Hum. Reprod.

Advance Access published December 5, 2012
Human Reproduction, Vol.0, No.0 pp. 1– 9, 2012 doi:10.1093/humrep/des398

ORIGINAL ARTICLE Reproductive epidemiology

Asthma in children born after infertility treatment: findings from the UK Millennium Cohort Study
C. Carson 1,*, A. Sacker 2, Y. Kelly 2, M. Redshaw 1, J.J. Kurinczuk 1, and M.A. Quigley 1
1

National Perinatal Epidemiology Unit, University of Oxford, Oxford OX3 7LF, UK 2Institute for Social and Economic Research, University of Essex, Colchester CO4 3SQ, UK *Correspondence address. claire.carson@npeu.ox.ac.uk

Downloaded from http://humrep.oxfordjournals.org/ by guest on December 24, 2012

Submitted on October 24, 2011; resubmitted on October 10, 2012; accepted on October 19, 2012

study question: Is asthma more common in children born after subfertility and assisted reproduction technologies (ART)? summary answer: Yes. Asthma, wheezing in the last year and anti-asthmatic medication were all more common in children born
after a prolonged time to conception (TTC). This was driven specifically by an increase in children born after ART.

what is known already: Few studies have investigated any association between ART and asthma in subsequent children, and
findings to date have been mixed. A large registry-based study found an increase in asthma medication in ART children but suggests underlying infertility is the putative risk factor. Little is known about asthma in children after unplanned or mistimed conceptions.

study design, size, duration: The Millennium Cohort Study is a UK-wide, prospective study of 18 818 children recruited at 9 months of age. Follow-up is ongoing. This study analyses data from follow-up surveys at 5 and 7 years of age (response rates of 79 and 70%, respectively). participants/materials, setting, methods: Singleton children whose natural mothers provided follow-up data were
included. Mothers reported whether their pregnancy was planned; planners provided TTC and details of any ART. The population was divided into ‘unplanned’ (unplanned and unhappy), ‘mistimed’ (unplanned but happy), ‘planned’ (planned, TTC , 12 months), ‘untreated subfertile’ (planned, TTC .12 months), ‘ovulation induced’ (received clomiphene citrate) and ‘ART’ (IVF or ICSI). The primary analysis used the planned children as the comparison group; secondary analysis compared the treatment groups to the children born to untreated subfertile parents. Outcomes were parent report of asthma and wheezing at 5 and 7 years, derived from validated questions in the International Study of Asthma and Allergies in Childhood, plus use of anti-asthmatic medications. A total of 13 041 (72%) children with full data on asthma and confounders were included at 5 years of age, and 11 585 (64%) at 7 years.

main results and the role of chance: Compared with planned children, those born to subfertile parents were significantly more likely to experience asthma, wheezing and to be taking anti-asthmatics at 5 years of age [adjusted odds ratio (OR): 1.39 (95% confidence interval (CI): 1.07, 1.80), OR: 1.27 (1.00, 1.63) and OR: 1.90 (1.32,2.74), respectively]. This association was mainly related to an increase among children born after ART (adjusted OR: 2.65 (1.48, 4.76), OR: 1.97, (1.10, 3.53) and OR: 4.67 (2.20, 9.94) for asthma, wheezing and taking anti-asthmatics, respectively). The association was also present, though reduced, at the age of 7 years. limitations, reasons for caution: The number of singletons born after ART was relatively small (n ¼ 104), and as such the
findings should be interpreted with caution. However, data on a wide range of possible confounding and mediating factors were available and analysed. The data were weighted for non-response to minimize selection bias.

wider implications of the findings: The findings add to the growing body of evidence suggesting an association between subfertility, ART and asthma in children. Further work is needed to establish causality and elucidate the underlying mechanism. These findings are generalizable to singletons only, and further work on multiples is needed.

& The Author 2012. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

one of the few large observational studies where data are available on conception status. At each interview mothers were also asked whether their child was taking any medication (pills. 2002.. complex. TTC . Patel et al.. In this study we assess the effects of pregnancy planning. and resident in the UK at 9 months. large registry-based study of Swedish children concluded that those born after assisted reproduction techniques (ART). We describe the prevalence of asthma medications. syrups or other liquids.. Klemetti et al. (vi) ART (planned.. ovulation induction (OI) (planned. including prenatal.... time to conception (TTC) and ART on asthma and wheezing in children at 5 and 7 years of age. Asher et al.. asthma diagnosis and key confounding factors. was drawn from the Department of Social Security Child Benefit Registers.2 Carson et al. 2007. 5 and 7 years. used ovulation inducing drugs such as clomiphene citrate). Baseline interviews captured socio-demographic and health data. The questions were taken from the International Study of Asthma and Allergies in Childhood (ISAAC) core questionnaire for asthma. and the children were subsequently followed up at 3.oxfordjournals. A random two-stage sample of all Age and sex of cohort member Known risk factors: mother’s history of asthma—reflecting a possible genetic component in the development of asthma in the child. These included the following. and therefore reflects severity of the condition. happy about pregnancy).. it was estimated that 1–5-year-old children with wheezing in the UK cost the health service a total of £53 million (Stevens et al. and gene-by-environment interactions (Subbarao et al. ‘Planners’ were then asked how long they took to conceive and if they received fertility treatment. 2012 Asthma and wheezing illness outcomes At 5 and 7 years mothers were asked about asthma and wheezing illnesses including occurrence..12 months). and also a possible link between maternal asthma and fertility owing to shared metabolic roots (Real et al. Materials and Methods The MCS The MCS is a nationally representative prospective cohort study of 18 818 children across the UK (Hansen. untreated subfertile (planned. 2005). Finnstrom et al. such as IVF. Children with asthma require more contact with doctors than non-sufferers. identified from the British National Formulary codes. Asthma can limit a child’s daily life. obstructive lung disease characterized by acute symptomatic episodes of bronchial restriction. patches. Others analysing Scandinavian registry data have also reported a significant increase in the use of asthma medications and hospitalization among children conceived after infertility treatment (Ericson et al. breathlessness and wheezing... 2009. Koivurova et al. We present findings from the UK Millennium Cohort Study (MCS). low birthweight and Caesarean delivery. 2008). Ethical approval for the Millennium Cohort Study was granted from the multi-centre research ethics committee. 2009).. Since these children were taking a daily dose it is likely that this reflects a maintenance dose of inhaled corticosteroids. creams. A recent. mistimed (unplanned. environmental and genetic factors.12 months). used ART such as IVF or ICSI). and may require medication and hospitalization. unhappy about pregnancy). There is still limited understanding of the aetiology of asthma but there are many identified risk factors for the condition. consideration of confounding factors and differing measures of asthma. which indicated a potential association with both the outcome and the exposure. Women were grouped into the following categories: (i) (ii) (iii) (iv) (v) unplanned (unplanned. 2003). TTC . making it one of the most common chronic childhood conditions (Kaur et al. and if so what was the name of the medication.. Potential confounding factors The factors which may potentially explain any observed association between conception history and asthma were identified from the literature. planned (planned. study funding/competing interest(s): This study was funded by a Medical Research Council project grant. In 2003. Conception history Mothers were asked if they had planned to conceive. 2007) or effects of anti-asthmatic . and how they felt when they discovered they were pregnant. 2006). including information on pregnancy and infertility treatment. This validated instrument has been widely used to measure childhood asthma and wheezing illnesses (Asher et al. The prevalence of childhood asthma is high in the UK: approximately one in five children are diagnosed by a doctor. 2010). frequency and severity indicators for each child. though some researchers have found no effect (Pinborg et al.org/ by guest on December 24. inhalers. In this study the main outcomes analysed are ‘ever had asthma’ and ‘wheezing in the last 12 months’ at the age of 5 and 7 years. were more likely to be prescribed anti-asthmatic medication compared with naturally conceived children but the underlying duration of subfertility appeared to be the putative risk factor rather than an effect of treatment (Kallen et al. 1998). 2003. suppositories or injections) prescribed by a doctor or hospital on a regular basis (every day for two weeks or more). Data for 5 and 7 years are presented here. 1998. The inconsistent results could be related to variations in participation rates. Downloaded from http://humrep. infants born in 2000 –2002.. social activities and may result in missed school days which then impacts on parents working life (Sennhauser et al. 2012). Smaller clinic-based studies in Turkish and American populations have found no increased risk of asthma after infertility treatment (Cetinkaya et al. No competing interests.. Sicignano et al. 2008). such as prescription records or self-report. 1995. Key words: infertility / assisted reproduction techniques / asthma / unplanned pregnancy Introduction Asthma is a chronic. Pregnancy-related risk factors for asthma include preterm birth. 2011).

2012 Statistical analysis First. 4. respectively].07. the effect was reduced at 7 years [OR: 1. delivery type and breastfeeding.39 (1. one parent currently smokes. socioeconomic and behavioural factors. respectively.58) at 5 and 7 years.9% (104) were born following ART (Table I). and were more likely to experience a Caesarean delivery (all P-values . see Table III]: they were more likely to be taking anti-asthmatic medications than their planned peers. cohabiting or married). while 1.. 2008). 2008.4% (173) had ovulation inducing drugs and 0. 52% of mothers (6575/13 041) reported a planned pregnancy. included as there is an evidence of a protective effect). to be born to less wealthy and less well-educated parents. All analyses took the clustered. non-white). mother’s age at birth of child. 15% of mothers reported that they felt unhappy or ambivalent about the pregnancy (‘unplanned’ n ¼ 2039). 1. Compared with the planned. mother’s BMI (because of link between maternal pre-pregnancy BMI and childhood asthma (Reichman and Nepomnyaschy. mother’s qualifications (National Vocational Qualifications or equivalent groups). Mothers in the unplanned groups were also more likely to smoke in pregnancy. ‘. we examined the effect of overall subfertility. Next. 2007). This group of children born after ART was also considerably more likely to be taking anti-asthmatic medications than the planned. on average. and maternal BMI and subfertility (van der Steeg et al. furry pets in household.org/ by guest on December 24. normal TTC Results Description of study population Figure 1 shows the study population. adjusted for gestational age.97 (1. 2008)). children born to parents who experienced a prolonged TTC (.84 (1. Considered separately. born at an earlier gestation and lower birthweight than the children from other groups. by combining the untreated subfertile.50 (0. though this did not reach statistical significance at the 5% level [e. 0. number of siblings in household. damp/condensation in the home (potential irritants and allergens).g.77. we investigated whether the treatment groups were at a higher risk than the untreated subfertile group.10. ethnicity (white. All reported estimates are weighted by sampling and non-response weights to account for missing data owing to non-response at later sweeps (Hansen. 0. 1. 0. assessed whether there was any evidence that the effect of conception group on asthma was mediated via these factors. four categories). 2007).84.65 (1. family type (lone parent. 42% (5684/13 041) of children were born after an unplanned pregnancy. unadjusted OR: 1.12 . fertile group. conceived in . while 27% of mothers were happy (‘mistimed’ n ¼ 3645).00. Children born after ART were. however. had lower educational attainment and a more disadvantaged socioeconomic position. Potential mediating factors Possible mediating factors considered to be on the causal pathway between conception group and childhood asthma included gestational age (in weeks). Boys are more likely to be asthmatic than girls (17 versus 12%).48.83) and OR: 1. Wheezing in the last year was more prevalent in the younger age group (16 versus 12% at ages of 5 and 7 years). Downloaded from http://humrep. fully adjusted OR: 1.76) and 1. parental smoking (coded as mother smoked during pregnancy. both parents currently smoke). polluted residential area (environmental effects).05) after controlling for other factors in the model. wheezing and medications) adjusting for potential confounding factors.53) for asthma and wheezing. instrumental or Caesarean section). 1.34 (0. OI and ART groups and comparing these to the planned pregnancies. we explored whether there were different effects dependent on degrees of infertility or treatment by separating out the untreated subfertile. A doubling in risk was seen at 5 years [adj OR: 2.15 (0. breastfeeding (coded as ‘none’. though the use of anti-asthmatic medications was again more common. Plewis.42). parent smoked earlier in childhood. by using children of untreated subfertile couples as the comparison group. family income.98. for asthma OR: 1. Asthma in subfertile and infertility treatment groups In comparison with the planned group. A final model.12 months) regardless of subsequent fertility treatment were significantly more likely to report asthma [at 5 years.28 (95% confidence interval (CI): 1. The children of mothers who underwent OI treatment showed no increase in asthma or wheezing symptoms. P .03. who were less likely to be in a relationship. 3.Conception history and childhood asthma 3 months (‘planned group’). 3. For each of these comparisons.80)]. to be born earlier and at a lower birthweight and were less likely to be breastfed than the children without asthma. delivery type (vaginal. Approximately 15% of the study population had asthma at ages of 5 and 7 years (the prevalence of asthma and related symptoms is shown in Table II). with details of exclusions and non-response.28) and OR: 1. medication on fertility (Kallen and Olausson.001 for the unplanned group compared with the normal TTC group). ‘. Children born after ART. 2009).4 months’.oxfordjournals. OI and ART groups and comparing them to the children born after planned pregnancies. children born after a prolonged TTC but conceived without fertility treatment (untreated subfertile group) showed a small increase in the odds of asthma or wheezing symptoms at both 5 and 7 years. were significantly more likely to have asthma at both 5 and 7 years of age and adjustment for confounding factors strengthened the observed association. Table I shows clear and consistent differences across the conception groups in terms of demographic. the unplanned children were generally born to younger mothers. Potential confounders were included if they were statistically significantly associated with the outcome at the 5% level (indicated by a Wald. type of childcare at the age of 3 years (both to try to capture some exposure to infections). Finally.001 for the ART group compared with the normal TTC group). Table 1 shows many of the expected differences in key risk factors between children with and without a doctor diagnosis of asthma. stratified study design into account by using the ‘survey commands’ in Stata version 11SE (StataCorp. Children with asthma are more likely to have a family history of asthma. 2. a further 4% (505) conceived after 12 months or longer (untreated ‘subfertile group’).92)].4 months’. 1. logistic regression was used to estimate odds ratios (OR) for the three outcomes (asthma. Sociodemographic factors: household socioeconomic position (higher of mother/father using UK National Statistics socioeconomic class. less likely to breastfeed and more likely to report damp housing or polluted residential areas (all P-values .

20. 9.31) and OR: 0.67 (2. 5.42 (1.20.34. though this is not seen at the age of 7 years.24) at 5 and 7 years. particularly by social circumstances. pattern is seen for wheezing in the last year at the age of 5 years.16)]. 1. gestational age and breastfeeding behaviour were seen to be independently associated with asthma but the effect of including these variables in the models of the association between conception group and asthma was minimal [adjusted OR for asthma in the ART group at 5 years. though the observed effects in the unadjusted analyses are smaller. group [adj OR: 4. ‘wheezing in the last year’ and prescribed asthma medications.09.29 (1. Among the potential mediators.96 (0.11 (0. but this is attenuated when adjusted for confounding factors [OR: 1.38 (1. 1. respectively].30 (1.oxfordjournals. Reported daily use of anti-asthmatic medications in the unplanned group is higher at the age of 5 years than among the planned group. including response as a percentage of those eligible at baseline. The effect was smaller at 7 years and no longer statistically significant. This association varies in strength but appears consistently across a number of indicators. breastfeeding and Caesarean section in the model: OR: 2. it is apparent from the adjusted analyses that this is likely to be a result of confounding.org/ by guest on December 24. While unadjusted results also suggest that unplanned and mistimed children are at greater risk of asthma and wheezing. Downloaded from http://humrep. 1. 4. including ‘ever had asthma’.94) and 2.79. There was no evidence of a difference between the untreated subfertile and the OI groups (see Table IV). When compared with the children born to untreated subfertile couples. respectively]. The pattern is identical for the mistimed group. Asthma and pregnancy planning Unadjusted analyses consistently indicate that unplanned children are more likely to have an asthma diagnosis than their planned peers [OR: 1. 2012 Figure 1 Flowchart to show study population.4 Carson et al.67) and OR: 1. A similar . and that this effect is greatest among those conceived following ART. but by the age of 7 years there is no evidence of an increase even in the unadjusted analysis.94.54) at 5 and 7 years. Discussion In this study of 13 000 UK children we found some evidence that subfertility is associated with an increased risk of asthma in subsequent children. 1.00. including gestational age. the ART group was significantly more likely to report an asthma diagnosis and asthma medications at 5 years.24)].

.... 2007.1 5.......9 3. Finnstrom et al.5 8.... mean) Preterm birth (.. ovulation induction..2 28. with OI only or following ART) with the children of parents who planned their conception and conceived in less than 12 months.2 24..... Prof/mgt...5 23.....org/ by guest on December 24.1 24..3 5.2 20....5 50.3 20..6 28....7 30....9 13...6 51. professional/management....0 27... Downloaded from http://humrep.. mean) Gestational age (weeks.....5 33...9 39..0 21.2 33..5 5..4 28.1 18.0 8.............5 44..8 3.1 29.4 27......5 42. The first compared the children of subfertile couples (who conceived with no treatment...4 35....34 39...... environmental problems—only available at 9 months.......8 12... However.6 8..... 2011.....5 6.6 5.33 39.2 7.... Other observational studies..2 11.3 25...7 51. wt% indicates percentages weighted for effects of sampling and non-response.2 18.6 29..........1 41..7 3.5 3..1 18..4 16........1 13..2 15..9 13..6 1956 (14....5 48.......9 41. 2006)..43 39...9 48....8 31..7 3.........9 29..0 20.. 2009... Unplanned 2039 (15.8 18..Conception history and childhood asthma 5 Table I Description of the study population from the UK Millennium Cohort Study (MCS) at 5-year survey (n 5 13 041).9 6....7 43..8 20.7) No 11 085 (85.....6 20..9 6...7 29........0 17.4 21.2 30..8 49...6 8.5 18.5 10. National Vocational Qualifications level 4/5 are equivalent to certificates of Higher education and above.6 38. which have been smaller and clinic based.5 48..3 48...7) Conception group Planned 6575 (51......33 39...6 57.6 26. Prof/ mgt (wt%) Maternal education.. grime.2 6.7 9.7 69...3 11.1 16......4 9.6 14.8 40.6 9.6 3..4 14.7 20.6 5. 2012 NVQ 4/5. The overall picture presented by our results is one of an increased risk of asthma in children born after infertility treatment..... normal TTC group the children born to subfertile parents were more likely to suffer from asthma and to be taking anti-asthmatic .16 38....9 13..3 39.29 38..8 2.. 2012) and hospitalizations among ART-conceived children (Ericson et al.4 20.5 16... Sicignano et al. Reported asthma Yes Unweighted n (wt%) Socio-demographic factors Mother’s age at birth of cohort member (years) Socioeconomic position....2 49.2 3...4 48...0 42...1 8.0 12.......5 5. NVQ 4/5 (wt%) Highest household income band ≥£52 000 (wt%) Single parent families (wt%) Ethnicity (non-white) (wt%) Possible risk factors Male child (wt%) Mother’s history of asthma (wt%) Mother’s pre-pregnancy BMI ..5 48.3 36....7 29..8 21.1 20.. have not reported any increase in asthma in ART children but these studies suffered from low participation (and thus potential selection bias) and were unable to control for key confounding factors (Cetinkaya et al....6 4.4 26..7 20.4 26..3 3.. OI... 2003.......2 10..0 7....8 11. assisted reproduction technologies.9 22.oxfordjournals...2 9.7 22. Subfertile 505 (4.30 kg/m2 (obese) One or both parents currently smoke (wt%) No siblings in household (wt%) Attended formal childcare (wt%)a Furry pets in household (wt%) House has damp problem (wt%) Residential area considered polluted (wt%)b Potential mediating factors Caesarean delivery (wt%) Birthweight (kg.. ART.3 44.2 32.....2 10. a At 3 years..7 51.7 15.....0 3..9 38.0 33. Koivurova et al...0 40.8 50......0) OI 173 (1. 2010)...9 32.......2 46...8 22..9) .8) ...7 10.1 7..........4 8....3) Mistimed 3645 (26...32 39...3 1...3) ... 2002....2 21... The existing literature on asthma after ART conception is limited but our findings are consistent with the findings of the larger Scandinavian registry-based studies which found an increase in both asthma medications (Finnstrom et al.8 6. 2011).0 21.4) ART 104 (0... Klemetti et al.2 31...9 8.7 7.9 45.0 20..5 28.1 34.6 37.... The second compared the different groups of subfertile couples to explore the influence of severity of infertility and the effects of infertility treatment... In the present study we found that in comparison with the planned...2 6. Asthma in children born to subfertile and infertile couples The effects of subfertility on asthma in the subsequent children were assessed in two ways.2 9.0 16...2 7..9 46..... Kallen et al....39 39.....37 weeks gestation) Breastfeeding ≥4 months (wt%) 22.. b Parents reported that residential area has problems with pollution.7 24. this is not always identified (Pinborg et al.9 10.9 17....

....48..... Asthmatic women are more likely to report prolonged childlessness (Kallen and Olausson.. suggesting that overreporting is not a major issue because you might expect to see it across all these relatively common conditions..... there is little effect of infertility treatment on patterns of asthma (measured by prescribed asthma medications) (Kallen et al........... It has also been reported that a greater than expected proportion of women undergoing IVF report the use of antiasthmatics (Kallen and Olausson.. 4..9 17.....72)].............3............ and that these medications are associated with annovulatory infertility (Svanes et al.....0 4.... A larger Swedish study has indicated that once duration of unwanted childlessness is accounted for.. There are other hypotheses about causal factors which we could not address in this analysis as the data were not available [e.4 17....4 15......3 11. 2012)... Tata et al. parents who sought medical help to conceive may be more likely to seek medical help for their child and therefore get a diagnosis of asthma or medication prescribed. there is no increase in other atopic conditions in this population [eczema and hayfever (data on request)]...org/ by guest on December 24..6 Carson et al. however... Asthma indicator Conception status Unplanned Unweighted n (asthma)/N Age 5 years Age 7 years Asthma Age 5 years Age 7 years Wheezing in the last year Age 5 years Age 7 years Asthma medicationsa Age 5 years Age 7 years 5...oxfordjournals... 2005).......7 18.. Downloaded from http://humrep...2 3.....9 16. or a consequence of the treatment: these data do not allow us to distinguish between the two possibilities.. This is not seen in our data..98 (1......... using appropriate weights for each sweep)..... and a shared aetiology (such as insulin resistance) has been hypothesized (Real et al.........65 (1.2 months versus 38. At 5 years ART children were .4 13. They also have a shorter average TTC than the untreated subfertile group (mean: 29..... Mistimed Planned Subfertile OI ART Total . 2007). it should be noted that in this population the OI group appear to be quite different from the other subfertile groups: they have a higher prevalence of obesity [which is associated with anovulation and polycystic ovary syndrome (PCOS)] and on average they are also wealthier.. If the risk of asthma in children was associated simply with prolonged infertility you may also expect to see an increase in risk among the OI group..... Subbarao et al. However.. a These are prescribed medications (any pills.5 times as likely to have asthma as the planned group [adjusted OR: 2.....9 23.... and twice as likely as the untreated subfertile group [adj OR: 1....7 11. Another possibility is that the results are related to residual confounding...........6 14..8 13.06...... though this appears to be a result of increases in asthma prevalence in the comparison group between 5 and 7 years.9 15. 2009) by looking at firstborn status.. and it has been suggested that folate supplementation in pregnancy can result in poorer respiratory outcomes in young children (Whitrow et al......... 2005.. Table II Prevalence of asthma and related symptoms in the MCS cohort (wt %. albeit smaller than that experienced by the ART group. perhaps suggesting that they are not representative of a ‘more infertile’ group but instead represent a more demanding subgroup who actively sought intervention and earlier treatment...2 4... Oligomennorhea (common in PCOS) has been found to be associated with both asthma and lung function. syrups or other liquids...0 11...2 12. though there is little evidence that this affects the eventual number of pregnancies or live births (Forastiere et al.....7 22.... 2007).5 372/2039 347/1827 580/3645 559/3217 885/6575 896/5837 83/505 83/463 18/173 23/154 18/104 18/87 1956/13 041 1926/11 585 .. 2007).... 2007)..8 13.... One possibility is overreporting by excessively protective ART parents.8 4..... If the observed increase in asthma among ART children is real..........3 16.... The observed effects are reduced by 7 years of age..... siblings and childcare type to try to capture some measure of exposure to infections but there could still be an unknown or unmeasured confounder driving the observed association... 2012 wt% indicates percentages weighted for effects of sampling and non-response.g. Similarly.... suppositories or injections) taken every day for 2 weeks or more..... more highly educated and their children are more likely to be in formal childcare by 3 years (perhaps indicating a return of parent(s) to the workforce). The higher risk we observed in the ART group could be related to an increased severity of infertility..7 18.........76)]. patches.......... medications........ inhalers... OI and ART it becomes clear that it is the ART group that is at highest risk of asthma..2 14........1 11.7 6............8 9..1 5. When the subfertile group was divided up into untreated subfertility. one must consider what may be driving this association.8 15...8 17... Our findings are adjusted for recognized risk factors..8 5...8 3..2 6.......... and we have tried to account for theories such as the ‘hygiene hypothesis’ (Strachan. 2009)]. 1989.8 7........... supplement use might be higher in women who have had fertility problems.............3 months)..0 4....6 22. rather than a reduction in the ART group....4 3....0 15........ perhaps suggesting earlier diagnosis in the ART children.... Parent reported the name of the medication and those used to treat asthma were identified from British National Formulary codes....0 16...0 17. .......3 16........8 12..... creams.2.......

2005.90) 1.67 (2....60 1.57 (0..07.77.94... we must consider that the observed association could be causal but we cannot as yet explain the mechanism.. and by subgroup....13....95.11) 1....24 (0.10 (0....... .77...28 (1.11 (1.. 3.24) Anti-asthmatic medications taken daily Odds ratios (95% confidence interval) presented for all subfertile...17) Wheezing in the last year Downloaded from http://humrep.. family smoking...48. 1.94.63 (1..78) 1.. The relatively small ART sample also demands that findings should be interpreted with caution.42) 1. identifying only the most serious cases.. 1. 1.86) 1...00. 3.. 3... 8..95.. 2. 4.88 (0...65 (0...66 (0. not just hospitalization or medication records..09.89.57 (0. The comparison group remains the ‘Planned.20....51) 1.64) 1..74) 1..27 (1. 1......63) 1. 2. 1..66) 1.34) 1. 1.78) 1..59 (1.34) 1...33 (1.20.70) 1.72.94..95..oxfordjournals..... 1.22 (0.. 1.. 2...95 (0. 5...67 (1..16. 1.11(0. 1.43) 1. in the MCS only children taking daily medications in the last 2 weeks are identified. 1.... social class... We controlled for maternal asthma and the effects persist.... 3....87. the sample included only 104 singletons born after ART...32.... maternal age.02.01 (0.28) 1.16..92) 1. 1.53) 1.. 1..08..52 (0.... siblings and pets in the home Italics indicate subgroups within the ‘All subfertile’ category...84..97 (1.84..55) 1. 5.44) 2..04 (0. 1..23 (0.23 (0... The use of antiasthmatic medications may be considered a more stringent outcome definition.. 3.05...81..03(0.. controlling for effects of confounding factors: Age 5: maternal history of asthma. 1.20.34) 1.... It should also be noted that asthma medications may be prescribed more to the children with the most concerned and health-conscious parents and that this may therefore be higher in the ART group (Cardol et al.03. normal TTC’ group. 2.....10....83.. and this is reflected in our results.76..98. 1... 2.......... 1......97...39) 1.63) 1.92. Finally.... 1..30..97.87 (1..65 (1.00 (0.12 (0.....22 (0.77..65) 1.17 (0.60) 1.......21 (1...13 (0. it is clear from the adjusted analyses that it is differences in social circumstances that explain most of the association.. Zuidgeest et al. 1....Conception history and childhood asthma 7 Table III Odds ratios for asthma.........57) 1...15 (0.76 (1.... 2...96..96 (0.80) 1.. 1. 1.53. among the children for whom we had data on paternal asthma..07.. family type. Asthma has a genetic component (Subbarao et al...31) 1.98 (0..07....18 (0...41) 0.76) 1.85..22 (0...91.61........30 (1.72. 3..96 (0..97 (0..43) 1.92...64 (0.90 (1..org/ by guest on December 24.23 (1...15) Comparison group 1....60) 0..15 (0.54) 1....33..93. 1.95..42) 1.86....38) 1.03 (0.. 1. Asthma Unplanned Mistimed Planned All Subfertile Untreated OI ART Unplanned Mistimed Planned All Subfertile Untreated OI ART Unplanned Mistimed Planned All Subfertile Untreated OI ART 2039 3645 6575 782 505 173 104 2039 3645 6575 782 505 173 104 2039 3645 6575 782 505 173 104 1....51 (0.. 1. an effect which persists after adjustment for confounding.22) 1.34) Comparison group 1..51) 4.. family smoking..30) 1... the parents of the unplanned pregnancy group report higher use of anti-asthmatic medication.. which precluded analysis by type of infertility treatment (IVF.94. 1...10 (0....79. family income.94. wheezing and medications at 5 and 7 years in each conception group. However. controlling for this made little difference (data on request)...51) 1. 3..00.06....65 (0.48 (1. 1... 3. 1.58) 1.. 2012 1.88....97. We were able to use a validated outcome measure (ISAAC questions). 1. 1..72) 0.. Age 7: maternal history of asthma.60) 0..65 (0. 1.. 2009).... 1...10 (1..46) 2.58..81) 1. 1.....34 (0.. 3...57.... so it may be that higher asthma in subfertile women would lead to higher asthma prevalence in their children... this is the only observational study of conception status and childhood asthma in a UK population.82... Group . 2... n Adjusted for sex only Fully adjusted model Age 5 years Age 7 years n .... 9. 1. 1..... normal time to conception’ children. 1...58) 1.38) 1..27 (0. 1.....16) 0..18 (0. 2..41) 1. There is a well-recognized socioeconomic gradient in childhood asthma (Subbarao et al....68.21 (0. At the age of 5 years.. compared with ‘planned...34..77.22) Comparison group 1.24) Comparison group 1.98.61) 2.41) 1. Strengths and Limitations To our knowledge.76) 1... 2.. 1.......84 (1.. 2009)..55) Comparison group 1...28) 0.. Adjusted for sex only Fully adjusted model ..55) 4..94..34 (1.. 1...08 (0.. ICSI).08 (0.20) 1..15..73. 1. 1.83) 0..39 (1.. Asthma in children born after unplanned and mistimed pregnancies Though the unadjusted analyses suggest that unplanned and mistimed children are more likely to be asthmatic...00...29 (1..56 (1.37 (1.00. 1..59) 1..24 (1...73 (0. 2009).. 3. Fully adjusted models.50 (0.84........15 (0...00..19) Comparison group 1. 1.. 1.57) 1.41) 2. 1.94) 1827 3217 5837 704 463 154 87 1826 3217 5837 704 463 154 87 1827 3217 5837 704 463 154 87 1..42 (1..21 (0. Further investigation is needed to disentangle the relative effects of prolonged subfertility and its treatment on asthma in the children.. 1. 2. 1.67) 1..68) 0.12) 1.10) 1.. 1..51 (0.

72) 463 153 87 0.. References Asher MI.. J....39.. Children born after ART have a much higher risk....35 (0...... however.39) 1....85) Comparison group 0...... there remains a possibility of residual confounding by unmeasured or unknown risk factors.8 Carson et al..12) 0.. Response was socially patterned and non-response weights.. Authors’ roles M..28....59 (0.. 2. 2.37) 1. 2. 1.. no treatment OI ART 505 173 104 505 170 104 1.09) 1...... Beasley R..39) 1.. International ........ family smoking. 3........ Pearce N.. All authors were involved in the design of the study and the interpretation of findings...80......... then the mechanism driving it remains unknown and further research in this area is warranted... this is consistent with recognized temporal changes in the prevalence and diagnosing of asthma. 1.. 1.. Adjusted for sex only Fully adjusted model .. University of Oxford...Q......01 (0. 2.. Funding to pay the Open Access publication charges for this article was provided by the National Perinatal Epidemiology Unit... is the principal investigator for this project...... and based at the NPEU...... and remains evident at 7 years.72 (0.32) 1.42...... Mitchell EA. 3...81) 1.. Y.. However.42...... 1. Acknowledgements We would like to thank all the children and their families who participate in the MCS.13) Comparison group 0..61. social class.. wheezing and the use of antiasthmatic medications are higher among children born to subfertile couples than those who conceived in less than 12 months.48 (0..... siblings and pets in the home.. 2012 1.93 (0..08) 1. Conclusion Our findings suggest that asthma.50 (0..60. maternal age.. no treatment OI ART Wheezing in the last year Subfertile....64....... 1. C.... Keil U..89) . completed the analysis and the first draft of the manuscript..26.. 1....87.10 (0.. 2004)].. 2.... acts as a guarantor. The MCS is designed to provide a representative sample of the UK population........J. family income......52.. Table IV Comparing the subfertile groups: odds ratios (95% confidence interval) for asthma.C.Q..65 (0.70 (0.. This data set included data on the most important potential explanatory factors... Martinez F. Funding This project was funded by a grant from the Medical Research Council...74) 2.R.88..73 (1.09 (0...27...71) Comparison group 1... the findings are only generalizable to the singleton population causal. awarded to M. however..... 5....K.....67) 1. 6..94) 0.... Since the analysis was restricted to singletons..87) Comparison group 1.. Age 7: maternal history of asthma. All authors contributed to the writing of the final document.. University of Oxford...47........81....45 (0....55 (0.. which take into account factors such as socioeconomic position.....S..79) 3.54 (0.03 (0.......58) Comparison group 0.. wheezing and medications at 5 and 7 years in each infertility treatment group.44.44......75) Comparison group 505 173 104 0... 1.. 3.org/ by guest on December 24..... 2.. family smoking...A.57.. and A.....06..79) 463 153 87 463 153 87 1.79) Fully adjusted models. Anti-asthmatic medications taken daily Downloaded from http://humrep. controlling for effects of confounding factors: Age 5: maternal history of asthma.... rather than simply comparing ART conceptions to all other children.59 (0. though the size of the effect is diminished...... though we cannot determine if this is indicative of a treatment effect or related to a greater degree of subfertility in this group of parents..81 (0.. C.. 2..... 2.... Anderson HR.46. Crane J.....10 (1.. If the observed association is Conflict of interest None declared........C.. M.. so unlike previous studies we were able to control for many key confounding factors.. Sibbald B............59 (0.. missing data owing to loss to follow-up can result in bias in cohort studies.62. Stewart AW et al. no treatment OI ART Subfertile..oxfordjournals. 2...88...... the data did not allow the exploration of possible causal pathways..... were used in the analysis to minimize the effects. This is most apparent at the age of 5 years.. Detailed data on conception history also provided the opportunity to examine the effect of a full range of conception histories.43.......... Adjusted for sex only Fully adjusted model Age 7 years n .....98 (1.. family type.. Group Age 5 years n Asthma Subfertile......... Although we attempted to examine the effects of possible mediating variables.. compared with the untreated subfertile group.......79 (0..25) 1.. The prevalence of asthma in our population (15%) is lower than estimates for prevalence in children in the UK in the 1990s from either ISAAC [23% in 1864 6– 7 year olds in Sunderland (1998)] or the Health Survey for England [21% of 2 –15 year old children in England (Gupta and Strachan.. 2.K..44) 1. 1.. 4.....01 (0..39...........30 (0..

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