0 2 259 0.6 233 87,722 41 6.0 2 461 0.6 334 87,220 14 6.0 1 581 0.6 335 86,625 27 6.0 2 1,010 0.6 636 85,588 0 6.0 0 2,172 0.6 1337 83,416 27 6.0 2 4,066 0.6 2438 79,323 13 6.0 1 9,708 0.6 5839 69,602 40 6.0 2 19,357 0.6 11640 50,205 67 6.0 4 27,986 0.6 16841 22,152 27 6.0 2 13,659 0.6 8242 8,467 0 6.0 0 6,340 0.6 3843 2,127 0 6.0 0 1,781 0.6 1144 346 0 6.0 0 346 0.6 2
Total 11,590 42.9 4,968 88,410 0.6 530
Columns (3) and (6) are copied from table 5.6; Column (4) < 28 weeks is based on J. Kline, A. Kinney,and D. Warburton, personal communication in 2000 (see table 6.10).
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Table 6.14 (continued)
Gestational Chromosomally aberrant SA/SBweeks Loss In utero Prevalence RR AR(E) EF
x d'x l'x % of lx(1) (9) (10) (11) (12) (13) (14)
5 126 5,498 5.5 6.9 0.856 0.2466 114 5,372 5.4 7.1 0.859 0.2477 196 5,258 5.3 7.2 0.861 0.2488 486 5,062 5.1 15.8 0.937 0.4339 630 4,576 4.7 22.1 0.955 0.497
10 861 3,946 4.1 33.8 0.970 0.57411 751 3,085 3.3 39.4 0.975 0.55612 756 2,334 2.5 51.8 0.981 0.55913 328 1,578 1.7 44.4 0.977 0.42614 200 1,250 1.4 52.2 0.981 0.41215 161 1,050 1.2 51.8 0.981 0.37016 132 889 1.0 53.1 0.981 0.33917 54 757 0.8 43.0 0.977 0.26118 40 702 0.8 31.7 0.968 0.19419 35 662 0.7 22.4 0.955 0.13720 15 628 0.7 16.2 0.938 0.09721 16 612 0.7 22.2 0.955 0.12722 10 597 0.7 16.5 0.939 0.09423 1 586 0.7 12.2 0.918 0.06924 3 585 0.7 18.9 0.947 0.10525 16 582 0.7 23.9 0.958 0.13026 5 566 0.6 17.9 0.944 0.09727 6 561 0.6 44.8 0.978 0.21728 4 555 0.6 10.1 0.901 0.05429 1 551 0.6 - - -30 4 551 0.6 10.2 0.902 0.05431 3 547 0.6 10.2 0.902 0.05432 4 544 0.6 10.3 0.903 0.05433 5 540 0.6 10.3 0.903 0.05434 4 535 0.6 10.3 0.903 0.05435 8 531 0.6 10.4 0.903 0.05436 13 523 0.6 - - -37 26 510 0.6 10.4 0.904 0.05438 59 484 0.6 10.4 0.904 0.05439 119 425 0.6 10.4 0.904 0.05440 172 306 0.6 10.4 0.904 0.05441 84 134 0.6 10.5 0.904 0.05442 38 51 0.6 - - -43 11 13 0.6 - - -44 2 2 0.6 - - -
Total 5,498 12.9 0.922 0.395
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of chromosomally abnormal cases in early neonatal deaths and late neonatal deaths to be 5.0% and 5.8% respectively. However, one should note that survival chances are not the same for all types of chromosomal anomalies. For example, trisomy 18 (Edwards’ syndrome) and trisomy 13 (Patau’s syndrome) cases hardly ever survive beyond 6 months, whereas cases with trisomy 21 (Down’s syndrome) have much better survival chances (Van der Veen 2001, p.100).
Relative risk and attributable risk: neonatal death Since data that refer specifically to the neonatal period are unavailable, it is difficult to estimate the relative risk of neonatal death. However, an attempt can be made on the basis of the estimates by Sutherland et al. (1978 cited by Van der Veen 2001). Supposing that the prevalence of chromosomal aberrations in live births (pB
1) is 0.6%, while the prevalence in neonatal deaths (pD
1) is 5.3%, then these figures can be substituted into equation (4.19) in combination with the numbers of live births and neonatal deaths from the hypothetical cohort, i.e. 88,410 and 383 respectively. The incidence of neonatal death in chromosomally aberrant live births (I1) then becomes 3.8%. The resultant RR is 9.3 which indicates that the risk of neonatal death for newborns with chromosomal anomalies is about 9 times the risk for those without. Subsequently, the attribution of neonatal deaths to chromosomal anomalies in the aberrant population and in the total population can be estimated as the AR(E) and the EF respectively. The AR(E) is found to be 89.2% while the EF is influenced by the low prevalence within the total population and is only 4.7%. For early neonatal death, the results can be expected to be slightly lower. If one assumes, on the basis of the data by Sutherland et al. (1978 cited by Van der Veen 2001), that the prevalence of chromosomal aberrations in early neonatal deaths is 5.0%, then the incidence of early neonatal death in aberrant live births is 2.8%. From this the RR is estimated as 8.7, the AR(E) as 88.5%, and the EF as 4.4%.
6.4 Neural tube defects (NTDs)
6.4.1 ANTEPARTUM AND BIRTH DATA
Induced abortion and selective abortion In Japan, Nishimura (1975 cited by Leck 1983) studied the products of induced abortions in a population of embryos and early foetuses. The prevalence of anencephaly and/or encephalocele was 2.7 per 1,000 and the prevalence of spina bifida aperta 3.4 per 1,000. Blanch et al. (1998) studied embryos that were artificially aborted using mifepristone and misoprostol before nine weeks gestation. In their study, 42% of detected structural anomalies were neural tube defects (NTDs). In other words, 6.3% of cases in which the researchers were able to recover and examine an embryo showed signs of the presence of an NTD (open posterior neurope, open anterior neurope, or encephalocele). Neural tube defects can be detected prenatally through diagnostic tests. Therefore, the prevalence of NTDs in artificially terminated pregnancies after 10 weeks gestation is likely to
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have increased over the years. Nearly all cases of anencephaly and open spina bifida are nowadays detected during routine ultrasound scanning (Chitty 1997 cited by Van der Veen 2001). Moreover, the majority of women who have been diagnosed as carrying a foetus with anencephaly or spina bifida opt for termination (Van der Veen 2001). In Atlanta (USA), in the period 1990-1991, 32% of NTD-affected pregnancies were detected prenatally and terminated before 20 weeks gestation (Roberts et al. 1995). Combined data from 12 EUROCAT registries show that the percentage of anencephaly cases that were prenatally diagnosed increased from 80% in 1980-1985 to 95% in 1989-1990. In total, 84% of anencephaly cases in 1989-1990 ended in induced abortion. With regard to spina bifida and hydrocephalus, 38% and 42% of cases respectively, were terminated artificially (EUROCAT 1993). Overall, of the detected NTD cases that were registered in one of 25 EUROCAT registries between 1990 and 1996, 39.0% ended in live birth, 7.8% in foetal death, and 53.2% in induced abortion (EUROCAT 2001).
Spontaneous loss and stillbirth Both Creasy and Alberman (1976) and Fantel et al. (1980) have examined the products of spontaneous abortions for abnormalities. Table 6.15 presents their results for NTDs by gestational age in which incomplete specimens have been excluded from the denominator. The data by Creasy and Alberman (1976) concern ASB-type malformations (i.e. anencephaly, craniochischisis, exencephaly, encephalocele, and spina bifida cystica) with no demonstrated chromosomal anomaly. Encephalocele, exencephaly, and spina bifida were the most frequently observed anomalies in this study.
Table 6.15: Prevalence of NTDs in spontaneous abortions*, by gestational age
Creasy and Alberman 1976, London, 1971-1974
Gestational age Sample size % Type of anomaly8-11 wks 232 2.2 ASB-type malformation
12-15 wks 316 2.2 ASB-type malformation16-19 wks 247 2.0 ASB-type malformation20-23 wks 239 0.8 ASB-type malformation24-27 wks 109 3.7 ASB-type malformation
Total 1,143 2.0 ASB-type malformation
Fantel et al. 1980, USA, 1971-1979Gestational age Sample size % Type of anomaly
2-8 wks 393 0.3 anencephaly, spina bifida, hydrocephalus9-13 wks 66 7.6 anencephaly, spina bifida, hydrocephalus
14-18 wks 60 0.0 anencephaly, spina bifida, hydrocephalus>= 19 wks 118 5.1 anencephaly, spina bifida, hydrocephalus
Total 637 1.9 anencephaly, spina bifida, hydrocephalus
Notes: *in complete specimens.ABS-type malformation: anencephalus, craniorachischisis, exencephalus, encephalocele, and spina bifida cystica;no demonstrated chromosomal anomaly.Based on: Creasy and Alberman 1976, table VIII, p. 13; Fantel et al. 1980, table 4, pp.80-81.
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On the basis of the figures in Table 6.15, there does not seem to be a clear pattern of prevalence proportion over gestational duration. This is probably explained by the relatively small sample sizes. In both studies, the total prevalence of NTDs in spontaneous abortions appeared to be about 2%. In their article, Creasy and Alberman (1976) also cited two other studies, by Singh and Carr (1967) and by Carter and Evans (1973). The results from Singh and Carr (1967) are comparable to the 2% in Table 6.15: the combined prevalence of meningocele and encephalocele in 168 spontaneously aborted embryos and foetuses was 1.8%. Carter and Evans (1973) studied stillbirths (> 27 gestational weeks) in Greater London (UK). In total, 604 out of 5,741 stillbirths, or 10.5%, had an ABS-type malformation. Creasy and Alberman (1976) combined the results from their own London study with data on the outcome of pregnancy by French and Bierman (1962) and data on live and stillbirths from Carter and Evans (1973). They estimated that, in total, 75.8% of embryos/foetuses who are affected by ASB-malformations end in either spontaneous loss or stillbirth. The distribution by gestational age was as follows: 28.6% are lost in weeks 8-11, 17.4% at 12-15 weeks, 4.5% at 16-19 weeks, 1.1% at 20-23 weeks, 1.9% at 24-27 weeks, and 22.3% are stillbirths (> 27 weeks). In Japan, Shiota (1993) estimated the incidence of loss for NTD-affected embryos and foetuses by gestational age. He concluded that about 21% of cases are lost before week 6 after fertilisation, 36.7% before week 7, 48.2% before week 8, 92.8% already by week 9, and as many as 98.4% before birth.
Live birth and all births Table 6.16 presents prevalences of NTDs in all births and live births. According to the table, prevalence is low (≤ 1.6 per 1,000) but the figures do show considerable variation. The birth prevalence of NTDs varies between 0.57 to 1.35 per 1,000 births, and from 0.77 to 1.6 per 1,000 live births. It is unlikely that prevalence in live births is higher than prevalence in all births since many of the foetuses affected by NTDs are stillborn. This is supported by EUROCAT data for the Northern Netherlands where the prevalence was 1.35 per 1,000 births but only 0.96 per 1,000 live births in 1981-1987 (Samrén et al. 1999). In general, the prevalence of neural tube defects at birth is higher in females than in males (Main and Mennuti 1986). The male/female sex ratio of affected cases varies by type of NTD but ranges between 0.6 and 0.8 (Shibuya and Murray 1998c). The birth prevalence of NTDs varies markedly by geographic region and over time (Windham and Edmonds 1982; Main and Mennuti 1986; Shibuya and Murray 1998c). Data from EUROCAT registries show large variations within Europe and the highest frequencies of NTDs are observed in the UK and Ireland. Further, the birth prevalence of NTDs has decreased over time in the EME region. For example, in the early and mid-1960s, prevalence figures as high as 5 to 9 per 1,000 were reported for the British Isles. In the period 1980-1986, the prevalence in this region had declined, according to EUROCAT, to 2.4-3.7 per 1,000 births (EUROCAT Working Group 1991). The decrease may in part be explained by the utilisation of prenatal diagnostic tests and subsequent selective abortions. For example, Velie and Shaw (1996) found that, because of selective pregnancy terminations, prevalence estimates in California for 1989-1991 were reduced by about 30% for spina bifida and 50%
CHAPTER 6: CONGENITAL ANOMALIES
175
Table 6.16: Prevalence of NTDs in births
In births
Source Region Period per 1,000 Remarks
Elwood et al. 1992 [a] USA NS 1 -Evans et al. 1992 Manitoba (Canada) 1988-1990 0.57 based on MCA RegistrySamrén et al. 1999 Netherlands (north) 1981-1987 1.35 based on EUROCAT registry
In live births
Source Region Period per 1,000 Remarks
Main & Menutti 1986 USA NS 1.4-1.6 -Roberts et al. 1995 Atlanta (USA) 1990-1991 0.77 based on MACDP registrySamrén et al. 1999 Netherlands (north) 1981-1987 0.96 based on EUROCAT registryNotes: NS - not stated; MCA Registry - Manitoba Congenital Anomalies Registry; EUROCAT - European Registrationof Congenital Anomalies; MACDP - Metropolitan Atlanta Congenital Defects Program.[a] cited by Velie and Shaw 1996
for anencephaly. The authors noted that other studies from Scotland, Western Europe, Canada, Australia, and the United States had reported similar or even higher reductions. Nevertheless, improvements in nutrition and, more recently, folic acid supplementation are also likely to have contributed to the reduction of NTDs over time (Roberts et al. 1995; Shibuya and Murray 1998c). At birth, the most common types of neural tube defects are anencephaly and spina bifida. The birth prevalence of anencephaly ranges from 0.03 to 1.19 per 1,000 births and the prevalence of spina bifida from 0.22 to 1.54 per 1,000 births (ACOG 1986 cited by Cunningham et al. 1993; Stone et al. 1988; EUROCAT Working Group 1991; Kato and Fujiki 1996; Shibuya and Murray 1998c). About half of the cases with anencephaly are believed to be stillborn while almost all the others die during the early neonatal period (Windham and Edmonds 1982; Main and Mennuti 1986). The majority of spina bifida cases are born alive. During 1990-1996, about 66.8% of spina bifida births in Europe were live births (EUROCAT 2001). In the past, spina bifida was considered a lethal condition but the introduction of new surgical techniques has improved survival (Shibuya and Murray 1998c).
Prevalence in utero Some authors have estimated the prevalence of NTDs among all embryos and foetuses in utero by combining data on the risk of spontaneous loss and the prevalence of NTDs among those lost. Table 6.17 presents estimates by gestational age from Creasy and Alberman (1976), and from Shiota (1993) who estimated the prevalence of NTDs to be much lower. The Japanese estimates show a rapid and considerable decline with gestational age: from 2.5% at the beginning of week 5 to only 0.2% at the beginning of the foetal period (week 9 since fertilisation). Creasy and Alberman (1976), on the other hand, believed the incidence of loss and stillbirth among NTD cases – and therefore, also the decline in in-utero prevalence by gestational age – to be much lower.
EARLY LIFE CHANGES
176
Table 6.17: Estimated prevalence of NTDs in utero, by gestational age
Creasy and Alberman 1976, London, 1971-1974
Gestational age % Remarksweek 8 5.3 ASB-type malformation
week 12 4.1 ASB-type malformationweek 16 3.2 ASB-type malformationweek 20 3.0 ASB-type malformationweek 24 3.0 ASB-type malformationweek 27 2.8 ASB-type malformation
Shiota 1993, Japan
Gestational age* % Remarks
week 5 2.5 -week 6 2.0 -week 7 1.7 -week 8 1.4 -
Fetal period 0.2 -
Notes: *since fertilisationABS-type malformation: anencephalus, craniorachischisis, exencephalus, encephalocele, andspina bifida cystica; no demonstrated chromosomal anomaly.Sources: Creasy and Alberman 1976, table VIX, p. 13; Shiota 1993, table IV, p.194.
For the hypothetical cohort, an estimate of the in-utero prevalence can be obtained on the basis of the data that have been discussed in the previous subsections. Supposing that the prevalence proportions of NTDs are: 2.0% in spontaneous losses (< 28 weeks), 10.5% in stillbirths (≥ 28 weeks), and 0.15% in live births; and further assuming that these figures have not been affected by selective abortion, then, in the hypothetical cohort of 100,000 embryos, 402 (223 SA + 46 SB + 133 LB) or 0.4% will develop an NTD. This estimate appears to be very low, even when compared to the figures from Shiota (1993). The difference is probably explained by changes over historical time and differences in the risk of loss and stillbirth. Creasy and Alberman (1976) based their calculations on the foetal life table from French and Bierman (1962) whereas our hypothetical cohort is based on more recent data from Goldhaber and Fireman (1991).
Relative risk and attributable risk: foetal loss Table 6.18 applies the estimated values from Creasy and Alberman (1976) and those from Shiota (1993) to the hypothetical cohort. In the first estimation, the initial prevalence of NTDs is 5.3% and the incidence of SA/SB in NTD-affected conceptuses 75.8%. In the latter estimation, the corresponding figures are 2.5% and 98.4% respectively. The results imply that the prevalence of NTDs in SA/SB (pD
1) is as high as 21 to 35%. The ranges for the other values are as follows: the RR is 9.5 to 10.5, the AR(E) is estimated to be 89.5 to 90.5%, and the EF 19.2 to 31.0%.
CHAPTER 6: CONGENITAL ANOMALIES
177
Input ResultsB D pB1 I1 pD1 RR AR(E) EF
(1) 100,000 11,590 0.053 0.758 0.347 9.5 0.895 0.310(2) 100,000 11,590 0.025 0.984 0.212 10.5 0.905 0.192
Notes: B - total no. of embryos or foetuses in utero at the beginning of the interval; D - total no. of SA/SB; pB1 - prevalenceof anomalies among B; I1 - incidence of SA/SB among anomalous embryos/foetuses; pD1 - prevalence of anomalies among See Chapter 4 for equations. Based on the hypothetical cohort and (1) Creasy and Alberman 1976, and (2) Shiota 1993.
hypothetical cohortTable 6.18: Estimated RR, AR(E), and EF of SA/SB in NTD-affected embryos/foetuses,
With the previous assumptions that 2% of SA, 10.5% of SB, and 0.15% of LB are affected by NTDs, the prevalence at the beginning of gestational week 5 was estimated to be much lower for the hypothetical cohort, namely 0.4%. Table 6.19 presents these estimates in combination with total numbers from the hypothetical cohort. Furthermore, the table assumes that the total percentage of NTD-affected foetuses at the beginning of gestational week 28 is 0.2%. The resultant relative risks of SA and SA/SB combined are quite similar (5.1 and 5.9 respectively), but the RR of only SB is much higher at 58.5 (see Table 6.19). As a result, the AR(E) and EF of stillbirth are also higher at 98.3% and 10.3% respectively. In comparison, the AR(E)s of SA and SA/SB are only 80.3% and 83.1% respectively. In addition, only 1.6% of SA and 1.9% of SA/SB in the total population can be attributed to NTDs. In Table 6.18, the estimated etiologic fractions of SA/SB were much higher. This can be explained by the much higher prevalence proportions of NTD-affected embryos/foetuses in the total population in utero (5.3% and 2.5% versus 0.4%). Overall, it can be concluded that neural tube defects are less important in terms of spontaneous abortion than chromosomal aberrations or congenital anomalies in general, especially at the population level. Table 6.19: Estimated RR, AR(E) and EF of SA and SB in NTD-affected embryos/foetuses,hypothetical cohort
B pB1 SA SB pSA1 pSB1 I1 I0 RR AR(E) EF
SA/SB 100,000 0.004 11,157 434 0.020 0.105 0.672 0.114 5.9 0.831 0.019SA 100,000 0.004 11,157 - 0.020 - 0.558 0.110 5.1 0.803 0.016SB 88,614 0.002 - 434 - 0.105 0.257 0.004 58.5 0.983 0.103
Notes: B - total no. of embryos or foetuses in utero at the beginning of the interval; pB1 - prevalence of anomalies among B;SA - total no. of SA; SB - total no. of SB; pSA1 - prevalence of anomalies among SA; pSB1 - prevalence of anomaliesamong SB; I1 - incidence of SA and/or SB among anomalous embryos/foetuses; I0 - incidence of SA and/or SB amongnon-anomalous embryos/foetuses.See Chapter 4 for equations. Based on the hypothetical cohort.
EARLY LIFE CHANGES
178
6.4.2 NEONATAL DATA
Neonatal death Most literature on neural tube defects in neonates discusses NTDs as a cause of death. Table 2.6a has already presented some data on spina bifida and hydrocephalus as the causes of neonatal mortality (ICD-9). The data were derived from WHO publications (World Health Statistics Annual, various years). According to these figures, spina bifida and hydrocephalus cause around 0.5 to 3.3% of neonatal deaths in the EME region. With regard to early neonatal death, additional data from the same source show that these two neural tube defects together cause 0.4% of early neonatal deaths in Japan, 0.7% in the USA, 0.9% in Italy, 1.0% in Sweden, 1.2% in Spain, and 2.7% in the Netherlands. The variation between the countries can be explained by factors such as the prevalence of the anomalies in question and their risk factors, the utilisation of prenatal diagnostic tests and the frequency of selective abortion, the quality of neonatal care, but also the relative importance of other disorders as causes of neonatal death. In Ireland, the birth prevalence of NTDs is high compared to other regions and countries. In an Irish sample of 34,375 live births (> 500 g) between 1991 to 1996, 153 did not survive the neonatal period. After categorisation of these deaths by cause, using Wigglesworth’s classification, neural tube defects accounted for as many as 10% of total neonatal mortality (Finan et al. 1999). The incidence of neonatal death varies strongly by type of neural tube defect. Infants suffering from anencephaly are either stillborn or expire soon after birth. They may survive for a few days after birth and survival beyond one week is unusual (Main and Mennuti 1986; ICBDMS 1991). Therefore, the incidence of neonatal death in anencephalic infants has been estimated at 100% by the American College of Obstetricians and Gynecologists (ACOG 1986 cited by Cunningham et al. 1993). Baird and Sadovnick (1984 cited by Main and Mennuti 1986) studied 181 live-born infants with anencephaly. They found that over 40% were alive at 24 hours of age but that only 5% of these lived to at least seven days of age. Data on the total birth cohort of 1988 in the USA revealed 520 infant anencephalic deaths, which represented 1.4% of infant deaths in the cohort (Van der Veen 2001). Their timing was distributed as follows: 32.3% occurred within 1 hour of birth, 46.5% at 1-23 hours, 14.0% at 1-6 days, 4.2% at 7-27 days, and only 2.9% survived 28 days. Prospects of survival are much better for infants with spina bifida, especially spina bifida occulta or closed spina bifida. Many infants with spina bifida survive if no other malformations exist and adequate neonatal care (including surgery) is provided, although they often remain significantly handicapped (Källén 1988). It is believed that 60 to 70% of term live births with spina bifida survive the first year of life (Van der Veen 2001). The Centers for Disease Control and Prevention (1989 cited by Roberts et al. 1995) in the USA even estimate that as many as 80 to 90% of infants with spina bifida survive into adulthood. The ACOG (1986 cited by Cunningham et al. 1993) estimates the incidence of neonatal death to be 33% for open spina bifida or spina bifida aperta, but only 7% for spina bifida occulta. As with spina bifida, the survival prospects for newborns with encephalocele are good provided no
CHAPTER 6: CONGENITAL ANOMALIES
179
other serious anomalies jeopardise the child’s life. However, neurological or mental deficits may occur if the malformation involves the brain (ICBDMS 1991).
Relative risk and attributable risk: neonatal death In the hypothetical cohort, 88,410 live births take place of whom 383 die during the neonatal period. Supposing: (1) the prevalence of NTDs in live births (pB
1) is 0.15%, (2) the incidence of neonatal death in NTD-affected live births (I1) is 65%, and/or (3) the prevalence of NTDs in neonatal deaths (pD
1) is 5%, then RR, AR(E), and EF can be estimated on the basis of the equations discussed in Chapter 4. Table 6.20 shows that the estimated RRs range from 35 to 193. The proportion of deaths in affected neonates that is attributable to NTDs is reflected in the AR(E): namely 97.1-99.5%. Since the prevalence of NTDs in the total population is low, the EF is only 4.9 to 22.4%. The last column in the table contains a calculation of the missing input data – either pB
1, I1, pD1 – to check the plausibility of the data combination and its
resultant estimates. Here, the difference between these re-estimated measures and their counterparts in the input assumptions is large. The best combination and estimates appear to come from the final series in which the resultant RR lies between the two extremes, at 158. In addition to neonatal death, Table 6.20 also presents estimates of early neonatal mortality in relation to NTDs. Again, it is assumed that the prevalence of NTDs in live births is 0.15% and that the prevalence of NTDs in early neonatal deaths is 5%. Naturally, the incidence proportion of early neonatal death in NTD-affected live births is assumed to be lower than the incidence of overall neonatal death: namely 60%. As a result, estimates of the RR of early neonatal death range from 35 to 241. The AR(E) is 97.1 to 99.6%, and the EF is between 4.9 and 26.5%. Again, the last column of the table, containing ‘checks’, shows that the specific combination of data is not plausible. The most plausible series of assumptions and estimates appears to be the final series, which lies between the other two extremes. Table 6.20: Estimated RR, AR(E), and EF of neonatal death in NTD-affected live births,hypothetical cohort
Input ResultsB D pB1 I1 pD1 RR AR(E) EF check*
nn 88,410 383 0.0015 0.650 - 193.3 0.995 0.224 pD1 = 0.22588,410 383 0.0015 - 0.050 35.0 0.971 0.049 I1 = 0.14488,410 383 - 0.650 0.050 157.9 0.994 0.050 pB1 = 0.000
early nn 88,410 299 0.0015 0.600 - 241.4 0.996 0.265 pD1 = 0.26688,410 299 0.0015 - 0.050 35.0 0.971 0.049 I1 = 0.11388,410 299 - 0.600 0.050 186.7 0.995 0.050 pB1 = 0.000
Notes: B - total no. of live births; D - total no. of deaths; pB1 - prevalence of anomalies among live births; I1 - incidence ofdeaths among anomalous live births; pD1 - prevalence of anomalies in deaths.*Check: calculation of either pB1, I1, or pD1 on the basis of the input assumptions.See Chapter 4 for equations. Based on the hypothetical cohort.
EARLY LIFE CHANGES
180
6.5 Congenital heart disease (CHD)
6.5.1 ANTEPARTUM AND BIRTH DATA
Induced abortion and selective abortion Data on the prevalence of congenital heart disease in induced abortions are scarce. On the basis of Japanese data, Semba (1976 cited by Leck 1983) found a prevalence as high as 21% for ‘congenital anomalies of heart and great vessels’. This result is somewhat old and, therefore, unlikely to incorporate any recent effects of prenatal diagnosis and selective abortion. However, the effects of prenatal diagnosis and selective abortion on the prevalence of congenital heart anomalies are believed to be limited. Van der Veen (2001) cited information on this from Cullen et al. (1992), Montana et al. (1996), and Chitty (1997). The main reason for the limited effects of prenatal diagnosis and selective abortion is that most congenital heart anomalies remain undetected with routine ultrasound scanning. In routine scanning for anomalies, the detection of cardiac anomalies is only 12% of cases. Moreover, pregnancy termination after the detection of congenital cardiac anomalies is not as frequent as in cases of NTD or Down’s syndrome. This may be related to the degree of severity of the anomalies as well as the options for medical intervention such as neonatal surgical intervention (Van der Veen 2001). Of the detected CHD cases which were registered in a total of 25 EUROCAT registries between 1990 and 1996, 91.1% ended in live birth, 1.9% in foetal death, and only 6.9% in induced abortion (EUROCAT 2001).
Spontaneous loss and stillbirth Hoffman (1995b) brought together the results of several studies on the prevalence of CHD in foetal deaths (see Table 6.21). Prevalence appears to range from 0.5% to 39.5% (median 7.3%). In addition to the proportions in Table 6.21, Creasy et al. (1976 cited by Ursell et al. 1985) found the prevalence of cardiac malformations among spontaneous abortuses to be 0.4% in the UK. Part of the variation between study findings can be explained by differences in gestational age. Also results concerning the effect of increasing gestational age on the prevalence of CHD are not unequivocal. Hoffman (1995b) cited two sources. According to Gerlis (1985), the prevalence decreases with increasing foetal age and foetal size (see Table 6.21). On the other hand, data from Chinn et al. (1989) suggest that prevalence increases with gestational age. With regard to stillbirth, Bower and Ramsay (1994) conducted a retrospective, population-based cohort study on the basis of data from the Western Australian Birth Defects Registry. In total, 3% of all stillbirths were known to have a cardiac defect. In California, in the 1970s, Hoffman and Christianson (1978 cited by Hoffman 1995b) found the prevalence among stillbirths (> 27 weeks) to be 8.2%. More recently, in a review article, Hoffman (1995b) assumed that as many as 10% of stillbirths have a CHD.
Tabl
e 6.
21: P
reva
lenc
e of
con
geni
tal h
eart
dise
ase
in sp
onta
neou
s los
ses
Foet
al d
eath
sA
ge*
orSo
urce
Yea
rsC
ount
ryTo
tal
CH
DC
HD
%si
ze**
Com
men
ts
Mitc
hell
et a
l. 19
7119
59-1
967
USA
(mul
ticen
tre)
1344
375.
7N
ot d
efin
ed-
Yas
uda
and
Pola
nd 1
975
1973
-197
4C
anad
a57
58.
8C
row
n-ru
mp
30-1
80 m
m-
(Brit
ish
Col
umbi
a)57
47.
0C
row
n-ru
mp
30-1
80 m
mEx
cl. p
ersi
sten
t LSV
CB
ound
and
Log
an 1
977
1957
-197
1U
K (B
lack
pool
)99
757
5.7
Not
def
ined
-Ta
kano
et a
l. 19
7719
66Ja
pan
933
475.
036
-47
days
Cur
etta
geH
offm
an a
nd C
hris
tians
on 1
978
1971
-197
7U
SA22
117
7.7
> 20
wks
-(N
orth
Cal
iforn
ia)
201
5.0
20-2
7 w
ks-
Byr
ne e
t al.
1985
1977
-198
1U
SA (N
Y C
ity)
1312
60.
5Em
bryo
, foe
tus
-G
erlis
198
519
75-1
983
UK
247
3815
.4<
25 w
ks-
(Yor
kshi
re)
3313
39.5
< 10
wks
-74
1317
.611
-15
wks
-72
68.
316
-20
wks
-42
37.
120
-25
wks
-Ša
mán
ek e
t al.
1985
1962
-197
9C
zech
oslo
vaki
a39
6981
2.1
Not
def
ined
Excl
. bic
uspi
d ao
rtic
valv
e;(B
ohem
ia)
N.B
. not
EM
E re
gion
Urs
ell e
t al.
1985
1976
-198
3U
SA (N
Y C
ity)
412
102.
48-
28 w
ksC
onse
cutiv
e sp
onta
neou
s abo
rtion
sC
hinn
et a
l. 19
8919
77-1
987
USA
(Sea
ttle)
400
5213
.09-
40 w
ks-
Not
es: L
SVC
- le
ft su
perio
r ven
a ca
va*A
ge: i
n w
eeks
' ges
tatio
n at
tim
e of
abo
rtion
, not
nec
essa
rily
time
of fo
etal
dea
th.
**Si
ze: r
elat
ion
of c
row
n-ru
mp
leng
th to
app
roxi
mat
e fo
etal
age
: < 2
5 m
m =
< 9
wks
, 25-
50 m
m =
9-1
2 w
ks, 5
0-10
0 m
m =
12-
16 w
ks, 1
00-1
50 m
m =
16-
20 w
ks.
Sour
ce: H
offm
an 1
995b
, Tab
le 1
, p. 1
57
EARLY LIFE CHANGES
182
Information on the incidence of loss among abnormal cases is available from Eronen (1997) who studied a group of 422 foetuses in Helsinki (Finland). The foetuses (16-41 weeks) had all been referred to a paediatric cardiologist for detailed echocardiology between 1983 and 1995. In total, 193 were found to have cardiac abnormalities and 181 of these resulted in live birth, i.e. 6.2% were lost.
Live birth and all births Results of studies on the prevalence of CHD in births are affected by factors such as length of follow-up, case definition, diagnostic procedures applied, and sample size (Buskens 1994; Hoffman 1995a; Shibuya and Murray 1998c). Early studies which estimated the prevalence of CHD at 3-5 per 1,000 live births are believed to be underestimations, mainly due to inadequate ascertainment. More recent studies suggest a higher birth prevalence of CHD: about 5.2-9.0 per 1,000 births or around 3.5-12.4 per 1,000 live births (see Table 6.22). The data are relatively consistent and do not appear to vary from country to country. Again, the lowest figures are assumed to represent underascertainment of CHD. In general, the prevalence of CHD in liveborn babies is estimated to be about 8 to 10 per 1,000 (Hafner et al. 1998; Hoffman 1995b). Various studies have recorded differences between the sexes for several congenital heart defects (Šamánek 1994). Yet, results are inconsistent and ratio of males to females in all congenital heart defects varies from 1.32:1 to the reverse of 1:1.27. In a population-based study covering 1977-1984 in Bohemia (Czechoslovakia, not part of the EME region), the male:female ratio in live births with a heart defect (1.09:1) did not differ significantly from the sex ratio in the total population of liveborn children (1.06:1) (Šamánek 1994).
Prevalence in utero Ultrasound scanning has been used to detect cases of congenital heart disease prenatally. Nevertheless, antenatal ascertainment of CHD may be even more susceptible to doubt and underestimation than detection after birth. Indeed, only about 12% of cardiac anomalies are detected in routine scanning (see above). Furthermore, most studies involving ultrasound screening of CHD focus on the performance of the test rather than on prevalence among embryos and foetuses. Buskens (1994) brought together the results of various studies on prenatal ultrasound screening programmes for CHD with estimated prevalence proportions ranging from 0.1% to 1.0%. Buskens (1994), himself, studied 5,319 foetuses that underwent a routine ultrasound scanning examination between 16 and 24 weeks’ gestational age. Overall, the prevalence of congenital heart disease, including those cases detected up to 6 months postnatally, was 1.17%. Likewise, Hafner et al. (1998) examined 6,541 pregnancies in the beginning of week 22 for cardiac anomalies. In addition, all the babies were examined on the first day of life and on days three and five. Overall, the prevalence of CHD was 1.3% but only 43.8% of these were diagnosed antenatally. Hoffman (1995b) estimated the total proportion of foetuses that have or will develop a congenital heart disease. He estimated that in a population of 100,000 pregnancies that last at least 4 weeks, about 21,800 will end in spontaneous abortion, 1,900 in stillbirth, and 76,000 in
CHAPTER 6: CONGENITAL ANOMALIES
183
live birth. Unfortunately, the author failed to explain the outcome of the other 300 pregnancies. In addition, Hoffman estimated the prevalence proportions of CHD in the outcome groups to be: 20%, 10%, and 1% respectively. Subsequently, the total number of cases with CHD was estimated to be 5,313 (4,360 SA + 190 SB + 763 LB) or 5.3% (Hoffman 1995b). Hoffman’s assumptions on prevalence can also be applied to the hypothetical cohort. However, in our hypothetical cohort, the general incidence of spontaneous loss is lower. Consequently, 2,231 SA, 43 SB, and 884 LB among the 100,000 hypothetical embryos will be affected by CHD: a prevalence of 3.2%. Results from the studies that were discussed in the subsections above, suggest that prevalence proportions of CHD may be somewhat lower, especially in spontaneous abortions. However, several of these studies may involve underestimation due to undetected CHD cases. Despite this, let us estimate the prevalence as: 8% in spontaneous abortions, 7% in stillbirths, and 0.8% in live births. Then, the prevalence in all embryos in utero is halved: 1,630 CHD-affected embryos (893 SA + 30 SB + 707 LB) in the hypothetical cohort, or 1.6%.
Relative risk and attributable risk: foetal loss Hoffman’s calculations may be expanded to estimate the RR, AR(E), and EF. In his hypothetical cohort, 85.6% (4,360 SA + 190 SB = 4,550) of 5,313 embryos/foetuses affected by CHD end in spontaneous loss or stillbirth. For cases without CHD, the incidence is 20.2% (19,150 out of 94,687). Therefore, the RR is calculated as 85.6 divided by 20.2, which equals 4.2. Subsequently, the AR(E) is estimated to be 3.2 divided by 4.2, or 76.1%, while the EF is approximated by: [0.053 * (4.2 – 1)] / [0.053 * (4.2 – 1) + 1] = 0.145 or 14.5%. Table 6.23 presents the assumptions and results for the hypothetical cohort of 100,000 embryos. The first series of assumptions are the ones by Hoffman (1995b). According to these assumptions, 20% of SA, 10% of SB, and 1% of LB are affected by CHD. In addition, the prevalence of CHD in the population in utero at the beginning of gestational weeks 5 and 28 are assumed to be 3.2% and 1%. Subsequently, the RR of SA and SB combined is 7.4, the AR(E) is 86.5%, and the EF is 17.0%. In the second set of assumptions, only 8% of SA, 7% of SB, and 0.8% of LB are affected by CHD, and the prevalences of CHD in the population in utero at the beginning of gestational weeks 5 and 28 are assumed to be 1.6% and 0.8%. As a result, the RR, AR(E) and EF are lower than the results in the first series: 5.3, 81.2%, and 6.5% respectively. In both sets of assumptions, the RR and AR(E) of stillbirth are higher than those of spontaneous abortion. Nevertheless, the EF of SB is lower or equal (see Table 6.23).
6.5.2 NEONATAL DATA
Neonatal death In the 1960s, Yerushalmy (1970) studied 19,000 liveborn children among members of the Kaiser Foundation Health Plan in California (USA). Within a follow-up period of 2-9 years,
Tab
le 6
.22:
Pre
vale
nce
of c
onge
nita
l hea
rt d
isea
se in
bir
ths
In li
ve b
irth
s
Sour
ceC
ount
ryPe
riod
No.
of
CH
DC
HD
Type
(s) o
f ano
mal
ies
Follo
w-u
pR
emar
ksbi
rths
no.p
er 1
,000
perio
d
Stoc
ker e
t al.
1980
[b]
Switz
erla
nd19
7578
,464
494
6.30
NS
NS
-B
orlé
e-G
rimée
et a
l. 19
84 [b
]B
elgi
um (H
aina
ut)
1986
-198
717
,647
132
7.48
NS
NS
-B
leue
r et a
l. 19
85 [a
]Sw
itzer
land
(Ber
n re
gion
)19
7527
,100
271
10N
S8
yrs
-Fe
renc
z et
al.
1985
[a]
USA
(Bal
timor
e-W
ashi
ngto
n)19
81-1
989
906,
624
4,39
04.
84IS
C, C
HD
C1
yr-
Bor
man
et a
l. 19
87 [a
]N
ew Z
eala
nd19
7851
,777
181
3.5
NS
1 yr
-G
rabi
tz e
t al.
1988
[a, b
]C
anad
a (A
lber
ta)
1981
-198
410
3,41
157
35.
54M
itche
ll (1
971)
+ IS
C; C
HD
C1
yr-
Die
z et
al.
1989
[b]
Spai
n (O
vied
a)19
76-1
985
53,5
7827
95.
21N
SN
S-
Šam
ánek
et a
l. 19
89 [a
]C
hech
oslo
vaki
a (B
ohem
ia)
1980
91,8
2358
96.
42sp
ecifi
ed fu
nctio
nal d
efin
ition
4 yr
sI
Fixl
er e
t al.
1990
[b]
USA
(Dal
las C
ount
y)19
71-1
984
379,
561
2,50
96.
61N
SN
S-
Fisc
her e
t al.
1991
[a, b
]A
ustri
a (T
yrol
)19
79-1
983
41,7
2534
18.
17M
itche
ll (1
971)
,5
yrs
-in
cl. b
icus
pid
aorti
c va
lves
Man
etti
et a
l. 19
93 [b
]Ita
ly (F
lore
nce)
1975
-198
446
,895
579
12.3
5N
SN
S-
Meb
erg
et a
l. 19
99N
orw
ay19
82-1
996
35,2
1835
310
"con
geni
tal h
eart
defe
ct"
11 y
rs-
EUR
OC
AT
2001
Euro
pe (v
ario
us re
gion
s)19
90-1
996
2,80
9,48
814
,453
5.14
"con
geni
tal h
eart
dise
ase"
NS
-
Not
es: N
S - n
ot st
ated
; ISC
, CH
DC
- In
tern
atio
nal S
ocie
ty o
f Car
diol
ogy,
Cla
ssifi
catio
n of
hea
rt di
seas
e in
chi
ldho
od.
I - N
.B. n
ot p
art o
f EM
E re
gion
.[a
] ci
ted
by B
uske
ns 1
994,
Tab
le I,
pp.
30-
31; [
b] c
ited
by H
offm
an 1
995a
, Tab
le 2
, p.1
05.
Tab
le 6
.22
(con
tinue
d)
In b
irth
s
Sour
ceC
ount
ryPe
riod
No.
of
CH
DC
HD
Type
(s) o
f ano
mal
ies
Follo
w-u
pR
emar
ksbi
rths
no.p
er 1
,000
perio
d
Cal
gren
et a
l. 19
87 [a
, b]
Swed
en19
8194
,778
853
9.00
ICD
(8th
rev.
) + IS
C, C
HD
C1
yrII
Stol
l et a
l. 19
89 [a
, b]
Fran
ce (B
as-R
hin)
1979
-198
610
5,37
480
17.
60IS
C, C
HD
C1
yrII
IB
ower
and
Ram
say
1994
Aus
tralia
(Wes
tern
)N
SN
SN
S7.
65"c
onge
nita
l hea
rt di
seas
e"N
S-
Kat
o an
d Fu
jiki 1
996
Japa
n (T
okyo
)19
79-1
993
138,
544
778
5.62
"ano
mal
ies o
f hea
rt an
d7
days
IVci
rcul
ator
y sy
stem
"EU
RO
CA
T 20
01Eu
rope
(var
ious
regi
ons)
1990
-199
62,
822,
465
14,7
605.
23"c
onge
nita
l hea
rt di
seas
e"N
S-
Not
es: N
S - n
ot st
ated
; ISC
, CH
DC
- In
tern
atio
nal S
ocie
ty o
f Car
diol
ogy,
Cla
ssifi
catio
n of
hea
rt di
seas
e in
chi
ldho
od.
II -
uncl
ear i
f stil
lbor
ns a
re in
clud
ed; I
II -
prod
ucts
of c
once
ptio
n >
26 w
ks; I
V -
hosp
ital-b
ased
.[a
] ci
ted
by B
uske
ns 1
994,
Tab
le I,
pp.
30-
31; [
b] c
ited
by H
offm
an 1
995a
, Tab
le 2
, p.1
05.
T
able
6.2
3: E
stim
ated
RR
, AR
(E) a
nd E
F of
SA
and
SB
in C
HD
-aff
ecte
d em
bryo
s/fo
etus
es, h
ypot
hetic
al c
ohor
t
BpB
1SA
SBpS
A1
pSB
1I1
I0R
RA
R(E
)EF
(1)
SA/S
B10
0,00
00.
032
11,1
5743
40.
200
0.10
00.
711
0.09
67.
40.
865
0.17
0SA
100,
000
0.03
211
,157
-0.
200
-0.
697
0.09
27.
60.
868
0.17
4SB
88,6
140.
010
-43
4-
0.10
00.
049
0.00
411
.00.
909
0.09
1
(2)
SA/S
B10
0,00
00.
016
11,1
5743
40.
080
0.07
00.
577
0.10
85.
30.
812
0.06
5SA
100,
000
0.01
611
,157
-0.
080
-0.
558
0.10
45.
30.
813
0.06
5SB
88,6
140.
008
-43
4-
0.07
00.
043
0.00
59.
30.
893
0.06
3N
otes
: B -
tota
l no.
of e
mbr
yos o
r foe
tuse
s in
uter
o at
the
begi
nnin
g of
the
inte
rval
; pB
1 - p
reva
lenc
e of
ano
mal
ies a
mon
g B
; SA
- to
tal n
o. o
f SA
; SB
- to
tal n
o. o
f SB
;pS
A1
- pre
vale
nce
of a
nom
alie
s am
ong
SA; p
SB1
- pre
vale
nce
of a
nom
alie
s am
ong
SB; I
1 - i
ncid
ence
of S
A a
nd/o
r SB
am
ong
anom
alou
s em
bryo
s/fo
etus
es; I
0 - i
ncid
ence
of S
A a
nd/o
r SB
am
ong
non-
anom
alou
s em
bryo
s/fo
etus
es.
See
Cha
pter
4 fo
r equ
atio
ns. B
ased
on
the
hypo
thet
ical
coh
ort,
and
(1) H
offm
an 1
995b
and
(2) a
ssum
ptio
ns b
ased
on
liter
atur
e.
EARLY LIFE CHANGES
186
206 (1.1%) of these children were diagnosed as having CHD. The incidence of neonatal death within this group was about 10% since one of 10 children who suffered from CHD did not survive the first month. Yerushalmy’s (1970) results are dated, and survival is likely to have increased over the years, in parallel with improvements in health care and new approaches in surgery. However, increased detection of CHD may have concealed improvements in survival. More recent information is available from Eronen’s (1997) study in Helsinki (Finland). Out of 181 live births with cardiac abnormalities, 39 (21.5%) died during the neonatal period. Most other published studies and data sets focus on mortality and survival at later ages, including infant mortality. In the 1940-50s, research showed that nearly half of babies born with CHD had died by their first birthday (Hoffman 1968 cited by Shibuya and Murray 1998c). However, this figure is believed to have decreased significantly over time. In Yerushalmy’s (1970) study during the 1960s, more than 85% of CHD cases survived the first year of life. Mortality was highest on the day of birth and declined gradually thereafter. Similarly, for a cohort of infants born in 1981-1989, the Baltimore Washington Infant Study estimated that 18.2% of infants with congenital heart anomalies did not survive their first year (Ferencz et al. cited by Van der Veen 2001). The prevalence of CHD among neonatal deaths was 7.9% in the study by Yerushalmy (1970). More recent data from Western Australia suggest a much higher prevalence. According to the Western Australian Birth Defects Registry, as many as 15.2% of neonatal deaths have a cardiac defect (Bower and Ramsay 1994). Over the years, as mortality due to other causes has declined, congenital heart disease has persisted as an important cause of death in infancy (Van der Veen 2001). Table 2.6a presented some data on the proportion of neonatal deaths that are caused by congenital anomalies of the heart and circulatory system, as categorised by the ICD-9. The data were derived from publications by the WHO (World Health Statistics Annual, various years). According to these figures, anomalies of the heart and circulatory system cause around 7.4 to 17.5% of neonatal deaths in the EME region. With regard to early neonatal death, additional data from the same source show that these anomalies cause 5.1% of early neonatal deaths in the USA, 7.2% in Italy, 7.8% in Spain, 8.6% in the Netherlands, 11.8% in Sweden, and 12.4% in Japan. The figures from WHO imply that the prevalence of 7.9% in neonatal deaths as observed by Yerushalmy (1970) is indeed somewhat low. However, both the low figure by Yerushalmy (1970) and the lowest figure for the EME region in Table 2.6a were observed in the USA.
Relative risk and attributable risk: neonatal death Table 6.24 presents two series of assumptions and estimates for neonatal mortality which are based on the literature and tables discussed above. In the first series, (1) the prevalence of CHD (pB
1) is set at 1%, (2) the incidence of neonatal death for affected infants (I1) at 16%, and (3) the prevalence of CHD among neonatal deaths (pD
1) at 12%. For early neonatal death, I1 and pD
1 are estimated to be somewhat lower: 14 and 9% respectively. In the second series, (1) pB
1 is assumed to be 0.8%, (2) I1 15%, and (3) pD1 12%. For early neonatal death, I1 and
pD1 are again estimated to be somewhat lower at 12% and 9% respectively.
CHAPTER 6: CONGENITAL ANOMALIES
187
Table 6.24: Estimated RR, AR(E), and EF of neonatal death in CHD-affected live births,hypothetical cohort
Input ResultsB D pB1 I1 pD1 RR AR(E) EF check*
(1) nn 88,410 383 0.010 0.160 - 58.0 0.983 0.363 pD1 = 0.36988,410 383 0.010 - 0.120 13.5 0.926 0.111 I1 = 0.05288,410 383 - 0.160 0.120 41.8 0.976 0.117 pB1 = 0.003
early nn 88,410 299 0.010 0.140 - 69.9 0.986 0.408 pD1 = 0.41488,410 299 0.010 - 0.090 9.8 0.898 0.081 I1 = 0.03088,410 299 - 0.140 0.090 45.4 0.978 0.088 pB1 = 0.002
(2) nn 88,410 383 0.008 0.150 - 47.5 0.979 0.271 pD1 = 0.27788,410 383 0.008 - 0.120 16.9 0.941 0.113 I1 = 0.06588,410 383 - 0.150 0.120 39.2 0.974 0.117 pB1 = 0.003
early nn 88,410 299 0.008 0.120 - 49.2 0.980 0.278 pD1 = 0.28488,410 299 0.008 - 0.090 12.3 0.918 0.083 I1 = 0.03888,410 299 - 0.120 0.090 38.9 0.974 0.088 pB1 = 0.003
Notes: B - total no. of live births; D - total no. of deaths; pB1 - prevalence of anomalies among live births; I1 - incidenceof deaths among CHD-affected live births; pD1 - prevalence of CHD in deaths.*Check: calculation of either pB1, I1, or pD1 on the basis of the input assumptions.See Chapter 4 for equations. Based on the hypothetical cohort.
With regard to overall neonatal mortality, the resultant RRs range from 13.5 to 58.0 (see Table 6.24). Within the group of CHD infants, between 92.6 and 98.3% of neonatal deaths are attributable to the anomaly, i.e. the AR(E). The etiologic fraction, or the proportion of neonatal deaths in the total population that can be attributed to CHD, is much lower at 11.1-36.3%. For early neonatal mortality, the variation in the results is even greater. The RR ranges between 9.8 and 69.9, the AR(E) is between 89.8 and 98.6%, and the EF varies from 8.1 to 40.8%. The estimated ranges for the RR and the EF are thus wide. Moreover, the recalculated missing input measures in the last column of Table 6.24, that serve as a check for plausibility, indicate the presence of inconsistencies.
6.6 Overlap and associations
Chromosomal aberrations, neural tube defects, and congenital heart disease are all included in the main category of congenital anomalies. Furthermore, there is some degree of overlap among them and associations have been observed between them. Indeed, many individuals affected by a congenital anomaly have more than one. When an infant has one congenital anomaly, this is referred to as a single or isolated anomaly (Cornel 1993). The term sequence is applied to the situation in which all anomalies in an individual with multiple anomalies can be explained on the basis of a single problem in morphogenesis that leads to a cascade of subsequent defects (Jones 1988 cited by Cornel
EARLY LIFE CHANGES
188
1993). An example is the Potter sequence in which kidney or other urinary tract anomalies result in oligohydramnios4 and this in turn leads to pulmonary hypoplasia5 and compression of the foetus. Subsequently, the compression leads to hand and foot abnormalities. Another common term used in the event of multiple anomalies is syndrome. One speaks of a syndrome when the multiple congenital anomalies are not part of one sequence – they may involve several sequences – but are thought to be due to a single cause (Jones 1988 cited by Cornel 1993). A classic example is Down’s syndrome (trisomy 21) which is caused by a chromosomal anomaly and characterised by a number of minor anomalies, mental retardation, and an increased risk of gross malformations (Källén 1988). Lastly, if the pattern is recognised in cases of multiple congenital anomalies but the aetiology and pathogenesis are unknown, this is referred to as an association. In fact, this refers to “the statistical observation that specific congenital anomalies occur together in patients more often than one would expect by chance alone” (Cornel 1993, p.3). Chromosomal aberrations are frequently observed in embryos, foetuses and newborns that are also affected by NTDs or CHD. These combinations of anomalies are discussed below.
6.6.1 NTDS AND CHROMOSOMAL ABERRATIONS A neural tube defect may be one of a number of anomalies present in foetuses and infants with chromosomal aberrations. Recognised causes of neural tube defects include trisomy 13, trisomy 18, and triploidy (Main and Mennuti 1986). Triploidy is the most common chromosomal abnormality found in abortuses with neural tube defects. Some results on abortuses are available from the study by Creasy and Alberman (1976) in the London region (UK) between 1971 and 1974. They examined pregnancies that ended in spontaneous abortion for congenital malformations of the central nervous system (CNS) as well as for abnormal karyotype. The category of CNS defects included neural tube defects and, in total, 3.6% of 995 complete, organised foetuses were found to have a CNS defect. In addition, chromosome constitution was determined for 25 of these 36 affected abortuses and 10 (40%) were found to have a chromosome abnormality. The majority of these cases were still in the embryonic stage of pregnancy (CRL < 30 mm). In comparison, of 544 karyotyped embryos and foetuses without CNS defects only 13% were chromosomally abnormal (Creasy and Alberman 1976).
6.6.2 CHD AND CHROMOSOMAL ABERRATIONS Multiple studies have demonstrated that congenital heart disease is closely associated with other congenital abnormalities, especially chromosomal aberrations (Hoffman 1995b). Chinn et al. (1989 cited by Hoffman 1995b) found that 27.9% of externally abnormal foetal deaths (9-40 weeks) suffer from CHD compared with only 7.3% of externally normal ones. Data from the EUROCAT registry for the Northern Netherlands suggest that 51% of births (live and stillbirths) with at least one congenital heart anomaly have a further anomaly (Konings- 4 Oligohydramnios: abnormally low volume of amniotic fluid (Cunningham et al. 1993). 5 Hypoplasia: underdevelopment of a tissue or organ (Stedman’s Medical Dictionary 1995).
CHAPTER 6: CONGENITAL ANOMALIES
189
Dalstra 1998). In 37% of these associated cases, the additional anomaly is another heart defect while 19% have a chromosomal anomaly. According to epidemiological studies in newborns, the association of congenital heart defects with chromosomal anomalies varies between 4 and 12% (Chaoui et al. 1999). However, the corresponding proportion is believed to be higher prenatally. Among 2,716 foetuses at risk of CHD, Chaoui and colleagues found 203 cases of foetal heart malformation. In total, 22% of them had associated chromosomal anomalies. In New York City, Ursell et al. (1985) examined foetal deaths (8-28 weeks) between 1976 and 1983. They found that the prevalence of heart defects was only 1.1% in abortuses with a normal karyotype compared to 20% among those with an abnormal karyotype. As a result, the authors concluded that the prevalence of heart defects among chromosomally normal spontaneous abortions is similar to that among liveborns which suggests that “heart defects per se may not jeopardise the survival of the developing foetus” (1985, p.1235).
6.7 Summary and discussion
The present chapter has assessed the relative importance of congenital anomalies in general and of three selected subcategories of anomalies (i.e. chromosomal aberrations, neural tubes defects, congenital heart disease) as risk factors for foetal loss and neonatal death in the EME region, at both the individual and the population level. In order to obtain the desired estimates, assumptions concerning the prevalence and incidence were derived from literature and combined with the hypothetical cohort constructed in Chapter 5. Hence, the chapter has presented a thorough and elaborate overview of previously published study results and estimates on congenital anomalies in the EME region during gestation, birth, and the neonatal period. The results of the various studies were tabulated and briefly discussed but comparison of results was complicated by differences in study design, methodology, inclusion criteria, observation period, age and gestational age, sample size, available technology, geographic region and ethnicity, and year of study. The assumptions that were derived from the literature, as well as the newly calculated estimates of relative importance, are summarised and discussed in the sections below. The first part deals with the effects of anomalies at the individual level and the following section discusses their influence within the population. It should be noted that the results represent educated guesses and are estimates.
6.7.1 INDIVIDUAL LEVEL The relative importance at the level of the individual has been established in terms of risk (cf. incidence) of loss or death for anomalous individuals, and in the relative risk of loss or death (see also Chapter 4). Table 6.25 summarises the assumed and estimated incidence proportions of loss and death by type of anomaly. The incidence of spontaneous abortion is highest among embryos/foetuses with chromosomal aberrations and lowest among those with neural tube defects (NTDs). Conversely, individuals affected by neural tube defects run the highest risks of stillbirth and neonatal death. Indeed, the majority of NTD cases (about 65%) do not survive the neonatal period. This might indicate the presence of a powerful prenatal selection
EARLY LIFE CHANGES
190
mechanism for chromosomal aberrations. Among anomalous persons in general, regardless of the type of anomaly, the incidences of spontaneous abortion, stillbirth, early neonatal death, and overall neonatal death are estimated to be around 62%, 2%, 5%, and 6% respectively. These incidence proportions for all congenital anomalies combined reflect type-specific incidences as well as general distribution by type. However, the figures for spontaneous abortion (62%) and stillbirth (2%) appear to be low in comparison to type-specific proportions (see Table 6.25). Moreover, in total, 63 to 93% of anomalous foetuses are assumed to be lost before live birth. Overall, it can be concluded that the majority of anomalous cases, regardless of the type of anomaly, do not survive gestation and birth, and do not make it to live birth. Those who are live-born face far better survival chances during the neonatal period, unless they have neural tube defects. How do the incidence proportions in Table 6.25 for anomalous individuals compare to incidence of loss and death in foetuses and neonates without these anomalies? Table 6.26 restates the estimates for the relative risk. The relative risk (RR) compares the incidence in affected individuals to the incidence in individuals who are not affected. It indicates how many times more likely persons with the risk factor will experience a particular outcome as compared to persons without the risk factor. Table 6.26 contains only relative risks with a value above 1.0, indicating that anomalous foetuses and neonates do indeed experience Table 6.25: Estimated or assumed incidence of spontaneous abortion, stillbirth, and neonataldeath, by type of anomaly, EME region
Incidence proportion (%)
SA [a] SB [a] SA+SB [a] ENND NND
Congenital anomalies (all) 62 2 63-93 5 6Chromosomal aberrations 89-90 4-5 90 3 4Neural tube defects (NTDs) 54-56 26 67-98 60 65 [b]Congenital heart disease (CHD) 56-82 4-5 58-86 12-14 15-16
Notes: SA - spontaneous abortion; SB - stillbirth (>= 28 wks); ENND - early neonatal death; NND - neonatal death.[a] In the absence of induced abortion; [b] 7-100% depending on type of NTD.Based on studies discussed in the literature and/or assumptions in combination with the hypothetical cohort. Table 6.26: Estimated relative risks of spontaneous abortion, stillbirth, and neonataldeath, by type of anomaly, EME region
Relative risk (RR)
SA SB SA+SB ENND NND
Congenital anomalies (all) 9 5 5-40 20-26 20-23Chromosomal aberrations 13 11 12-13 9 9Neural tube defects (NTDs) 5 59 6-11 35-241 35-193Congenital heart disease (CHD) 5-8 9-11 4-7 10-70 14-58
Notes: SA - spontaneous abortion; SB - stillbirth (>= 28 wks); ENND - early neonatal death; NND - neonatal death.Based on studies discussed in the literature and/or assumptions in combination with the hypothetical cohort.
CHAPTER 6: CONGENITAL ANOMALIES
191
Table 6.27: Estimated or assumed prevalence of anomalies in embryos, spontaneous abortions,stillbirths, live births, all births, and neonatal deaths, by type of anomaly, EME region
Prevalence proportion (%)
wk 5 (LMP) SA SB LB all births ENND NND
Congenital anomalies (all) 7-10 40 14 3 3 38 38Chromosomal aberrations 5-6 40 6 0.6 0.6 5 5Neural tube defects (NTDs) 0.4-5 2 [a] 11 [a] 0.15 0.15 5 5Congenital heart disease (CHD) 2-5 8-20 7-10 0.8-1 0.8-1 9 12
Notes: LMP - since last menstrual period; SA - spontaneous abortion; SB - stillbirth (>= 28 wks); LB - live birth;ENND - early neonatal death; NND - neonatal death.[a] N.B. Estimates on the basis of the hypothetical cohort imply that prevalence of NTDs among SA/SB may beas high as 21-35%.Based on studies discussed in the literature and/or assumptions in combination with the hypothetical cohort.
elevated risks of loss and death as compared to their non-anomalous counterparts. Anomalous foetuses are about 9 times as likely as non-anomalous foetuses to experience spontaneous abortion. The relative risks of stillbirth, early neonatal death, and overall neonatal death for anomalous individuals are estimated to be around 5, 20-26, and 20-23 respectively. Despite the high incidence of spontaneous loss during gestation (see Table 6.25), the RR of spontaneous abortion is not extremely high for anomalous foetuses. This implies that the incidence of loss during gestation must also be high for non-anomalous foetuses. Nevertheless, the separate figures for spontaneous abortion and stillbirth seem low when compared to the RR of SA and SB combined (RR = 5-40, see Table 6.26). Broken down by type, the elevated risk of spontaneous abortion is most distinct with chromosomal aberrations. Conversely, the RRs of stillbirth and neonatal death are highest among infants with neural tube defects. Overall, the effect of chromosomal aberrations is most strong during gestation while the impacts of neural tube defects and congenital heart disease (CHD) are most powerful during the neonatal period.
6.7.2 POPULATION LEVEL The relative importance at the level of the population has been established in terms of frequency (cf. prevalence) of congenital anomalies within the total population, and in the proportion of losses or deaths in a population that can be attributed to the anomaly (see also Chapter 4). Table 6.27 lists prevalence proportions of anomalies by type, for losses and deaths, for the total population at 5 completed gestational weeks, and among births. In early gestation, about 7-10% of embryos have potential or real anomalies with chromosomal aberrations being the most common type. At live birth, around 3% of newborns are anomalous, with congenital heart disease being the most prevalent and neural tube defects being rare. The prevalence of congenital anomalies among spontaneous abortions, stillbirths, and neonatal deaths is 40%, 14%, and 38% respectively. The type of anomaly that is most frequently observed in spontaneous abortions is chromosomal aberration. In stillbirths and neonatal deaths, the most common observations are neural tube defects and congenital heart
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disease respectively. Among spontaneous abortions, the prevalence of chromosomal anomalies roughly equals the prevalence of all anomalies combined (40%). Although this seems unlikely, this is not impossible since persons may be affected by more than one type of anomaly. Among neonatal deaths, the estimated prevalence of all anomalies combined is high (38%) in comparison to the figures for the three specified subcategories of anomalies. In conclusion, the prevalence of anomalies (including the three selected subtypes) declines between gestational week 5 and live birth, while the frequency among abortions, stillbirths, and neonatal deaths remains relatively high. These findings support the elevated relative risks for anomalous foetuses and neonates in Table 6.26. Table 6.28 summarises the estimates of attributable risk, both among the exposed and for the total population, by type of anomaly. The attributable risk among the exposed, AR(E), indicates the proportion of losses/deaths in anomalous cases that are due to the anomaly. The table shows that about 88% of spontaneous abortions, 81% of stillbirths, and 95-96% of neonatal deaths in the anomalous population can be attributed to the anomaly or anomalies. The remainder of losses and deaths are to be explained by other factors. For the three selected subcategories of anomalies, the AR(E) is also high. Among newborns with neural tube defects or congenital heart disease, nearly all stillbirths and neonatal deaths are due to the anomalies in question. In conclusion, the great majority of losses and deaths in the anomalous population (regardless of type of anomaly) can be attributed to the anomaly or anomalies. A more interesting measure from a population point of view is the etiologic fraction (EF). The EF indicates the proportion of losses/deaths in the total population that can be attributed to the anomaly and is calculated on the basis of prevalence in the population (see Table 6.27) and relative risk of loss/death (see Table 6.26). For example, 5% of stillbirths in the total population can be attributed to chromosomal aberrations. Table 6.28 shows that the most important contributors to spontaneous abortion and stillbirth in the population are chromosomal aberrations and neural tube defects respectively. In the case of neonatal death, congenital heart disease is the largest contributor despite the high relative risk of neonatal death for NTD neonates. This is explained by the higher prevalence of congenital heart disease among live births. Overall, congenital anomalies are responsible for about 35% of spontaneous abortions, 11% of stillbirths, 36-43% of early neonatal deaths, and 36-40% of all neonatal deaths in the EME population. However, their contribution to spontaneous abortion is probably underestimated. In the table, the contribution of chromosomal aberrations to spontaneous abortion (37%) is larger than the contribution to spontaneous loss of all anomalies combined (35%). Moreover, between 31 and as high as 80% of all losses before and during birth (i.e. SA and SB) are estimated to be due to congenital anomalies. The low EF of spontaneous abortion is probably explained by a too low value of RR (see earlier) that may be the result of data problems in early gestation.
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Table 6.28: Estimated attributable risks of spontaneous abortion, stillbirth, and neonataldeath, by type of anomaly, EME region
AR(E): Attributable risk among the 'exposed' (%)
SA SB SA+SB ENND NND
Congenital anomalies (all) 88 81 81-98 95-96 95-96Chromosomal aberrations 92 91 92 89 89Neural tube defects (NTDs) 80 98 83-91 97-100 97-100Congenital heart disease (CHD) 81-87 89-91 76-87 90-99 93-98
EF: Etiologic fraction (%), in total population
SA SB SA+SB ENND NND
Congenital anomalies (all) 35 11 31-80 36-43 36-40Chromosomal aberrations 37 5 36-40 4 5Neural tube defects (NTDs) 2 10 2-31 5-27 5-22Congenital heart disease (CHD) 7-17 6-9 7-17 8-41 11-36
Notes: SA - spontaneous abortion; SB - stillbirth (>= 28 wks); ENND - early neonatal death; NND - neonatal death.Based on studies discussed in the literature and/or assumptions in combination with the hypothetical cohort.