ICD codes and descriptions used in the project · Web viewTetralogy of Fallot Q220 Pulmonary valve atresia Q224 Congenital tricuspid stenosis Q225 Ebstein's anomaly Q226 Hypoplastic

Supplemental material

Risk of congenital anomalies near municipal waste incinerators in England and Scotland: retrospective

population-based cohort study.

Authors

Brandon Parkes, Anna L Hansell, Rebecca E Ghosh, Philippa Douglas, Daniela Fecht, Diana Wellesley, Jennifer J Kurinczuk, Judith Rankin, Kees de Hoogh, Gary W. Fuller, Paul Elliott, professor and director and Mireille B Toledano.

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ContentsICD codes and descriptions used in the project....................................................................3

Table S1. ICD codes and descriptions...............................................................................3

Potential confounders..........................................................................................................7

Table S2. Potential confounder definitions and data sources*........................................7

Table S3. Other sources of emissions, main industry groups included in the “other sources of emissions” variable*.......................................................................................9

Table S4. Pearson correlation coefficients between exposure and potential confounder variables......................................................................................................................... 10

Sensitivity analyses.............................................................................................................12

Table S5. Descriptions and justifications of sensitivity analyses.....................................12

Table S6. Sensitivity analysis results. Risk of congenital anomaly outcomes associated with a. Modelled exposure to PM10 and b. proximity to a MWI.....................................14

Table S7. Risk of congenital anomaly outcomes associated with a. Modelled exposure to PM10 and b. proximity to a MWI. Analysis repeated excluding one MWI each time.. 19

Table S8. Risk of congenital anomaly outcomes associated with proximity to a MWI – Alternative distance distributions..................................................................................22

Regression models............................................................................................................. 23

Table S9. Regression models and covariates*................................................................23

Numbers of congenital anomaly cases...............................................................................24

Table S10. Numbers of cases by congenital anomaly groups for England and Scotland 24

Results of main models with P-values and correction for multiple testing........................25

Table S11. Risk of all congenital anomalies and all congenital anomalies without chromosomal congenital anomalies for modelled emissions and proximity to nearest MWI................................................................................................................................25

Table S12. Risk of congenital anomaly outcomes by congenital anomalies grouping (chromosomal anomalies excluded) for modelled emissions and proximity to nearest MWI................................................................................................................................27

References..........................................................................................................................32

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ICD codes and descriptions used in the project

Table S1. ICD codes and descriptionsCongenital anomaly group

ICD10 codes Description

All congenital anomalies

Q00 – Q99 Chapter XVII: Congenital malformations, deformations and chromosomal abnormalities

D215 Benign neoplasm of connective and other soft tissue of pelvis

D821 Di George's syndromeD1810 Cystic hygromaP350 Congenital rubella syndromeP351 Congenital cytomegalovirus infectionP371 Congenital toxoplasmosis

All congenital anomalies excl. chromosomal

excl. Q90-Q99

Q9 codes are all chromosomal anomalies

Nervous system Q00 Anencephaly and similar malformationsQ01 EncephaloceleQ02 MicrocephalyQ03 Congenital hydrocephalusQ04 Other congenital malformations of brainQ05 Spina bifidaQ06 Other congenital malformations of spinal cordQ07 Other congenital malformations of nervous systemExcl. Q0461 Single congenital cerebral cystExcl. Q0782 Crocodile tears

Congenital heart defects

Q20 Congenital malformations of cardiac chambers and connections

Q21 Congenital malformations of cardiac septaQ22 Congenital malformations of pulmonary and tricuspid

valvesQ23 Congenital malformations of aortic and mitral valvesQ24 Other congenital malformations of heartQ25 Congenital malformations of great arteriesQ26 Congenital malformations of great veinsExcl. Q2111 Patent or persistent foramen ovaleExcl. Q2541 Persistent right aortic archExcl. Q261 Persistent left superior vena cavaExcl. Q250 Patent ductus arteriosus if GA < 37 weeksExcl. Q256 Peripheral pulmonary artery stenosis if GA < 37 weeks

Abdominal wall defects

Q792 ExomphalosQ793 GastroschisisQ795 Other congenital malformations of abdominal wallQ7950 Congenital malformation of abdominal wall, unspecified

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Q7951 Congenital hernia of bladderQ7959 Other congenital malformations of abdominal wall

Oro-facial clefts Q35 Cleft palateQ36 Cleft lipQ37 Cleft palate with cleft lip

Limb defects Q65-Q74 excluding Q7400Q65 Congenital deformities of hipQ66 Congenital deformities of feetQ67 Congenital musculoskeletal deformities of head, face,

spine and chestQ68 Other congenital musculoskeletal deformitiesQ69 PolydactylyQ70 SyndactylyQ71 Reduction defects of upper limbQ72 Reduction defects of lower limbQ73 Reduction defects of unspecified limbQ74 Other congenital malformations of limb(s)Excl. Q653 Congenital partial dislocation of hip, unilateralExcl. Q654 Congenital partial dislocation of hip, bilateralExcl. Q655 Congenital partial dislocation of hip, unspecifiedExcl. Q656 Congenital unstable hipExcl. Q662 Congenital metatarsus (primus) varusExcl. Q663 Other congenital varus deformities of feetExcl. Q664 Congenital talipes calcaneovalgusExcl. Q665 Congenital pes planusExcl. Q666 Other congenital valgus deformities of feetExcl. Q667 Congenital pes cavusExcl. Q668 Other congenital deformities of feetExcl. Q669 Congenital deformity of feet, unspecifiedExcl. Q670 Congenital facial asymmetryExcl. Q671 Congenital compression faciesExcl. Q672 DolichocephalyExcl. Q673 PlagiocephalyExcl. Q674 Other congenital deformities of skull, face and jawExcl. Q675 Congenital deformity of spineExcl. Q676 Pectus excavatumExcl. Q677 Pectus carinatumExcl. Q678 Other congenital deformities of chestExcl. Q680 Congenital deformity of sternocleidomastoid muscleExcl. Q681 Congenital deformity of finger(s) and handExcl. Q682 Congenital deformity of kneeExcl. Q683 Congenital bowing of femurExcl. Q684 Congenital bowing of tibia and fibulaExcl. Q685 Congenital bowing of long bones of leg, unspecified

4

Excl. Q7400 Accessorry carpal bonesDigestive system

Q790 Congenital diaphragmatic herniaQ38 Other congenital malformations of tongue, mouth and

pharynxQ39 Congenital malformations of esophagusQ40 Other congenital malformations of upper alimentary tractQ41 Congenital absence, atresia and stenosis of small intestineQ42 Congenital absence, atresia and stenosis of large intestineQ43 Other congenital malformations of intestineQ44 Congenital malformations of gallbladder, bile ducts and

liverQ45 Other congenital malformations of digestive systemExcl. Q381 AnkyloglossiaExcl. Q382 MacroglossiaExcl. Q3850 High arched palateExcl. Q400 Congenital hypertrophic pyloric stenosisExcl. Q401 Congenital hiatus herniaExcl. Q4021, Q430, Q4320, Q4381 & Q4382

Functional gastro-intestinal disorders

Urinary system Q60 Renal agenesis and other reduction defects of kidneyQ61 Cystic kidney diseaseQ62 Congenital obstructive defects of renal pelvis and

congenital malformations of ureterQ63 Other congenital malformations of kidneyQ64 Other congenital malformations of urinary systemQ794 Prune belly syndromeExcl. Q610 Congenital renal cystExcl. Q627 Congenital vesico-uretero-renal refluxExcl. Q633 Hyperplastic and giant kidney

Genital system Q50 Congenital malformations of ovaries, fallopian tubes and broad ligaments

Q51 Congenital malformations of uterus and cervixQ52 Other congenital malformations of female genitaliaQ54 HypospadiasQ55 Other congenital malformations of male genital organsQ56 Indeterminate sex and pseudohermaphroditismExcl. Q523 Imperforate hymenExcl. Q525 Fusion of labiaExcl. Q527 Other and unspecified congenital malformations of vulvaExcl. Q5520 Unspecified congenital malformations of testis and

scrotumExcl. Q5521 Polyorchism

Congenital

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anomaly sub-groupsNeural tube defects

Q00 Anencephaly and similar malformationsQ01 EncephaloceleQ05 Spina bifida

Severe congenital heart defects

Q200 Common arterial trunkQ201 Double outlet right ventricleQ202 Double outlet left ventricleQ203 Discordant ventriculoarterial connectionQ204 Double inlet ventricleQ212 Atrioventricular septal defectQ213 Tetralogy of FallotQ220 Pulmonary valve atresiaQ224 Congenital tricuspid stenosisQ225 Ebstein's anomalyQ226 Hypoplastic right heart syndromeQ230 Congenital stenosis of aortic valveQ232 Congenital mitral stenosisQ233 Congenital mitral insufficiencyQ234 Hypoplastic left heart syndromeQ251 Coarctation of aortaQ252 Atresia of aortaQ262 Total anomalous pulmonary venous connection

Gastroschisis Q793 GastroschisisCleft palate Q35 Cleft palateCleft lip with or without cleft palate

Q36 Cleft lipQ37 Cleft palate with cleft lip

Limb reduction defects

Q71 Reduction defects of upper limbQ72 Reduction defects of lower limbQ73 Reduction defects of unspecified limb

Oesophageal atresia

Q390 Atresia of esophagus without fistulaQ391 Atresia of esophagus with tracheo-esophageal fistulaQ3911 Atresia of esophagus with fistula between trachea and

upper oesophagusAnomalies of the renal system

Q60 Renal agenesis and other reduction defects of kidneyQ61 Cystic kidney diseaseExcl. Q610 Congenital renal cyst

Obstructive defects of renal pelvis

Q62 Congenital obstructive defects of renal pelvis and congenital malformations of ureter

Q64 Other congenital malformations of urinary systemExcl. Q627 Congenital vesico-uretero-renal reflux

Hypospadias Q54 Hypospadias

6

7

Potential confoundersPotential confounders were selected a priori to reflect factors that have previously been associated with risk of congenital anomalies, for example maternal age (Cleary-Goldman et al. 2005), ethnicity (van der Zanden et al. 2012), deprivation (Varela et al. 2009), air pollution (Dolk and Vrijheid 2003).

Table S2. Potential confounder definitions and data sources*Confounder Definition Use Data SourceMaternal Age (years)

4 Groups:1. < 202. 20-29 (reference category)3. 30-394. >= 40

Models 2,3,4,5,6.

Within routine health datasets

Year of birth 2003-2010 Models 2,3,4,5,6.

Sex Sensitivity analysis

Multiple birth

yes/no Sensitivity analysis

Area level ethnicity

Percentage of white women, all women of reproductive age (16-49) from the 2011 census at Middle Layer Super Output area.

Models 3, 4, 5, 6.

Office for National Statistics; National Records of Scotland (2016): 2011 Census aggregate data. UK Data Service (Edition: June 2016). DOI: http://dx.doi.org/10.5257/census/aggregate-2011-1

Deprivation Carstairs Index 2011 at Census Output Area Level based on census data standardised for Great Britain Quintiles of score:1. Least deprived (reference category)5. Most deprived

Models 4, 5, 6.

Other sources of emissions

Number of industries divided by years of incinerator operation (see supplemental table 2)

Models 4, 5, 6.

Environment Agency Environmental Permitting Regulations – Industrial sites (England), Industrial sites and the Scottish Pollutant Release Inventory.

Incinerator road density

Total length of roads in km (motorways, A-roads, B-roads) within 10km of each incinerator.

Models 4, 5, 6.

Meridian 2014 road lengths.Ordnance Survey data © Crown copyright and database right 2014.

Subject road density

Total length of road in km (motorways, A-roads, B-roads) within 250m of subject’s postcode.

Smoking Tobacco expenditure in £ per Sensitivity CACI tobacco expenditure

8

http://dx.doi.org/10.5257/

proxy person (population 16 years and older) at Census Output Area level. England only.

analysis data © Copyright 1996-2014 CACI Limited.

Individual ethnicity

White (ref), Black, Asian, Other Sensitivity analysis

Routine health data, not available before 2006. Not available for Scotland.

*We have included three potential confounders to represent the background or other sources of emissions to which the subject may be exposed (Other sources of emissions; Incinerator road density; and Subject road density). However, these are imperfect proxies which may not adequately represent the background pollution exposure to the subject. Consequently we have added a random intercept for the MWI to the fully adjusted statistical model.

9

Table S3. Other sources of emissions, main industry groups included in the “other sources of emissions” variable*

Main group number

Main group Included

1 Energy sector Yes2 Production and processing of metals Yes3 Mineral industry Yes4 Chemical industry Yes5 Waste and waste-water management Yes6 Paper and wood production and processing Yes7 Intensive livestock production and aquaculture No

8Animal and vegetable products from the food and beverage sector

No

9 Other activities Yes10 Radioactive Substances Act Activities No

*The data are yearly so the earliest permit issued for duplicate industries was taken as the

start date of that industry. The data do not contain closure date of industry so the

assumption was that the industries remained open until 2010.

England data are from the Environment Agency (EA) Environmental Permitting

Regulations – Industrial sites 2001-2015

Scottish data are from the Scottish Pollutant Release Inventory (10 mile radius

around Dundee incinerator).

The various datasets were harmonised so that the industrial sites could be consistently

grouped and certain industry groups removed (Supplemental table S2). This mapping

was based on the Pollutant Release Inventory coding mapped on to the main EA Activity

Schedule Reference grouping (using the EA regulatory sector to check the mapping).

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Table S4. Pearson correlation coefficients between exposure and potential confounder variables

Maternal age

Year of birth

% non-w

hite wom

ena

(MSO

A)

Deprivationb (CO

A)

Other sources of em

ission

Major road length – 10 km

of M

WI

Major road density – 250m

of individual

Mean PM

10 concentration from

nearest MW

I

Proximity to M

WI c

Maternal age 1

Year of birth 0.01 1

% non-white womena (MSOA)

-0.03 -0.05 1

Deprivationb (COA)

-0.31 -0.05 0.39 1

Other sources of emission

-0.09 -0.09 -0.17 0.20 1

Major road length – 10 km of MWI

0.04 -0.17 0.34 0.10 -0.05 1

Major road density – 250 mof individual

-0.01 0.00 0.22 0.07 -0.10 0.09 1

Mean PM10 exposure from nearest MWI

-0.03 -0.01 0.08 0.08 0.14-

0.060.04 1

Proximity to MWIc -0.03 0.01 0.45 0.22 -0.10 0.07 0.12 0.31 1

a Defined as % of non-white women aged 16-49 at the middle layer super output area

(MSOA) level (2,000 to 6,000 households).

b Defined as the Carstairs deprivation quintile (Carstairs and Morris 1990) at the census

output area (COA) level (40 to 250 households).

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c Proximity of the nearest MWI was calculated as a continuous measure of linear distance

(km) from the postcode centroid of maternal residence at birth.

Each dataset is yearly so industries can appear multiple times. The data were cleaned so

that the earliest permit issued for duplicate industries was taken as the start date of that

industry. Closure date was not available so it was assumed all industries remained open

until 2010. All industries in each 10 km buffer around a MWI that were open before the

associated incinerator was commissioned were removed.

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Sensitivity analyses

Table S5. Descriptions and justifications of sensitivity analyses Analysis Description/justificationUse 91 day pre-pregnancy period as exposure

The exposure period of the main model is 91-day pre-pregnancy plus first trimester. It may be that the crucial period is one or other of these, not both.Use first trimester as exposure

periodInclude tobacco expenditure as a confounder

Smoking is associated with congenital anomalies (CAs) (Hoyt et al. 2016; Lee and Lupo 2013), but individual smoking data are unavailable, furthermore the tobacco expenditure data are incomplete so they are used as a covariate in a sensitivity analysis.

Include individual ethnicity as a confounder (2006-2010)

Ethnicity is a risk factor for certain CAs (Knowles et al. 2017). Data on ethnicity were not routinely collected with health data before 2006.

Include terminations in denominator

Due to information governance issues, the (live born) cases are duplicated in the denominator. We decided not to duplicate the terminations in the denominator for the main model.

Include women with unknown maternal age (and remove maternal age as a covariate)

The majority of women with missing maternal age data were mothers of CA cases. In the main model those cases were excluded because maternal age is a potential confounder. This provides information on any potential selection bias.

Exclude individuals with unknown sex (and add sex as a covariate)

The majority of individuals with missing sex were CA cases that were terminations. We decided that excluding these individuals from the main model may introduce bias.

Duplicate Scottish cases in denominator

Due to information governance issues, the (live born) cases in England are duplicated in the denominator, but this was not the case for Scotland (where the data came in one dataset). A sensitivity analysis was performed with the Scottish CA cases duplicated in the denominator.

Scotland only, minor congenital anomalies included

Minor CA data are not available for England

1 extra duplication of cases in denominator

To inform us of the effect of the duplication of cases in the denominator, we performed sensitivity analyses with additional duplications.2 extra duplications of cases in

denominatorAdd multiple birth as covariate Multiple birth data are available for all individuals.English data only The Scottish data are collected in a different way to

the English data.Exclude individuals born in 2003 The exposure data are available from the start of

2003; this is the earliest date for the start of the 91-

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day pre-pregnancy period. Consequently the majority of the 2003 births are terminations and late miscarriages; this may have introduced a bias.

Exclude individuals for whom there are > 50% missing MWI emission days

Missing MWI data are imputed from median annual values (Douglas et al. 2017). This provides information on any potential selection bias.

Tighten missing ADMS cut-off to 5%

The missing ADMS cut-off for the main models was 10%. Tightening or loosening the cut-off results in more or less exclusions respectively. These provide information on any potential selection bias.

Loosen missing ADMS cut-off to 15%Alternative PM10 exposure- quintiles

The assumed dose relation in the main model is log-linear. This investigates another possible dose relation, e.g. threshold.

Scotland data only The Scottish data are collected in a different way to the English data.

Repeat analysis leaving out 1 MWI each time

To identify which MWIs influence the results

Remove all TOPFAs To inform us of the effects of including/excluding TOPFAs. (No TOPFA data available for Scotland)

Remove area level covariates from fully adjusted analysis

Carstairs deprivation and ethnicity covariates are used at area level leading to potential misclassification.

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Table S6. Sensitivity analysis results. Risk of congenital anomaly outcomes associated with a. Modelled exposure to PM10 and b. proximity to a MWIa.) Modelled exposure to PM10 from a MWI.

Analysis Outcome n cases/ n total births

Risk per doubling in modelled PM10

1 over exposure period2

OR3 95% CIUse 91 day pre-pregnancy period as exposure


5,145/ 219,486

1.00 0.99-1.01


4,172/ 219,020

0.99 0.98-1.01

Use first trimester as exposure period


5,145/ 219,486

1.00 0.98-1.01


4,172/ 219,020

0.99 0.98-1.01

Include tobacco expenditure as a confounder


4,929/ 211,393

0.99 0.97-1.01


3,959/ 210,927

0.99 0.96-1.01

Include individual ethnicity as a confounder


1,972/ 161,914

1.11 0.90-1.37


1,684/ 161,785

1.04 0.91-1.19



5,154/ 220,205

1.00 0.98-1.02


4,172/ 219,235

0.99 0.97-1.01

Include those with unknown maternal age (& remove maternal age as a covariate)


5,455/ 219,787

1.00 0.97-1.09


4,412/ 219,260

0.99 0.97-1.01

Exclude those with unknown sex (& add sex as a covariate)


4,893/ 219,223

1.00 0.98-1.02


3,930/ 218,758

0.99 0.97-1.02



5,154/ 219,711

1.00 0.98-1.02

All congenital anomalies excl.

4,172/ 219,245

0.99 0.97-1.01

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chromosomalScotland only, minor congenital anomalies included

All congenital anomalies, incl. minor

704/ 8,093 0.98 0.93-1.04



5,154/ 223,294

1.00 0.98-1.02


4,172/ 222,828

0.99 0.97-1.01

2 extra duplications of cases in denominator


5,154/ 227,102

1.00 0.98-1.02


4,172/ 226,636

0.99 0.97-1.01

Add multiple birth as covariate


5,145/ 219,486

1.00 0.98-1.02


4,172/ 219,020

0.99 0.97-1.01

English data only All congenital anomalies

4,926/ 211,393

0.99 0.97-1.01


3,959/ 210,927

0.99 0.97-1.01

Exclude individuals born in 2003


5,099/ 219,416

0.99 0.97-1.01


4,139/ 218,952

0.99 0.97-1.01

Exclude individuals with > 50% missing incinerator exposure days


5,153/ 219,468

1.00 0.98-1.02


4,171/ 219,002

0.99 0.97-1.01



5,074/ 214,698

0.99 0.98-1.01


4,118/ 214,247

0.99 0.97-1.01

Loosen missing ADMS cut-off to 15%


5,246/ 224,524

1.00 0.97-1.02


4244/ 224052

1.00 0.97-1.02

Alternative PM10

exposure- quintilesAll congenital anomalies

5,154/ 219,486

1.01 0.98-1.04

16


4,172/ 219,020

0.99 0.97-1.01

Scotland only All congenital anomalies

225/8,093 1.01 0.92-1.12


213/8,093 0.99 0.90-1.10

Remove TOPFAs All congenital anomalies

4,071/ 218,403

1.00 0.98-1.02


3,593/ 217,937

0.99 0.97-1.02

Remove area level covariates


5,145/ 219,486

1.01 0.99-1.03


4,172/ 219,020

1.00 0.98-1.03

b.) Proximity to a MWI.

Analysis Outcome n cases/ n total births

Proximity to MWI (continuous) per km

OR3 95% CIInclude tobacco expenditure as a confounder


4,929/ 211,393

1.02 1.00-1.04


3,959/ 210,927

1.02 1.00-1.04

Include individual ethnicity as a confounder


1,972/ 161,914

0.89 0.77-1.03


1,684/ 161,785

0.93 0.83-1.05



5,154/ 220,205

1.02 1.00-1.04


4,172/ 219,235

1.02 1.00-1.04

Include those with unknown maternal age (& remove maternal age as a covariate)


5,455/ 219,787

1.02 1.00-1.04


4,412/ 219,260

1.02 0.99-1.06

Exclude those with All congenital 4,893/ 1.02 1.00-1.04

17

unknown sex (& add sex as a covariate)

anomalies 219,223All congenital anomalies excl. chromosomal

3,930/ 218,758

1.02 1.00-1.04



5,154/ 219,711

1.02 1.00-1.04


4,172/ 219,245

1.02 1.00-1.04

Scotland only, minor congenital anomalies included

All congenital anomalies, incl. minor

704/ 8,093 0.99 0.96-1.03



5,154/ 223,294

1.02 1.00-1.04


4,172/ 222,828

1.02 1.00-1.04

2 extra duplications of cases in denominator


5,154/ 227,102

1.02 1.00-1.04


4,172/ 226,636

1.02 1.00-1.04

Add multiple birth as covariate


5,145/ 219,486

1.02 1.00-1.04


4,172/ 219,020

1.02 1.00-1.04

English data only All congenital anomalies

4,929/ 211,393

1.02 1.00-1.04


3,959/ 210,927

1.02 1.00-1.04

Exclude those born in 2003


5,099/ 219,416

1.02 1.00-1.04


4,139/ 218,952

1.02 1.00-1.04



5,074/ 214,698

1.02 1.00-1.05


4,118/ 214,247

1.02 0.99-1.06

Loosen missing ADMS cut-off to 15%


5,246/ 224,524

1.02 1.01-1.04

All congenital anomalies excl.

4,244/ 224,052

1.02 1.00-1.04

18

chromosomalScotland only All congenital

anomalies225/8,093 1.00 0.94-1.06


213/8,093 0.99 0.94-1.05

Remove TOPFAs All congenital anomalies

4,071/ 218,403

1.02 1.00-1.04


3,593/ 217,937

1.02 1.00-1.04

Remove area level covariates


5,145/ 219,486

1.03 1.01-1.04


4,172/ 219,020

1.03 1.01-1.05

1 Modelled exposure to mothers (10-3 μg/m3): range 0 – 29.4, IQR 0.14- 0.76, median 0.339, mean 0.64.

2 Exposure is mean modelled PM10 concentration over 91-day pre-pregnancy period plus first trimester of pregnancy unless otherwise specified.

3 Unless otherwise specified in sensitivity analysis description, adjusted for maternal age, year of birth, area level ethnicity, area-level deprivation, other potential sources of emissions, MWI road density, road density; Random effect for MWI area and random slope for the exposure.

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Table S7. Risk of congenital anomaly outcomes associated with a. Modelled exposure to PM10 and b. proximity to a MWI. Analysis repeated excluding one MWI each time.a.) Modelled exposure to PM10 from a MWI.

Excluded MWI Outcome n cases/ n total births

Risk per doubling in modelled PM10

1 over exposure period2

OR3 95% CIChineham All congenital

anomalies4,988/ 209,489

0.99 0.97-1.01


4,061/ 209,044

0.99 0.97-1.01

Dundee All congenital anomalies

4,929/ 211,393

0.99 0.97-1.02


3,959/ 210,927

0.99 0.97-1.01

Eastcroft All congenital anomalies

4,119/ 170,429

0.99 0.96-1.01


3,342/ 170,048

0.99 0.96-1.02

Isle of Wight All congenital anomalies

5,149/ 219,301

1.00 0.98-1.02


4,169/ 218,835

0.99 0.97-1.02

Marchwood All congenital anomalies

4,565/ 192,980

1.00 0.98-1.02


3,734/ 192,594

0.99 0.97-1.02

Newlincs (Grimsby) All congenital anomalies

4,901/ 208,083

1.00 0.98-1.02


3,950/ 207,637

1.00 0.971.02

Porthmellon All congenital anomalies

5,149/ 219,363

0.98 0.92-1.05


4,168/ 218,898

0.99 0.97-1.02

Portsmouth All congenital anomalies

4,825/ 197,812

1.00 0.97-1.02

All congenital 3,942/ 0.99 0.97-1.02

20

anomalies excl. chromosomal

197,398

Sheffield All congenital anomalies

3,469/ 163,670

1.00 0.98-1.02


2,738/ 163,303

0.99 0.96-1.02

Stockton-on-Tees All congenital anomalies

4,292/ 182,854

1.00 0.99-1.02


3,485/ 182,469

0.99 0.97-1.01

b.) Proximity to a nearest MWI.

Excluded MWI Outcome n cases/ n total births

Risk per km (continuous) closer to MWI

OR3 95% CIChineham All congenital

anomalies4,988/ 209,489

1.02 1.00-1.04


4,061/ 209,044

1.02 1.00-1.04

Dundee All congenital anomalies

4,929/ 211,393

1.02 1.00-1.04


3,959/ 210,927

1.02 1.00-1.04

Eastcroft All congenital anomalies

4,119/ 170,429

1.03 1.01-1.05


3,342/ 170,048

1.03 1.01-1.05

Isle of Wight All congenital anomalies

5,149/ 219,301

1.02 1.00-1.04


4,169/ 218,835

1.02 0.99-1.06

Marchwood All congenital anomalies

4,565/ 192,980

1.02 1.00-1.04


3,734/ 192,594

1.02 1.00-1.04

Newlincs (Grimsby) All congenital anomalies

4,901/ 208,083

1.02 1.01-1.04

All congenital 3,950/ 1.02 1.00-1.04

21

anomalies excl. chromosomal

207,637

Porthmellon All congenital anomalies

5,149/ 219,363

1.02 1.00-1.037


4,168/ 218,898

1.02 0.99-1.06

Portsmouth All congenital anomalies

4,825/ 197,812

1.02 1.00-1.04


3,942/ 197,398

1.02 0.99-1.05

Sheffield All congenital anomalies

3,469/ 163,670

1.01 0.99-1.04


2,738/ 163,303

1.00 0.98-1.03

Stockton-on-Tees All congenital anomalies

4,292/ 182,854

1.02 1.01-1.04


3,485/ 182,469

1.02 1.00-1.04

1 Modelled exposure to mothers (10-3 μg/m3): range 0 – 29.4, IQR 0.14- 0.76, median 0.339, mean 0.64.

2 Exposure is mean modelled PM10 concentration over 91 day pre-pregnancy period plus first trimester of pregnancy unless otherwise specified.

3 Unless otherwise specified in sensitivity analysis description, adjusted for maternal age, year of birth, area level ethnicity, area-level deprivation, other potential sources of emissions, MWI road density (length of motorways, A-roads and B-roads within 10 km of the MWI), individual road density (length of motorways, A-roads and B-roads within 250 m of mother’s postcode); random effect for MWI area and random slope for the exposure.

22

Table S8. Risk of congenital anomaly outcomes associated with proximity to a MWI – Alternative distance distributions.Description of analysis

Unit for OR Outcome OR 95% CI

Distance as binary variable (above/below median)

Risk for distance below median


1.10 1.03-1.18


1.09 1.01-1.19

Inverse distance Risk per km-1 All congenital anomalies

1.14 0.96-1.36


1.10 0.89-1.32

Inverse distance, capped at 1 km

Risk per km-1 All congenital anomalies

1.21 0.97-1.51


1.13 0.88-1.45

Inverse square distance


1.02 0.96-1.08


0.99 0.91-1.08

Inverse square distance, capped at 1 km


1.16 0.95-1.40


1.05 0.83-1.33

23

Regression models.

Table S9. Regression models and covariates*Model Description

Model 1** Unadjusted

Model 2** Adjusted for Maternal age + Year of birth

Model 3** Model 2 + Adjusted for: Area level ethnicity; Deprivation quintile

Model 4** Model 3 + Adjusted for: Other sources of emissions; Major roads

within 10 km of MWI; major roads within 250 m of subject’s

address

Model 5*** Model 4 + random intercept (MWI)

Model 6*** Model 5 + random slope (exposure)

* As well as the models described above, sensitivity analyses were run to examine the

behaviour when adjusting the dataset, confounders or exposures (see Table S5)

** Fixed effects regressions (models 1-4) were performed using the glm function in R

version 3.2.2 (R Core Team 2015).

*** Mixed effects models (models 5 and 6) used the glmer function in the lme4 library

(Bates et al. 2015).

24

Numbers of congenital anomaly cases

Table S10. Numbers of cases by congenital anomaly groups for England and Scotland Congenital anomaly group

ICD10 codes England Scotland Total


Q00 – Q99, D215, D821, D1810, P350, P351, P371

4,929 225 5,154


excl. Q90-Q99 3,959 213 4,172

Nervous system Q00 – Q07 excl. Q0461 & Q0782 525 18 543Congenital heart defects

Q20- Q26 excluding Q2111, Q2541, Q261, Q250 (> 37 weeks gestation), Q256 (> 37 weeks gestation)

1,174 58 1,232


Q792, Q793, Q795, Q7950, Q7951, Q7959

211 11 222

Oro-facial clefts Q35-Q37 326 13 339Limb defects Q65-Q74 excluding Q653-Q656, Q662-

Q678, Q680-685, Q7400702 44 746

Digestive system

Q790, Q38-Q54 excluding Q381, Q382, Q3850, Q400, Q401, Q4021, Q430, Q4320, Q4381, Q4382

336 19 355

Urinary system Q60-Q64 excluding Q794, Q610, Q627, Q633

506 28 534

Genital system Q50-Q52, Q54-Q56 excluding Q523, Q525, Q527, Q5520, Q5521

428 44 472

25

Results of main models with P-values and correction for multiple testing

Table S11. Risk of all congenital anomalies and all congenital anomalies without chromosomal congenital anomalies for modelled emissions and proximity to nearest MWIa.) Modelled emissions from nearest MWI

Outcome n cases/ n total births

Unadjusted Adjusted for maternal age and year of birth

Fully adjusteda

ORb 95% CI P-value ORb 95% CI P-value ORb 95% CI P-valueAll congenital anomalies 5,154/

219,4861.01 1.00-1.03 0.059 1.02 1.01-1.04 0.007 1.00 0.98-1.02 0.651


4,172/ 219,020

1.02 1.00-1.03 0.055 1.02 1.00-1.04 0.024 0.99 0.97-1.01 0.464

b.) Proximity to nearest MWI

Outcome n cases/ n total births


Fully adjusteda

ORc 95% CI P-value ORc 95% CI P-value ORc 95% CI P-valueAll congenital anomalies 5,154/

219,4861.03 1.02-1.04 <0.001 1.03 1.02-1.04 <0.001 1.02 1.00-1.04 0.013


4,172/ 219,020

1.04 1.02-1.05 <0.001 1.04 1.02-1.05 <0.001 1.02 1.00-1.04 0.070

Note: OR, odds ratio; CI, confidence interval.

26

a Adjusted for maternal age, year of birth, area level ethnicity, area-level deprivation, other potential sources of emissions, MWI road density

(length of motorways, A-roads and B-roads within 10 km of the MWI), individual road density (length of motorways, A-roads and B-roads

within 250 m of mother’s postcode); random effect for MWI area and random slope for the exposure.

b Risk per doubling in modelled mean PM10 over exposure period. Modelled exposure to mothers (10-3 μg m-3): range 0 – 20.4, IQR 0.14- 0.76,

median 0.34, mean 0.64. Exposure is mean modelled PM10 concentration over 91 day pre-pregnancy period plus first trimester of pregnancy.

c Risk per km closer to nearest MWI (continuous).

27

Table S12. Risk of congenital anomaly outcomes by congenital anomalies grouping (chromosomal anomalies excluded) for modelled emissions and proximity to nearest MWI.a.) Modelled exposure to PM10 from nearest MWI

n cases/ n total births


Fully Adjusteda

ORb 95% CI

P-value Adjusted P-valuec

ORb 95% CI


ORb 95% CI


Congenital anomaly groupsNervous system

543/215,863

1.02 0.97-1.07

0.407 1.02 0.98-1.07

0.320 0.97 0.92-1.02

0.271

Congenital heart defects

1,232/216,644

1.08 1.05-1.12

<0.001 <0.001 1.09 1.05-1.12

<0.001 <0.001 0.99 0.93-1.05

0.761


222/ 215,788

0.99 0.93-1.07

0.880 0.99 0.92-1.06

0.761 1.00 0.92-1.08

0.943

Oro-facial clefts

339/ 215,931

1.04 0.98-1.10

0.248 1.04 0.98-1.10

0.220 1.00 0.94-1.07

0.970

Limb defects 746/ 216,252

0.92 0.89-0.96

<0.001 <0.001 0.92 0.89-0.96

<0.001 <0.001 1.01 0.94-1.08

0.788

Digestive system

355/ 215,928

1.04 0.98-1.10

0.185 1.038

0.98-1.10

0.208 1.00 0.92-1.09

0.980

Urinary system

534/ 216,037

1.03 0.98-1.08

0.283 1.03 0.98-1.08

0.212 1.00 0.94-1.07

0.925

Genital system

472/ 216,053

0.96 0.92-1.01

0.152 0.97 0.92-1.02

0.204 1.03 0.95-1.13

0.454

Congenital anomaly sub-groupsNeural tube defects

264/ 215,695

1.04 0.97-1.11

0.303 1.04 0.97-1.11

0.282 1.00 0.92-1.07

0.911

28

Severe congenital heart defects

436/ 215,954

1.07 1.02-1.13

0.010 0.100 1.08 1.02-1.13

0.007 0.070 1.03 0.97-1.10

0.280

Gastroschisis 133/ 215,753

1.04 0.95-1.15

0.379 1.03 0.94-1.13

0.547 1.04 0.94-1.15

0.452

Cleft palate 124/ 215,749

1.03 0.94-1.14

0.526 1.032

0.94-1.14

0.527 1.02 0.92-1.13

0.780

Cleft lip with or without cleft palate

217/ 215,822

1.04 0.96-1.12

0.341 1.04 0.97-1.12

0.302 1.00 0.93-1.08

0.931

Limb reductiondefects

122/ 215,725

1.04 0.94-1.15

0.470 1.04 0.94-1.14

0.472 1.02 0.91-1.14

0.701

Oesophageal atresia

51/ 215,681

1.07 0.92-1.25

0.391 1.07 0.92-1.26

0.398 1.04 0.88-1.22

0.637

Anomalies of the renal system

241/ 215,803

1.04 0.97-1.12

0.289 1.04 0.97-1.12

0.282 1.02 0.95-1.10

0.597


255/ 215,840

0.97 0.91-1.04

0.440 0.98 0.91-1.05

0.507 0.97 0.90-1.04

0.344

Hypospadias 407/ 216,004

0.96 0.91-1.01

0.138 0.96 0.91-1.02

0.174 1.00 0.90-1.12

0.981

b.) Proximity to nearest MWI

n cases/ n total


Fully Adjusteda

29

births ORd 95% CI


ORd 95% CI


ORd 95% CI


Congenital anomaly groupsNervous system

543/ 15,863

1.02 0.98-1.05

0.403 1.02 0.98-1.05

0.388 0.97 0.93-1.02

0.206

Congenital Heart Defects

1,232/ 216,644

1.04 1.01-1.06

0.002 0.012 1.04 1.02-1.07

0.001 0.006 1.04 1.01-1.08

0.023 0.161


222/ 215,788

0.97 0.92-1.03

0.359 0.97 0.92-1.03

0.279 1.00 0.94-1.07

0.914

Oro-facial clefts

339/ 215,931

0.99 0.95-1.04

0.742 0.99 0.95-1.04

0.746 0.99 0.94-1.05

0.805

Limb defects 746/ 216,252

1.06 1.03-1.09

<0.001 0.002 1.06 1.03-1.09

<0.001 0.002 1.02 0.97-1.08

0.478

Digestive system

355/ 215,928

0.98 0.93-1.02

0.279 0.97 0.93-1.02

0.258 1.00 0.95-1.06

0.890

Urinary system

534/ 216,037

1.02 0.98-1.06

0.287 1.02 0.98-1.06

0.276 1.02 0.97-1.06

0.475

Genital system

472/ 216,053

1.10 1.06-1.15

<0.001 <0.001 1.10 1.06-1.15

<0.001 <0.001 1.07 1.02-1.12

0.004 0.032

Congenital anomaly sub-groupsNeural tube defects

264/ 215,695

1.00 0.95-1.05

0.946 1.00 0.95-1.05

0.958 0.97 0.91-1.03

0.313

Severe Congenital Heart Defects

436/ 215,954

1.02 0.98-1.07

0.249 1.03 0.99-1.07

0.223 1.02 0.97-1.07

0.453

Gastroschisis 133/ 215,753

0.95 0.88-1.02

0.155 0.94 0.87-1.01

0.094 0.97 0.89-1.05

0.411

Cleft palate 124/ 0.96 0.89- 0.280 0.96 0.89- 0.275 0.98 0.90- 0.596

30

215,749 1.03 1.03 1.06Cleft lip with or without cleft palate

217/ 215,822

1.01 0.95-1.07

0.745 1.01 0.95-1.07

0.738 1.00 0.94-1.07

0.941

Limb reduction defects

122/ 215,725

1.04 0.96-1.12

0.331 1.04 0.96-1.12

0.372 0.98 0.90-1.08

0.724

Oesophageal atresia

51/ 215,681

0.95 0.85-1.07

0.431 0.95 0.85-1.07

0.436 0.92 0.80-1.05

0.216

Anomalies of the renal system

241/ 215,803

1.00 0.95-1.05

0.961 1.00 0.94-1.05

0.914 1.00 0.93-1.07

0.959


255/ 215,840

1.04 0.99-1.10

0.137 1.04 0.99-1.10

0.125 1.03 0.97-1.10

0.304

Hypospadias 407/ 216,004

1.11 1.07-1.16

<0.001 <0.001 1.11 1.07-1.16

<0.001 <0.001 1.07 1.01-1.12

0.015 0.150

Note: OR, odds ratio; CI, confidence interval.

a Adjusted for maternal age, year of birth, area level ethnicity, area-level deprivation, other potential sources of emissions, MWI road density

(length of motorways, A-roads and B-roads within 10 km of the MWI), individual road density (length of motorways, A-roads and B-roads

within 250 m of mother’s postcode); random effect for MWI area and random slope for the exposure.

b Risk per doubling in modelled mean PM10 over exposure period. Modelled exposure to mothers (10-3 μg m-3): range 0 – 20.4, IQR 0.14- 0.76,

median 0.34, mean 0.64. Exposure is mean modelled PM10 concentration over 91 day pre-pregnancy period plus first trimester of pregnancy.

31

c Adjusted P-values using Simes procedure for multiple tests of significance.(Simes 1986) Shown for P-values that are nominally <0.05.

d Risk per km closer to nearest MWI (continuous).

32

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maternal age on obstetric outcome. Obstetrics and Gynecology 105:983-990.Dolk H, Vrijheid M. 2003. The impact of environmental pollution on congenital anomalies. British

Medical Bulletin 68:25-45.Douglas P, Freni-Sterrantino A, Sanchez ML, Ashworth DC, Ghosh RE, Fecht D, et al. 2017. Estimating

particulate exposure from modern municipal waste incinerators in great britain. Environmental Science & Technology 51:7511-7519.

Hoyt AT, Canfield MA, Romitti PA, Botto LD, Anderka MT, Krikov SV, et al. 2016. Associations between maternal periconceptional exposure to secondhand tobacco smoke and major birth defects. American Journal of Obstetrics and Gynecology 215.

Knowles RL, Ridout D, Crowe S, Bull C, Wray J, Tregay J, et al. 2017. Ethnic and socioeconomic variation in incidence of congenital heart defects. Archives of Disease in Childhood 102:496-502.

Lee LJ, Lupo PJ. 2013. Maternal smoking during pregnancy and the risk of congenital heart defects in offspring: A systematic review and metaanalysis. Pediatric Cardiology 34:398-407.

R Core Team. 2015. R: A language and environment for statistical computing. R foundation for statistical computing, vienna, austria. Available from: Https://www.R-project.Org/.

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van der Zanden LFM, van Rooij I, Feitz WFJ, Franke B, Knoers N, Roeleveld N. 2012. Aetiology of hypospadias: A systematic review of genes and environment. Human Reproduction Update 18:260-283.

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ICD codes and descriptions used in the project · Web viewTetralogy of Fallot Q220 Pulmonary valve atresia Q224 Congenital tricuspid stenosis Q225 Ebstein's anomaly Q226 Hypoplastic