stillbirth and neonatal mortality due to congenital anomalies: temporal trends and variation by...

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© Blackwell Science Ltd. Paediatric and Perinatal Epidemiology 2001, 15, 364–373

Introduction

Perinatal mortality rates have been widely used as asummary statistic for evaluating child health and effi-cacy of health care. Although, in general, the relation-ship between perinatal mortality and socio-economicdeprivation has been well documented,1,2 less isknown about the impact of deprivation on perinatalmortality that is due to specific congenital anomalies.Bambang et al.3 found that congenital anomaliesaccounted for over one-third of all-cause perinatalmortality and reported trends of increasing perinatalmortality with increasing deprivation for total con-genital anomalies combined. However, most studies

investigating grouped or specific anomalies have usedeither birth prevalence or total prevalence (the latterincluding livebirths, stillbirths and pregnancy termi-nations due to birth defects) as the outcome measure.Consistent findings have been recorded for neural tubedefects (NTDs), with higher birth prevalence amongmore deprived social class, Carstairs or neighbour-hood groups.4–6 Increased risk with increasing scales ofdeprivation has also been noted for non-chromosomalanomalies, multiple anomalies, malformations of thecardiac septa, oral clefts, limb reduction defects, poly-dactyly and congenital cataract.5,7–9 Down’s syndromehas shown both elevated7 and decreased risk5 among

Stillbirth and neonatal mortality due to congenital anomalies:temporal trends and variation by small area deprivation scores in England and Wales, 1986–96David Neashama, Helen Dolkb, Martine Vrijheidb, Tina Jensena and Nicky Besta

aDepartment of Epidemiology and Public Health, Imperial College School of Medicine, and bEnvironmental Epidemiology Unit, Department of

Public Health and Policy, London School of Hygiene and Tropical Medicine, London, UK

Correspondence:David Neasham, Departmentof Epidemiology and PublicHealth, St Mary’s Hospital,Imperial College School ofMedicine,16 South Wharf Rd.,Paddington, London W2 1PG,UK. E-mail:[email protected]

Summary

We investigated the variation of stillbirth and neonatal mortality due to congenitalanomalies in relation to small-area measures of deprivation in a population-basedstudy in England and Wales, 1986–96. We found 10 954 stillbirths and neonatal deathsfrom all non-chromosomal and chromosomal anomalies during the study period out of a total of 7487 007 live and stillbirths. The extended perinatal mortality rate(EPM rate) (defined as babies who were stillborn or died within 28 completed daysafter birth per 10 000 total live and stillbirths) for all chromosomal and all non-chromosomal anomalies was 1.5/10000 and 13.2/10 000, respectively, over the wholeperiod. The rate for non-chromosomal anomalies halved over the decade while therate for chromosomal anomalies remained unchanged. The relative risks of EPM forchromosomal and non-chromosomal anomalies were 0.71 [0.80, 0.95] and 1.17 [95%CI1.06, 1.30], respectively, in the group of wards with highest deprivation compared withthe least deprived group. Increasing gradients of EPM with increasing deprivationwere observed for (1) grouped non-chromosomal anomalies including neural tubedefects, all renal and urinary anomalies, all musculoskeletal anomalies, and multipleanomalies, and (2) several specific non-chromosomal anomalies including anen-cephaly, limb reduction defects, diaphragm and abdominal wall defects. This studyprovides strong evidence that increased deprivation is associated with increased EPMdue to most non-chromosomal anomalies; the finding of decreased relative risk forchromosomal anomalies is probably related to differences in maternal age distributionbetween deprivation groups.

Congenital anomalies, stillbirth and neonatal mortality 365


more deprived population groups, although the de-crease was not statistically significant after adjustmentfor maternal age.

Evidence linking congenital anomalies to socio-economic status suggests that environmental factorsassociated with deprivation may be aetiologically sig-nificant.10 One well-documented group of environ-mental factors associated with increased risk of NTDsis nutritional deficiencies. Many studies have nowlinked periconceptional folate supplementation to areduction in the birth prevalence of NTDs.11–13 Earlyindication of an environmental factor was highlightedby observational reports showing that low socio-economic status and conception in Spring (assumed tobe related to poor diet and low body reserves of nutri-ents over the winter preceding conception) were riskfactors for NTDs.10,14,15

Although the importance of this work has beenwidely accepted, few studies have looked at a com-prehensive range of major structural birth defects andpotential association with socio-economic status. Thisis particularly important, not only to contribute to our understanding of the aetiology of congenitalanomalies, but also in evaluating the relative impact of deprivation on anomalies compared with otherimportant perinatal outcomes and indicators such asantepartum and intrapartum asphyxia and trauma,preterm birth, immaturity-related mortality and birth-weight. Quantification of the relationship betweendeprivation and risk of congenital anomalies providesa way of assessing inequalities in perinatal healthwhich, in turn, could be alleviated through preventivestrategies (e.g. targeted periconceptional folate sup-plementation in deprived areas). We therefore con-ducted a study to look at the relationship betweenextended perinatal mortality (including stillbirths andneonatal deaths) caused by major congenital anom-alies and social deprivation, measured by theCarstairs’ index,16 using national data for England andWales, 1986–96.

Methods

Data

Numerator data on extended perinatal mortality(defined as stillbirth or neonatal death before 28 com-pleted days of life) caused by congenital anomaliesand denominator data on total live plus stillbirths wereobtained for England and Wales, 1986–96, from the

Office for National Statistics (ONS). This database isheld by the UK Small Area Health Statistics Unit.17 Themother’s postcode of residence was linked to 9503census wards for England and Wales to enable calcu-lation of counts of mortality and total births in thesmall-area Poisson analysis. Before 30 September 1992,stillbirths were legally defined as late fetal deaths onor after 28 completed weeks gestation. After 1 October1992 this definition was changed to late fetal deaths onor after 24 completed weeks of gestation.18 Analysiswas conducted separately for the periods 1986–92 and1993–96 as well as for combined periods to assess theeffect of this change.

The level of socio-economic deprivation of eachcensus ward of residence was assessed using theCarstairs index.16 This index is based on variables from the 1991 UK census including access to car, over-crowding, unemployment and social class. In thestudy we divided wards into five socio-economicgroups. This was based on quintiles of the distributionof ward-level Carstairs’ scores for Great Britain, inwhich quintile 1 contained the most affluent wards ofresidence and quintile 5 the most deprived. ThePoisson regression analyses were controlled for levelof urbanisation and year of birth. The urban or ruralnature of the area of residence was determined usingthe population density of the 1991 census ward of residence. Wards were classed according to five groupsbased on quintiles of population density.

For the main analysis we divided congenital anom-alies into chromosomal and non-chromosomal groupsas their respective aetiologies are known to be differentand chromosomal anomalies are strongly associatedwith high maternal age.5 Secondary analyses werecarried out for specific congenital anomalies, sub-grouped according to distinct pathology and type. Allgrouped and specific anomalies investigated are listedin Table 2. They are ordered according to the ICD9 clas-sification system.19 Our analysis was based on theunderlying cause of death and did not include otheranomalies mentioned on the death certificate.

Extended perinatal mortality

Analyses were conducted using extended perinatalmortality (EPM) as the main outcome measurement.Table 1 outlines several mortality rate definitionsincluding EPM rate. With improvements in neonatalintensive care, deaths normally attributed to the peri-natal period may either be prevented or deferred until

366 D. Neasham et al.


later. Some authors have suggested that most lateneonatal deaths (between 7 and 28 days) due to con-genital anomalies are likely to be deferred from theperinatal period and therefore EPM may be a moreinformative clinical indicator.20,21

Statistical analysis

Rates

EPM rates were calculated for different congenitalanomalies for the whole study period and separatelyfor each year.

Test for trend

Trends in EPM rates were assessed for different con-genital anomalies across quintiles of deprivation andover time. The analysis used Nptrend, a non-parametric test for trend across ordered groups.22

Poisson regression

In order to obtain quantitative estimates of the relativerisk of EPM for different malformations associatedwith deprivation, we carried out Poisson regressionanalysis using the statistical package STATA. For eachanomaly, the dependent variable was counts of deathsin each ward. The explanatory variables includedward-level quintiles of deprivation and populationdensity, and year of birth. The number of livebirthsand stillbirths in each ward was used as an offsetfactor. The statistical significance of the explanatoryvariable was assessed using likelihood ratio tests. Werepeated the analysis using stillbirths and neonatalmortality separately to determine whether the resultswere significantly different than those obtained usingcombined stillbirth and neonatal mortality. We alsorepeated the Poisson regression analyses including anadditional term to account for extra-Poisson variabil-ity in the small area data due to, for example, sparse

data at small-area level and possible confounding byunmeasured covariates.

The latter analysis was carried out using theWINBUGS statistical software.23

Results

Extended perinatal mortality – numbers and rates

Table 2 summarises the numbers and EPM rates dueto congenital anomalies for England and Wales,1986–96. There were 10 954 stillbirth and neonataldeaths from all chromosomal and non-chromosomaldefects in a population of 7487 007 total live and still-births. The EPM rate was nine times higher for non-chromosomal than for chromosomal anomalies overthe whole period 1986–96 (Table 3). While the numbersof non-chromosomal and chromosomal anomalieswere highest in the most deprived Carstairs depriva-tion quintile, it must be noted that the denominatortotal live and stillbirths were also three-fold higher inCarstairs quintile five compared with Carstairs quin-tile one.

Fig. 1 shows temporal trends in EPM rates for non-chromosomal and chromosomal anomalies. The

Table 1. Mortality rate definitions

Statistic Definition

Stillbirth rate Late fetal deaths on or after 24 weeks of gestation per 1000 or 10000 live and stillbirthsa

Perinatal mortality rate Stillbirths and deaths in the first week of life per 1000 or 10000 live and stillbirthsNeonatal mortality rate Deaths in the first 28 completed days of life per 1000 or 10000 livebirthsExtended perinatal mortality rate Stillbirths and deaths in the first 28 completed days of life per 1000 or 10 000 live and stillbirths

aBefore 30th September 1992, stillbirths defined as late fetal deaths on or after 28 weeks of gestation per thousand live and stillbirths.

Figure 1. Extended perinatal mortality rates for chromosomaland non-chromosomal anomalies, England and Wales, 1986–96.



rate for non-chromosomal anomalies halved over thedecade, while the rate for chromosomal anomaliesremained largely unchanged. Nptrend showed a significant decreasing temporal gradient for non-chromosomal anomalies (Z = –8.35; P < 0.001) and anon-significant gradient for chromosomal anomalies (Z = –0.8; P = 0.42). Significant negative temporal trendsfor NTDs (Z = –8.04; P < 0.001) and all other non-chromosomal anomalies excluding NTDs (Z = –6.39; P <0.001) were also found. NTDs, central nervous system(CNS) anomalies and all cardiac defects accounted for10%, 9% and 33%, respectively, of the total EPM due to

non-chromosomal anomalies (Table 2). 37% of allcardiac defect deaths were attributed to ‘other specifiedcardiac anomalies’ (ICD9: 746), excluding 830 ‘unspeci-fied cardiac anomalies’ (ICD9: 746.9).

Relative risk of extended perinatal mortality fromcongenital anomalies with increasing deprivation

Table 4 displays the results of Nptrend and the relativerisk estimates for each congenital anomaly associatedwith deprivation quintile. The latter were obtainedfrom the ward-level Poisson regression analysis and

Table 2. Extended perinatalmortality rate (per 10000 totalbirths) due to specific andgrouped congenital anomaliesin England and Wales1986–96: ICD9 coding,numbers and rates

Congenital anomaly (ICD9 code) No. of deaths EPM rate (n = 7487007)

All chromosomal (758) 1094 1.5Down’s syndrome (758.0) 162 0.2

All non-chromosomal (740–757) 9860 13.2All NTDs (740,741,742.0) 978 1.3

Anencephaly (740) 434 0.6Spina bifida (741) 401 0.5Encephalocele (742.0) 143 0.2

All other CNS anomalies (742.1–742.9) 881 1.2Microcephaly (742.1) 104 0.1Reduction deformities of brain (742.2) 85 0.1Hydrocephaly (742.3) 546 0.7Other specified anomalies (742.4–742.9) 146 0.2

All cardiac (745.0–747.9) 3290 4.4Bulbus cordis (745.0–745.3) 411 0.5Septal closure (745.4–745.9) 370 0.5Other specified anomalies (746.0–746.8) 1109 1.5Great arteries and veins (747.0–747.4) 398 0.5

All renal and urinary (753.0–753.9) 588 0.8All musculoskeletal (754–756) 710 0.9

Limb reduction (755.2–755.4) 86 0.1Diaphragm and abdominal wall (756.6–756.7) 605 0.8

Multiple and unspecified defects (759.0–759.7) 903 1.2

Total (740–758) 10954 14.6

Table 3. Numbers (No.) andunadjusted rates of extendedperinatal mortality (EPMR)per 10000 live and stillbirthsdue to chromosomal (Chrom),non-chromosomal (Non-chrom) and all congenitalanomalies by Carstairs quin-tile: England and Wales,1986–96

Carstairs No. live + No. No. No. all EPMR EPMR EPMR allquintile stillbirths chrom non-chrom anomalies chrom non-chrom anomalies

1 860112 148 1025 1173 1.72 11.92 13.642 1077210 160 1196 1356 1.49 11.10 12.593 1280408 190 1554 1744 1.48 12.14 13.624 1724967 251 2343 2594 1.46 13.58 15.045 2544310 345 3742 4087 1.36 14.71 16.06

Total 7487007 1094 9860 10954 1.46 13.17 14.63

Carstairs Quintile 1 = most affluent wards.Carstairs Quintile 5 = most deprived wards.



Table 4. Trend across Carstairs quintile groups (test statistic z; P-value) and adjusted relative riska of extended perinatal mortality [95%confidence intervals] due to congenital anomalies in Carstairs quintiles 2, 3, 4 and 5 compared with 1 for England and Wales, 1986–96

Carstairs quintiles

Congenital (Most affluent) (Most deprived)anomalies 1b 2 3 4 5 Trend

All chromosomal 1.00 0.82 0.80 0.79 0.71* (–)2.58; 0.01[0.61, 1.10] [0.60, 1.07] [0.59, 1.05] [0.53, 0.94]

Down’s syndrome 1.00 0.85 0.90 0.70 0.41* (–)3.01; <0.001[0.34, 2.10] [0.38, 2.16] [0.29, 1.70] [0.16, 0.98]

All non-chromosomal 1.00 0.88 0.96 1.09 1.17* 3.18; <0.001[0.78, 1.00] [0.86, 1.07] [0.99, 1.21] [1.06, 1.30]

All NTDs 1.00 0.87 1.08 1.34 1.47* 3.43; <0.001[0.62, 1.23] [0.78, 1.49] [0.99, 1.83] [1.08, 2.00]

Anencephaly 1.00 1.07 1.76* 2.29* 2.54* 5.25; <0.001[0.60, 1.92] [1.03, 2.90] [1.36, 3.80] [1.51, 4.26]

Spina bifida 1.00 1.08 1.03 1.31 1.46 1.80; 0.07[0.64, 1.83] [0.62, 1.73] [0.81, 2.15] [0.90, 2.36]

Encephalocele 1.00 0.37* 0.44* 0.48* 0.50* (-)0.7; 0.48[0.16, 0.82] [0.21, 0.89] [0.25, 0.93] [0.27, 0.94]

All other CNS 1.00 0.89 0.84 1.15 1.31 1.75; 0.15[0.60, 1.31] [0.57, 1.24] [0.80, 1.66] [0.91, 2.18]

Microcephaly 1.00 0.46 0.63 1.35 2.18 1.86; 0.10[0.11, 1.93] [0.18, 2.24] [0.46, 3.98] [0.98, 6.25]

Brain reduction defects 1.00 8.45* 1.29 4.06 4.62 1.19; 0.28[1.09, 10.78] [0.11, 3.52] [0.49, 5.21] [0.57, 5.87]

Hydrocephaly 1.00 0.63 0.73 0.99 1.30 1.55; 0.20[0.39, 1.01] [0.47, 1.15] [0.65, 1.51] [0.99, 2.22]

All cardiac 1.00 0.89 0.91 0.92 0.89 0.58; 0.56[0.75, 1.06] [0.78, 1.08] [0.78, 1.08] [0.75, 1.04]

Bulbus cordis 1.00 0.96 1.43 1.37 1.18 0.77; 0.44[0.57, 1.63] [0.89, 2.32] [0.85, 2.21] [0.74, 1.91]

Septal closure 1.00 1.28 0.92 1.06 1.21 0.72; 0.47[0.75, 2.18] [0.53, 1.62] [0.62, 1.83] [0.71, 2.07]

Other specified anomaliesc 1.00 0.77* 0.73* 0.82 0.79 (–)0.60; 0.55[0.60, 0.99] [0.57, 0.93] [0.65, 1.04] [0.62, 1.03]

Great arteries and veins 1.00 0.92 0.73 0.81 0.68 (–)0.61; 0.54[0.59, 1.44] [0.46, 1.15] [0.53, 1.26] [0.44, 1.05]

All renal & urinary 1.00 1.03 1.05 1.71* 1.77* 4.42; <0.001[0.68, 1.57] [0.70, 1.59] [1.17, 2.49] [1.21, 2.59]

All musculoskeletal 1.00 0.93 1.16 1.39* 1.41* 3.56; <0.001[0.68, 1.26] [0.87, 1.55] [1.06, 1.85] [1.07, 1.87]

Limb reduction 1.00 1.08 1.20 1.64* 1.65* 4.08; <0.001[0.71, 1.65] [0.80, 1.81] [1.11, 2.42] [1.14, 2.40]

Diaphragm and abdominal wall 1.00 1.40 1.96 1.75 2.66* 4.77; <0.001[0.55, 3.56] [0.81, 4.70] [0.72, 4.25] [1.13, 6.28]

All multiple defectsd 1.00 1.07 1.11 1.25 1.76* 4.01; <0.001[0.72, 1.60] [0.76, 1.64] [0.86, 1.86] [1.23, 2.52]

aAdjusted for population density quintile and year of birth.bReference category.cICD9 746.0–746.8.dTwo or more major anomalies.*Significant at P <0.05.



were adjusted for year of birth and population densityquintile.

Nptrend showed a significant increasing gradient ofEPM from the least deprived to the most deprived quin-tile for non-chromosomal malformations (P < 0.001)and a significant decreasing gradient for all chromoso-mal anomalies (P = 0.01). The relative risks of EPM fromall non-chromosomal and chromosomal anomalies inthe most deprived quintile of wards compared with theleast were 1.17 [95% CI 1.06, 1.30] and 0.71 [0.53, 0.94]respectively. Controlling for extra-Poisson variationresulting from unmeasured confounding only slightlyreduced the strength of the association with depriva-tion. The relative risk for all non-chromosomal anom-alies, in the most deprived quintile compared with theleast, was 1.14 [1.09, 1.18]. For all chromosomal anom-alies the relative risk was 0.87 [0.80, 0.95]. Significantlyincreased trends and relative risks in the most deprivedquintile compared with the least were also shown formost major subgroups of non-chromosomal anomalies(all NTDs, all renal and urinary, all musculoskeletal,and all multiple anomalies) except for cardiac and all other CNS anomalies (the latter group excluded allNTDs). Although overall the relative risk of EPM for allNTDs increased with increasing deprivation, this waslargely because of the increased risk for anencephaly;other specific NTDs, such as encephalocele showed a significantly lower risk of mortality in the mostdeprived quintile compared with the least. The mainsubgroup of chromosomal anomalies (i.e. Down’s syn-drome) showed a similar pattern of decreasing risk ofmortality with increasing deprivation as that seen forall chromosomal anomalies.

Finally, repeating the analyses for stillbirth andneonatal anomalies separately did not substantiallyalter the results. Separate analyses for 1986–92 and1993–96 also showed there was little bias introducedas a result of the change in stillbirth definition fromOctober 1992. Relative risks of EPM (adjusted for yearof birth and level of urbanisation) due to non-chromosomal and chromosomal anomalies, respec-tively, in the most deprived quintile compared with theleast, were 1.19 [1.04–1.45] and 0.68 [0.55–0.92] for1986–92, and 1.15 [1.01–1.64] and 0.73 [0.45–0.97] for1993–96.

Discussion

We found a positive gradient in extended perinatalmortality (EPM) for non-chromosomal anomalies with

increasing deprivation and a significant excess risk inthe most deprived compared with the least deprivedwards of residence in England and Wales, 1986–96. Theopposite was the case for chromosomal anomalieswhich showed a negative gradient with increasingdeprivation and a significant deficit in EPM in themost deprived compared with the most affluent population group. Sub-grouped analyses for all NTDs,all renal and urinary, all musculoskeletal and all multiple anomalies showed striking positive gradientsof EPM with increasing deprivation. No socio-economic gradients were noted for cardiac defects, all other CNS anomalies – excluding NTDs – orencephalocele.

The association linking increased risk of NTDs, limbreduction defects and genitourinary anomalies withincreased deprivation has been shown previously.5–7,24

Higher social status has also been associated withlower recurrence risk of NTDs.25 The significant excess risk for anencephaly in the most deprivedgroup compared with the least was particularly striking and seemed to be the dominant factor explain-ing increased risk in the NTDs subgroup. The results for NTDs are important in the context of rec-ommendations from the UK Expert Advisory Group26

concerning vitamin and periconceptional folate supplementation. Further studies are needed to evaluate whether recent implementation of the UKHealth Education Authority Awareness Campaign27

(initiated in 1996) has significantly reduced the excessrisk in perinatal mortality or EPM among moredeprived compared with more affluent populationgroups.

In a similar study, Vrijheid et al.5 investigated therelationship between total prevalence of congenitalanomalies (including livebirth anomalies, fetal deathsfrom 20 weeks gestation and terminations of preg-nancy following prenatal diagnosis of birth defects)and socio-economic deprivation. They found anincreased risk of non-chromosomal anomalies withincreasing deprivation. Their analysis lacked statisticalpower for most subgroups, but a significant relation-ship between increasing deprivation was also foundfor defects of the cardiac septa. Other studies have alsoshown trends of increasing risk with increasing socio-economic deprivation among livebirths with ventricu-lar septum defects,8 and aortic stenosis anomalies.28 Incontrast, we found no effect for cardiac anomalies.Inconsistency between our results and other reportedstudies may reflect the use of different outcome

measures (extended perinatal mortality in our studyand prevalence in the other studies).

The decreasing temporal trend in non-chromosomalanomalies is probably not explained by a predominantdecreasing trend in EPM due to NTDs. Excluding NTDs from the analysis still resulted in a significantnegative trend for the remaining non-chromosomalanomalies. The trend is probably explained by increasing terminations of pregnancies in which non-chromosomal anomalies have been detected prenatally,and improvements in both neonatal surgery and specialist care.29–31 However, other factors may also beimportant. Previous studies exploring the decrease inbirth prevalence of NTDs in England and Wales foundthat terminations of NTDs could not account for morethan half of the decline.32,33 Some authors have attrib-uted the decreasing trend in NTDs to improvements indiet and intake of dietary folate.34 For chromosomalanomalies, EPM remained relatively stable over thesame time period in spite of increased prenatal diag-noses of Down’s syndrome. This might be largelyattributed to the demographic trend towards startingfamilies later in life – the overall increase in the propor-tion of cases of Down’s syndrome among older mothersmay offset the increase in terminations following pre-natal diagnosis.35

Potential impact of unmeasured risk factors andother possible sources of bias

Information about maternal age is not routinely avail-able from the ONS and we were unable to include thisvariable in our analysis. Vrijheid et al.5 found that,having controlled for maternal age, an apparent rela-tionship between more affluent population groups andincreased prevalence of Down’s syndrome and chro-mosomal anomalies disappeared. The percentage ofolder mothers was higher in the most affluent popula-tion quintile than in the most deprived quintile. Like-wise, Lopez et al.36 found a statistically significantexcess risk of Down’s syndrome pregnancies in themore affluent population group. After standardisingthe rates for maternal age, although this excess risk stillpersisted, it was no longer statistically significant. Inour analysis of all chromosomal anomalies, Down’ssyndrome only accounted for 15% of the EPM due tochromosomal anomalies, while trisomy 18 accountedfor 56% and trisomy 13, 25%. However, increasedmaternal age (as well as being associated with Down’ssyndrome) has also been associated with maternal

meiotic non-disjunction in trisomies 15, 16, and 18.37

Therefore, it seems likely that our negative gradient forboth Down’s syndrome and all chromosomal anom-alies with increasing deprivation was confounded bymaternal age.

For non-chromosomal anomalies, increased riskwith increasing maternal age has been reported insome large studies38,39 but not in others.40,41 Increasedrisk with lower maternal age has been noted for patentductus arteriosus,40 hypertrophic pyloric stenosis,40

and gastroschisis.42 A literature review by Fretts andUsher43 suggests that advanced maternal age is notassociated with increased risk of fetal death due tolethal non-chromosomal anomalies. Other studieshave also shown that maternal age may not be a sig-nificant confounder when investigating birth out-comes resulting from non-chromosomal anomalies.Balarajan et al.24 found that significant socio-economicand ethnic differences in stillbirth and infant mortalitydue to congenital anomalies remained after standard-ising for maternal age. Similarly, Vrijheid et al.5 showedthat significantly increased odds ratios (for the mostdeprived compared with the most affluent deprivationquintile) for all non-chromosomal anomalies persistedafter maternal age adjustment.

Another important underlying factor is the effect ofterminations due to congenital anomalies on the mor-tality rate. Few studies have assessed the impact of terminated pregnancies in relation to birth defects.Julian-Reynier et al.44 found that the increase in the per-centage of terminations of isolated anomalies in preg-nancies was mainly due to an increase in the numberof terminations of pregnancies resulting from lethalanomalies or associated with very low survival rates.The effect on EPM would therefore be greater for par-ticular kinds of anomaly, especially anomalies such asanencephaly, and less for malformations with highsurvival rates and good prognosis. In addition, relativerisk estimates based on EPM may vary depending onwhether those women who electively terminate a birthdefect-affected pregnancy are different in some respectto those who do not. Velie and Shaw45 found that, com-pared with women who delivered stillborn or liveborninfants with an NTD, those who electively terminatedNTD-affected pregnancies were disproportionatelywhite, more educated and had higher incomes. Differ-ential access to prenatal diagnosis and/or uptake ofpregnancy termination may alter deprivation gradi-ents in mortality so that they do not reflect the true gradient in risk of an affected pregnancy. Therefore,




deprivation gradients in EPM from our study must beevaluated in light of birth prevalence studies in whichterminations due to birth defects have been includedin the analysis. Our results for non-chromosomalanomalies combined are in concordance with otherprevalence studies, such as that of Vrijheid et al.5 whoincluded terminations and showed increased risk ofnon-chromosomal anomalies with increasing socio-economic deprivation. However, for subgroups suchas NTDs, Vrijheid et al.5 found no significant depriva-tion gradient, in contrast to our findings. This differ-ence may be because of differential access to prenataldiagnosis and/or uptake of termination due to NTD-affected fetuses.

Additional factors that might be important includemarital status, number of natural children, whetherpregnancies are unplanned, and attitudes to abortion.46

Differences between low and high deprivation groupscould also be explained by differences in parity,lifestyle factors (such as smoking or alcohol consump-tion), ethnic origin, maternal illness, chronic disease(e.g. diabetes), occupational, nutritional or environ-mental factors.

Other limitations also need to be considered. Firstly,our study used the Carstairs deprivation indexobtained from the 1991 census, whereas the period ofstudy covers 1986–96. This means that any changes inthe socio-demographic structure of the population inEngland and Wales were not taken into account.Unlike most congenital malformation surveillancesystems in Great Britain, stillbirths and neonataldeaths due to congenital malformations must belegally notified on death certificates. Therefore, mor-tality due to congenital anomalies should be reason-ably well ascertained. However, some reports haveshown that there may be up to 10% misclassificationof congenital malformations leading to under-ascertainment.47 We also found that the overall rate of stillbirth and neonatal mortality from congenitalmalformations obtained using death certificates wasunder-ascertained compared with rates in local regis-ters, in which data on congenital malformations arecollected from multiple sources. CARIS48 (CongenitalAnomaly Register and Information Service in Wales)found a rate of 1.9 per 1000 live and stillbirths, whilethe equivalent geographical area data for ONS was 1.4 per 1000 live and stillbirths. Provided under-ascertainment is consistent across deprivation groupsand geographical areas, then this should not introducebias into the analysis.

Even in view of the limitations of this study, we consider that the findings are important and warrantfurther investigation in studies focusing on underlyingfactors related to socio-economic deprivation. Theincreased risk of EPM for non-chromosomal anomalieswith increasing deprivation should be taken intoaccount in resource distribution in maternal, paediatricand related health services.

Acknowledgements

We would like to thank the ONS for their contributionto the study and making available the data for analy-sis. The work for this paper was carried out under an ESRC scholarship for David Neasham. Conflict ofinterest: none.

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Molecular Epidemiology of Infectious DiseasesEdited by R.C.A. Thompson. London: Arnold, 2000, pp. 326, £70.00. ISBN 0340 75909 7.

This hard-backed book brings together contributionsfrom 36 authors with wide-ranging expertise in theepidemiology of infectious diseases. The first half ofthe book concentrates on methods and includes chap-ters on molecular epidemiology and evolutionarygenetics, population genetics, within host ecology andmathematical modelling. The second part of the bookincludes chapters illustrating the application of mole-cular methods in studies of the epidemiology of spe-cific diseases, including many of those that have amajor impact on human health such as malaria, tuber-culosis and HIV/AIDS. Other chapters cover measles,enteric protozoan infections, pneumocystis, popula-tion genetics of human pathogenic fungi, rabies, try-panosomiases and Australian arboviruses. There isalso a chapter on insect disease vector epidemiology.

Each chapter is well written and presented clearlyand, in general, could be followed without specificbackground or training in the epidemiology of infec-tious diseases. The book is not inclusive but workswell to illustrate the application of molecular methodscombined with appropriate interpretation and analy-sis to the elucidation of problems in the epidemiologyof infectious diseases. The description of molecularmethods gives most reference to nucleic acid tech-nologies. Readers are referred to other texts for adescription of protein-based typing methods. There isno general discussion of the relative merits of differentapproaches to microbial typing. Many of the chap-ters on specific agents of infection discuss protein and immunological typing methods; for example, theuse of isoenzyme variation for trypanosomiasis, andserotyping of viruses. It would help the general readerto see an overview illustrating the complementarity of different methods. There is little discussion on the

practicality or cost-effectiveness of molecular typingmethods. Currently, these methods are restricted intheir application to centres with access to resourcesthat are not widely available in those parts of the worldwhere many of the diseases discussed in this book arecommon.

The public health implications and derived benefitsof applying molecular methods to the study of the epidemiology of infectious diseases receive little em-phasis. Some of the chapter contents are somewhatidiosyncratic; for example, the chapter on nosocomialepidemiology of microbial infections includes quite alot of discussion of pneumococcal disease including asection on virulence determinants. Although Strepto-coccus pneumoniae does cause outbreaks of hospital-acquired infection, it is given an inappropriateemphasis in this chapter compared with vancomycin-resistant enterococci, multiresistant Gram-negativebacteria and MRSA, which cause more problems inhospital practice than S. pneumoniae. The epidemiologyof antibiotic resistance and of transmissible antibioticresistance determinants, and the use of mathematicalmodelling techniques to describe the epidemiology ofantibiotic-resistant community-acquired pathogenssuch as S. pneumoniae is given little emphasis. Thechapter on tuberculosis gives most emphasis to a dis-cussion of methodologies and does not do justice tocurrent research on the epidemiology of tuberculosis.There is no discussion of prion diseases. These minorcriticisms aside, the editor is to be congratulated onbringing together a well-presented and informativecollection of articles illustrating the present and futurebenefits associated with the application of moleculartechnologies in studies of the epidemiology of infec-tious diseases. Chapters on fungal and protozoal dis-eases are to be particularly recommended. This bookshould appeal to anyone with an interest in infectiousdiseases.

MICHAEL MILLAR

Book review

stillbirth and neonatal mortality due to congenital anomalies: temporal trends and variation by...

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