IJE Advance Access published online on April 9, 2008
International Journal of Epidemiology, doi:10.1093/ije/dyn070
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Pre-natal exposure to paracetamol and risk of wheezing and asthma in children: A birth cohort study
1Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
2Municipal Institute of Medical Research (IMIM-Hospital del Mar), Barcelona, Spain.
3Autonomous University of Barcelona, Barcelona, Spain.
4CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
5Medical School, University of Crete, Heraklion, Greece.
6Department of Clinical Epidemiology, Aarhus University Hospital, Denmark.
7Department of Epidemiology, Boston University, MA, USA.
8The Institute of Public Health, University of Aarhus, DK-80000, Aarhus, Denmark.
9Department of Epidemiology, School of Public Health, UCLA, Los Angeles, USA.
*Corresponding author. Centre for Research in Environmental Epidemiology—Municipal Institute of Medical Research, Dr Aigüader 88, E-08003 Barcelona, Spain. E-mail: crebordosa{at}imim.es
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Abstract |
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Background Paracetamol use has been associated with increased prevalence of asthma in children and adults, and one study reported an association between pre-natal exposure to paracetamol and asthma in early childhood.
Methods To examine if pre-natal exposure to paracetamol is associated with the risk of asthma or wheezing in early childhood, we selected 66 445 women from the Danish National Birth Cohort for whom we had information on paracetamol use during pregnancy and who participated in an interview when their children were 18-months-old and 12 733 women whose children had reached the age of 7 and estimated the prevalence of physician-diagnosed asthma and wheezing at the ages of 18 months and 7 years. We also linked our population to the Danish National Hospital Registry to record all hospitalizations due to asthma up to age of 18 months.
Results Paracetamol use during any time of pregnancy was associated with a small but statistically significant increased risk of physician-diagnosed asthma or bronchitis among children at 18 months [relative risk (RR) = 1.17, 1.13–1.23)], hospitalizations due to asthma up to 18 months (hazard ratio = 1.24, 1.11–1.38) and physician-diagnosed asthma at 7 years (RR = 1.15, 1.02–1.29). The highest risks were observed for paracetamol use during the first trimester of pregnancy and persistent wheezing (wheezing at both 18 months and 7 years) (RR = 1.45, 1.13–1.85).
Conclusion Paracetamol use during pregnancy was associated with an increased risk of asthma and wheezing in childhood. If this association is causal, we may need to revisit the clinical practice on use of paracetamol during pregnancy.
Keywords Analgesics, non-steroidal anti-inflammatory drugs, paracetamol, acetaminophen, pregnancy, child development, asthma, wheezing
Accepted 17 March 2008
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Introduction |
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Paracetamol is frequently used in many populations1–2 and an increase in asthma prevalence among paracetamol users has been found in both genders and in different age groups and geographic regions.3–7
The Avon Longitudinal Study of Parents and Children (ALSPAC)8–9 found an increased prevalence of wheezing at 30–42 months (OR = 2.10, 95% CI: 1.30–3.41) among children whose mothers used paracetamol ‘most days’ during late pregnancy (20–32 weeks gestational age), and an increased prevalence of asthma at 69–81 months (OR = 1.22, 95% CI: 1.06–1.41) among children whose mothers used paracetamol ‘sometimes’ during late pregnancy. In spite of this paracetamol is believed to have no foetotoxic effects in therapeutic doses and is often the pain reliever of choice during pregnancy.10 Apparently, the ALSPAC study has not convinced the clinical community and it needs to be corroborated by other data.
A dose-dependent decrease in levels of the anti-oxidant glutathione in the lungs is a possible mechanism between paracetamol use and asthma11–16 but ‘reverse causation’ must also be considered. Some authors suggest that acetylsalicylic acid (aspirin) and other non-steroidal anti-inflammatory drugs (NSAIDs) may be avoided by some asthmatic women11–13 and this would lead to artificially increased risks associated with alternative analgesics such as paracetamol.3,17,18
We evaluated the association between paracetamol use during pregnancy (in utero exposure) and asthma in children at 18 months and 7 years of age.
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Methods |
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The Danish National Birth Cohort (DNBC) is a population-based cohort study of approximately 100 000 newborns recruited between 1996 and 2003. Women were asked to complete a self-administered enrolment questionnaire and participate in four telephone interviews (two during pregnancy and two more when the child was 6 months and 18 months of age). Women enrolled early in the study had at the time of our study completed a fifth self-administered questionnaire when the child was 7-years-old. An English version of all the questionnaires can be found at http://www.bsmb.dk.19
From 90 549 women in the cohort who gave birth to a singleton and provided information on paracetamol use during pregnancy, we selected 66 445 women who took part in the 18-month interview and 12 733 mothers who completed a fifth questionnaire when their child reached the age of 7. Among the 12 733 women answering the fifth interview, 9900 had also completed the 18-months interview (Figure 1).
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Drug use
Information about paracetamol, aspirin and ibuprofen use was obtained from the interviews. Women were asked for the use of any kind of painkiller and to identify the drugs from a list of 44 specific painkillers including paracetamol available in Denmark. The same procedure was done for drugs used for joint and muscle diseases, inflammations, infections, fever, allergy, asthma and several other diseases. They were also asked to indicate the specific gestational weeks of use, on a week-by-week basis. Duration of exposure was defined as total number of weeks exposed within each trimester. Number of pills per week was only collected in the second and third interview, thus we could not estimate the dose taken in early pregnancy. Information about paracetamol use by the child was obtained from the 6 months- and the 18-months-old interviews; questions were more open and less indication-driven than those asked during pregnancy and not all possible indications for which paracetamol can be used were asked.
Asthma outcomes
When the children were 18-months-old, their mothers were asked if they had ever had wheezing or whistling and if a physician had ever diagnosed them with asthma or bronchitis. At the 7-year interview, the International Study of Asthma and Allergies in Childhood (ISAAC)20 questionnaire was used to get information about their children's asthma symptoms, physician-diagnosed asthma, ever wheezing or whistling and wheezing or whistling in the past 12 months. Transient wheezing was defined as occurring only in the first 18 months of life; late onset wheezing as occurring only the past 12 months at the age of 7 years and persistent wheezing as symptoms reported in both time periods. Using Danish residents’ unique civil registration numbers to link to the Danish National Hospital Registry we identified all children's hospitalizations due to or with asthma and bronchitis.
Statistical analysis
Poisson regression with robust estimation of error was used to compute cumulative incidence risk ratios for having had physician-diagnosed asthma at 18 months or 7 years and prevalence risk ratios for wheezing in the past 18 months. Cox proportional regression models were used to compute hazard ratios (HR) of hospitalization due to asthma and/or bronchitis up to the age of 18 months. Hereafter, we use the notation relative risk (RR) for all relative effect measures. Follow-up started on the date of birth and ended at the time of the first hospitalization for asthma and/or bronchitis, death, emigration or at 18 months of age, which ever came first. We adjusted for a priori selected variables described as asthma risk factors in several other studies, including mother's asthma, gestational age at birth, gender of the child, socio-economic status, duration of breastfeeding, smoking during pregnancy and antibiotic use during pregnancy. An additional list of potential confounders was also evaluated but none of them changed risk estimates (Table 1). Linearity of the association between duration of use and the endpoint was evaluated by using generalized additive models. Statistical analysis was performed with Stata 8.0 software (Stata Corporation, College Station, TX, USA). Ethical approval was obtained from the Ethics Committee for the Municipalities of Copenhagen and Frederiksberg (reference number j. no (KF) 01-471/94).
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Results |
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Socio-demographic and other characteristics of the population are presented in Table 1. Baseline characteristics for the full cohort (N = 90 549), the 18 months cohort (N = 66 445) and the 7-years-old cohort (N = 12 733) were compared and no differences were found between respondents and the full cohort.
Paracetamol was used by 30% (n = 19 988) of women from the 18-months-old population during the first trimester of pregnancy, 23% (n = 15 034) in the second trimester, 30% (n = 19 508) in the third and 54.7% (n = 36 316) ever during pregnancy. Similarly, for the 7-years-old population the figures were 3786 (29.8%), 2523 (19.8%) and 3237 (25.4%) and 6752 (53%).
The distribution of asthma-related outcomes is reported in Table 2. The estimated cumulative incidence of physician-diagnosed asthma or bronchitis at 18 months of age was higher than the cumulative incidence of asthma alone estimated at 7 years of age, probably due to the fact that the question in the 18-month interview included diagnosed asthma and bronchitis, since the two diagnoses are difficult to separate at that age and to a certain degree of recall bias. RRs in Table 2 are shown for each trimester separately. Risk estimates do not change substantially when exposure during a particular trimester is adjusted for exposure in other trimesters (not shown).
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Pre-natal exposure to paracetamol was associated with wheezing and asthma both at 18 months and at 7 years of age (Table 2). An increased RR of physician-diagnosed asthma at 7 years of age was associated with paracetamol use during the first and the third trimester and ever use during pregnancy. Paracetamol use during the first trimester was also associated with an increased RR of wheezing in the past 12 months when children were 7-years-old. These estimates changed little when compared with a crude model (no adjustments) or an adjusted model that did not include parental asthma. Compared with the results presented in Table 2, the crude RR of physician diagnosed asthma or bronchitis at 18 months associated to paracetamol exposure ever during pregnancy was RR = 1.23 (95% CI: 1.19–1.27) and when excluding parental asthma from the fully adjusted model the RR was RR = 1.20 (95% CI: 1.15–1.24). For physician-diagnosed asthma at 7 years, the crude RR was RR = 1.22 (95% CI: 1.11–1.34) and the risk when excluding parental asthma was RR = 1.17 (95% CI: 1.04–1.31).
The highest risk was observed for the association between paracetamol use in the first trimester and persistent wheezing. Persistent wheezing was also associated with paracetamol use during the third trimester; however, after adjusting for exposure during the other trimesters, only paracetamol use in the first trimester remained statistically significant (RR = 1.35, 95% CI: 1.02–1.78). The crude estimate for persistent asthma associated to paracetamol exposure during the first trimester was RR = 1.47 (95%CI: 1.20–1.80) and the estimate excluding only parental asthma from the fully adjusted model was RR = 1.41 (95% CI: 1.10–1.81). A subgroup of mothers used paracetamol only in the first trimester and the asthma risk for their children was RR = 1.50, (95% CI: 1.02–2.21), compared with unexposed children during their entire pregnancy.
Use of paracetamol during pregnancy was associated with an increase in the rate of hospitalizations up to 18 months of age for asthma (HR = 1.24, 95% CI: 1.11–1.38) and asthma or bronchitis (HR = 1.22, 95% CI: 1.10–1.36) (Table 2), but not for hospitalizations due to bronchitis only (HR = 1.08, 95% CI: 0.74–1.56).
The association between paracetamol use during pregnancy and wheezing at 18 months (RR = 1.14, 95% CI: 1.10–1.17) remained statistically significant when we restricted the analysis to children who had been exposed to the drug only during pregnancy. Information on use of paracetamol by the child after birth was completed by a small percentage of the population and indicated that use of paracetamol both pre- and post-natally (RR = 1.3, 95% CI: 1.19–1.44) was associated with a higher risk than only post-natal use (RR = 1.22, 95% CI: 1.07–1.38). Similar results were obtained for physician-diagnosed asthma/bronchitis.
There was no general pattern of asthma risk associated with use of aspirin or ibuprofen ever during pregnancy (Table 3) neither for use in specific trimesters.
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Pain was the main reason for paracetamol use. Among the 49 029 women who reported having taken paracetamol during pregnancy, 44 139 (91%) answered that they used paracetamol when asked for drugs taken for pain, 15 897 (32%) when they were asked for fever, 7900 (16%) when they were asked for infection or inflammation and 9591 (20%) when they were asked for drugs taken for muscle or joint diseases. Most women that used paracetamol for pain also reported use for other indications. Only 8725 women (18%) used paracetamol only for fever without pain, 5578 (11%) only for infection or inflammation and 4318 (9%) only for muscle or joint diseases. Adjusting the models for indication of use did not modify the risk estimates for paracetamol use nor did the estimates change when stratifying for indication of use. No effect modification or interaction was seen, except for a small increase of the risk associated with use of paracetamol when the indication of use was inflammation or infection (RR = 1.30, 95% CI 1.17–1.44). When stratifying by antibiotics use, (that have also been implicated in children's asthma), those women who had inflammation or infection but did not use antibiotics had an increased risk of physician diagnosed asthma at 18 months (RR = 1.26, 95% CI 1.07–1.48) that was slightly lower than the risk for those who used antibiotics (RR = 1.38, 95% CI 1.16–1.52).
Since confounding by indication is also expected to be present for other pain killers, we examined children exposed to these drugs. Risks for wheezing and for physician-diagnosed asthma at 18 months among children whose mothers took only paracetamol during pregnancy were similar to those whose mother took both paracetamol and aspirin (Table 4). In contrast, risks were lower for children whose mothers took only aspirin. Results were similar for asthma and wheezing at 7 years of age.
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Use of paracetamol during the first trimester was associated with severity of asthma attacks at 7 years of age, measured as the number of wheezing attacks affecting sleep. Compared with children who never woke up with wheezing in the last 12 months, a statistically significant increased risk was observed for wheezing attacks affecting sleep less than once a week (RR = 1.27, 95% CI: 1.03–1.57) and for wheezing attacks affecting sleep one or more nights per week (RR = 1.68, 95%CI: 1.06–2.66) (see Supplementary Table S5 available at IJE online).
Total number of weeks of paracetamol use during the entire pregnancy, or weeks of use within specific trimesters, was not associated with a higher probability of having a child with asthma or wheezing at the age of 7 years (data not shown).
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Discussion |
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Children pre-natally exposed to paracetamol had a slightly increased risk of wheezing and physician-diagnosed asthma at 18 months and at 7 years of age, especially for use of paracetamol during the first trimester of pregnancy and asthma and wheezing at the age of 7. Also, pre-natal exposure to paracetamol was associated with an increased risk of hospitalization due to asthma. These associations did not appear to be confounded by indication for mothers’ use nor by post-natal paracetamol use or by parental asthma risk. Similar associations were not seen for pre-natal exposures to other painkillers.
Our data corroborate the findings made in the ALSPAC cohort but we also found discrepancies. Our data indicate the highest risk to be associated with first trimester exposure and not third trimester exposure as the ALSPAC9–10 study suggests and our associations were lower than those reported by the ALSPAC study.
Although the findings were robust in our analysis, we cannot rule out uncontrolled confounding a possible explanation of the association. The lack of a dose response effect is probably less important, since timing of exposure is often more important than the dose during pregnancy.
Paracetamol crosses the placenta and the observed increased risk may be related to the limited capacity of the foetus to metabolize paracetamol. In adults, the main detoxification pathway of paracetamol is glucuronidation to the non-toxic metabolite glucuronide, while in the foetus the main metabolic pathway initially involves sulphation. Glucuronidation starts at the 18th gestational week and increases until the 23rd week-a pattern that could be related to an increased risk from exposure in the first trimester.21 Metabolism of paracetamol to the highly reactive oxide N-acetyl-p-benzoquinoneimine (NAPQI), depends on the activity of the cytochrome P450 system and on Glutathione S Transferase (GST). In adults, cytochrome P450 enzymes metabolize 4–5% of the paracetamol to NAPQI, and this percentage increases when glucuronidation and sulphation are saturated.21,22 NAPQI is then detoxified by GST. The expression of GST in the lung of the foetus progressively decreases after week 15 of gestation, and this could be related to an increase in risk from use of paracetamol in the third trimester.23, 24
A paracetamol dose-dependent decrease in levels of the anti-oxidant glutathione in the lung has been proposed. Recent studies25–27 suggest that glutathione depletion in the lung may occur in relatively low doses. This may reduce the capacity to counteract the toxic effects of NAPQI and may affect the response to oxidative stress and possibly also to impaired antigen processing.
Avoiding NSAIDs may exert an effect on the lungs mediated by the lack of suppression of COX, an anti-inflammatory pathway that promotes prostaglandin E2 production in favour of T-helper type 2 response while inhibiting T-helper type I lymphocytes. This would promote an allergic tendency in the immune response to various antigenic stimuli. Yet, another possible mechanism is an immune-modulating IgE mediated effect of paracetamol as an antigenic agent, which would increase asthma provocation.11–16,28
Among the potential biases affecting our results, differential exposure misclassification is unlikely since the reported drug use was recorded before birth. Outcome misclassification is present to some extent but is hardly influenced by pre-natal exposure to a common drug that it is not well known to have a potential effect on asthma, and two different data sources provided consistent estimates of asthma prevalence. Women with asthma might be more likely to take paracetamol instead of aspirin or other NSAIDs, but our estimates did not change when we adjusted for indications for its use, mother's history of allergy or eczema, nor did we see any associations for other painkillers used for similar indications.
An important limitation of our study is the limited data we have on post-natal drug use in children. Risks for pre-natal exposure to paracetamol were similar after adjustment for children's use of paracetamol reported to the first 18 months of age. However, the reported prevalence of use of paracetamol up to 18 months of age is much lower than what is described in other studies29,30 and might be underreported due to incomplete exposure assessment.
Possible adverse effects related to the use of paracetamol in pregnancy need further investigation, especially regarding the possible duration of an effect and the importance of combined pre-natal and post-natal exposures.
Pre-natal exposure to paracetamol may be one of several causes of asthma. Although the associations we found were moderate, the health consequences may well be important due to the frequent use of this drug during pregnancy and the high prevalence of asthma in childhood. Long term health consequences of drug use during pregnancy for the offspring should always be considered.
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Supplementary data |
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Supplementary data are available at IJE online.
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Acknowledgements |
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We acknowledge Inge Eisensee (Danish Epidemiology Science Centre, University of Aarhus) for dataset preparation and Estel Plana (Centre for Research in Environmental Epidemiology) for her support in data management and analysis. We are especially grateful to the physicians, nurses, interviewers and mothers without whose participation the study would not have been possible. This work was funded by the Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is, furthermore, a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation and the Health Foundation. C.R. was partly supported by the Spanish Ministry of Health (Carlos III Institute, ISCIII-CM06/00118) and by the European Union Sixth Framework Program (FP6-2003-Food-3-A), and this article will be part of her PhD thesis at the Autonomous University of Barcelona. The authors work was independent of the funders.
Conflict of interest: None declared.
KEY MESSAGES
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1 Headley J, Northstone K, Simmons H, Golding J, ALSPAC Study Team. Medication use during pregnancy: data from the Avon Longitudinal Study of parents and children. Eur J Clin Pharmacol (2004) 60:355–61.[Web of Science][Medline]
2 Werler MM, Mitchell AA, Hernandez-Diaz S, Honein MA. Use of over-the-counter medications during pregnancy. Am J Obstet Gynecol (2005) 193:771–77.[CrossRef][Web of Science][Medline]
3 Barr RG, Wentowski CC, Curhan GC, et al. Prospective Study of Acetaminophen use and newly diagnosed asthma among women. Am J Respi Crit Care Med (2004) 169:836–41.
4 Newson RB, Shaheen SO, Chinn S, Burney PGJ. Paracetamol sales and atopic disease in children and adults: an ecological analysis. Eur Respir J (2000) 16:817–23.[Abstract]
5 Shaheen SO, Sterne JAC, Songhurst CE, Burney PGJ. Frequent paracetamol use and asthma in adults. Thorax (2000) 55:266–70.
6 McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA. The Association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am J Respir Crit Care Med (2005) 171:966–71.
7 Davey G, Berhane Y, Duncan P, Aref-Adib G, Britton J, Venn A. Use of acetaminophen and the risk of self-reported allergic symptoms and skin sensitization in Butajira, Ethiopia. J Allergy Clin Immunol (2005) 116:863–68.[CrossRef][Web of Science][Medline]
8 Shaheen SO, Newson RB, Sherriff A, et al. Paracetamol use in pregnancy and wheezing in early childhood. Thorax (2002) 57:958–63.
9 Shaheen SO, Newson RB, Henderson AJ, et al. Prenatal paracetamol exposure and risk of asthma and elevated immunoglobulin E in childhood. Clin Exp Allergy (2005) 35:18–25.[CrossRef][Web of Science][Medline]
10 Rathmell JP, Viscomi CM, Ashburn MA. Management of nonobstetric pain during pregnancy and lactation. Anesth Analg (1997) 85:1074–87.[CrossRef][Web of Science][Medline]
11 Allmers H. Frequent acetaminophen use and allergic diseases: is association clear? J Allergy Clin Immunol (2005) 116:859–62.[CrossRef][Web of Science][Medline]
12 Nuttall SL, Williams J, Kendall MJ. Does paracetamol cause asthma? J Allergy Clin Immunol (2003) 28:251–57.
13 Eneli I, Sadri K, Camargo C Jr, Barr RG. Acetaminophen and risk of asthma: the epidemiologic and pathophysiologic evidence. Chest (2005) 127:604–12.[CrossRef][Web of Science][Medline]
14 Fogarty A, Davey G. Paracetamol, antioxidants and asthma. Clin Exp Allergy (2005) 35:700–02.[CrossRef][Web of Science][Medline]
15 Dimova S, Hoet PHM, Dinsdale D, Nemery B. Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro. IJBCB (2005) 37:1727–37.
16 Dimova S, Hoet PHM, Nemery B. Paracetamol (acetaminophen) cytotoxicity in rat type II pneumocytes and alveolar macrophages in vitro. Biochem Pharmacol (2000) 59:1467–75.[CrossRef][Web of Science][Medline]
17 Lesko SM, Mitchell AA. The Safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics (1999) 104:39–43.[CrossRef]
18 Lesko SM, Louik C, Vezina RM, Mitchell AA. Asthma morbidity after short-term use of ibuprofen in children. Pediatrics (2002) 109:20–23.[CrossRef]
19 Olsen J, Melbye M, Olsen SF, et al. The Danish National Birth Cohort—its background, structure and aim. Scand J Public Health (2001) 29:300–7.
20 The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC). Eur Respir J (1998) 12:315–35.[Abstract]
21 Wilkes JM, Clark LE, Herrera JL. Acetaminophen overdose in pregnancy. South Med Assoc (2005) 98:1118–22.
22 Klaassen CD. Cassarett, & Doul
s: Toxicology. The basic science of poisons. (2001) 6th edn. NY: Mc Graw-Hill.
23 Fryer AA, Hume R, Strange RC. The development of glutathione S-transferase and glutathione peroxidise activities in human lung. Biochim Biophys Acta (1986) 883:448–53.[Medline]
24 Cossar D, Bell J, Strange R, Jones M, Sandinson A, Hume R. The alpha and pi isoenzymes of glutathione S-transferase in human fetal lung: in utero ontogeny compared with differentiation in lung organ culture. Biochim Biophys Acta (1990) 1037:1467–75.
25 Ludmir J, Main DM, Landon MB, Gabbe SG. Maternal acetaminophen overdose at 15 weeks of gestation. Obstet Gynecol (1986) 67:750–51.[Web of Science][Medline]
26 Nuttall Sl, Khan JN, Thorpe GH, Path FRC, Langford N, Kendall MJ. The impact of therapeutic doses of paracetamol on serum total antioxidant capacity. J Clin Pharm Ther (2003) 28:289–94.[CrossRef][Web of Science][Medline]
27 Rollins DE, von Bahr C, Glaumann H, Moldens P, Rane A. Acetaminophen: potentially toxic metabolite. Science (1979) 205:1414–16.
28 Wong ICK, Furnes J, MacDonald F, et al. Paracetamol and asthma. Thorax (2000) 55:882–4.
29 Headley J, Northstone K. Medication administered to children from 0 to 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Eur J Clin Pharmacol (2007) 63:189–95.[CrossRef][Web of Science][Medline]
30 Walsh A, Edwards H, Fraser J. Over-the-counter medication use for childhood fever: A cross-sectional study of Australian parents. J Paediatr Child Health (2007) 43:601–6.[CrossRef][Web of Science][Medline]
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