Between April 1997 and June 2000, a total of 3,413 women were invited to participate in a study of asthma in pregnancy (). Pregnant women with a history of physician-diagnosed asthma (n=1,343) and a simple random sample of pregnant women without asthma (n=2,070) were recruited while receiving prenatal care from 56 private obstetric practices and 15 clinics at six hospitals in southern New England (Bridgeport, Danbury, Hartford, and New Haven, Connecticut, and Springfield, Massachusetts). After accounting for refusals (n=531), ineligibility at the home interview, usually because they were more than 24 weeks pregnant (n=389), miscarriages (n=73), and nonparticipation for other reasons (n=41), 2,379 women (69.7%) were enrolled in the study. After enrollment, 174 women were excluded from analysis because of a stillborn fetus, molar pregnancy, a planned or spontaneous abortion (n=69), multiple birth (n=43), loss to follow-up or withdrawal (n=60), or inadequate information on asthma status (n=2). Of the singleton live births eligible for study, 1,871 children, including those with mothers with diagnosed asthma (n=872), mothers with asthma symptoms or taking asthma medication (n=449), and a random sample of mothers without asthma (n=550), were selected for subsequent follow-up. After excluding non-English speakers (n=61) and neonatal deaths (n=3), 1,807 women were eligible for the interview at 6-year follow-up. Of the eligible women, 302 women were excluded because of refusal, inability to locate, and missed interviews. Finally, 1,505 women were interviewed and included in the analysis.
Flowchart of patients showing inclusion and exclusions applied to the total cohort population for the acetaminophen and asthma analysis.
The Human Investigation Committee of Yale University (New Haven, Connecticut) approved this study, and all respondents provided informed consent before participation.
At enrollment, women were interviewed at home before 24 weeks of gestation. The standardized questionnaire administered included indepth questions about demographic factors, pregnancy history, health care use, smoking, asthma history, activity limitations due to asthma, household exposures, and other chronic conditions during the year before pregnancy and the period since conception. A postpartum interview was conducted in the hospital (n=1,344) or by telephone within 1 month of delivery (n=544). Data on pregnancy outcomes were abstracted from hospital delivery records. Information related to infancy and early childhood was collected during the structured interview (n= 1,505) when the child was 6 years (±3 months) of age.
Information on acetaminophen use was obtained before 24 weeks of gestation from the following questions in the prenatal questionnaire: “Have you taken any medications for asthma, allergies, sinus, respiratory, or other breathing problems? Please include over-the-counter medication as well as prescription medications” and “Have you taken any medications or drugs (including over-the-counter and prescription drugs) other than those for respiratory conditions during the first 3 months of the pregnancy?” If a respondent answered affirmatively, a follow-up question resulted: “What is the name of the drug or medication that you used? Please include strength, form, and whether it was prescription or over-the-counter.” To measure frequency and dose of the medication, respondents were asked, “How often did you use this medication in the first, second, and third months of the pregnancy?” with responses in the following categories: none, 1–7 days per month, 8–14 days per month, more than 14 days (but not every day) per month, and every day. They were also asked, “How many tablets or doses of the medication did you usually take per day during this month?” The same set of questions was repeated during the post-partum interview to ascertain acetaminophen use during the last 3 months of the pregnancy.
All reported medications taken by the women were investigated to determine the active ingredients and, particularly, the total milligrams of acetaminophen contained, if any. This information was obtained from drug labels, the manufacturers, or other online drug indexes. An imputation method was used to estimate the total milligrams of acetaminophen in the drug where this information was not easily accessible or clearly evident (n=61). Uncertain amounts of acetaminophen in such drugs were substituted using total milligrams of acetaminophen of similar medications in the data set. Ever use of any medication that contained acetaminophen was classified as use of acetaminophen during the first and third trimester of pregnancy. Information on second-trimester exposure was not ascertained.
To explore the cumulative dose response, average monthly acetaminophen consumption during pregnancy was calculated. The dose was divided into six levels: 0, 1,300 or less, 1,301–2,600, 2,601–5,200, 5,201–10,400, and more than 10,400 mg per month, where 1,300 mg is equivalent to four tablets of regular-strength acetaminophen at 325 mg each. Additional exposure evaluations, based on the average consumption by the participant per day of use during the first and third trimesters, were performed. The dose was divided into four levels: 0, 650 or less, 651–1,300, and more than 1,300 mg per day of use. The categorical response for days per month (0, 1–7 days per month, 8–14 days per month, more than 14 days [but not every day] per month, and every day) were reassigned to their median values (0, 4, 11, 21, and 30 days per month) for the calculation of the dose and level for each participant. For women who used more than one medication containing acetaminophen in 1 month, it was assumed that the medications were taken on different days of the same month. Additional exposure evaluations, based on the assumption that multiple acetaminophen medications were taken on the same days of the month, were performed as a sensitivity analysis. The calculations and formulas are available on request.
When the child was 6 years (±3 months) old, the mothers were asked, “Has the child ever been diagnosed by a doctor or health professional as having asthma?” Mothers were also asked, “Has your child ever had wheezing or whistling in the chest at any time in the past?” and, if yes, “Has your child had wheezing or whistling in the chest in the last 12 months?” The primary outcome in this analysis was physician-diagnosed asthma ever with history of wheezing at the sixth year of age. Positive responses to both questions were considered a positive asthma outcome. In addition, phenotypes for persistent wheezing, ever wheezing, diagnosed bronchitis, sneezing/runny nose ever, and allergy were examined to allow more direct comparison with other reports in the literature.
Information on a large number of potential con-founding variables was collected from the interviews conducted during early pregnancy, postpartum, and at 6-year follow-up. Confounders measured during the first and second interviews were mother’s demo-graphics (age, ethnicity, marital status, and education), mother’s smoking and exposure to passive smoking during pregnancy, mother’s diagnosed asthma and other health conditions (asthma symptoms and high blood pressure during pregnancy, and diagnosed/treated allergies), offspring’s gestational age at birth and low birth weight, and preterm labor and delivery. Confounders measured during the interview at 6-year follow up were father’s ethnicity and education, history of father’s asthma and other health conditions (wheezing, allergies, and eczema), mother’s diagnosed or treated eczema, yearly household income, household exposures (mold/mildew growth at home and water leaks/damage at home during child’s first year, pets inside home and cockroaches observed in home during child’s first and sixth years), use of various home appliances (use of wood-burning stove, wood-burning fireplace, unvented gas fire-place/space heater, portable kerosene heater, gas stove, continuously burning pilot light, and air conditioner during sixth year), child’s ethnicity, number of biologic siblings, attendance at a program before elementary school, child’s asthma symptoms (wheezing and persistent cough in the first year, cough, shortness of breath, and chest tightness in the sixth year), use of emergency room and overnight stay at the hospital for asthma, allergy, or respiratory illnesses, use of neonatal intensive care unit and pediatric intensive care unit, use of intubation/ventilation in neonatal intensive care unit and pediatric intensive care unit, breastfeeding, child’s exposure to tobacco smoke for 2 hours or more ever, mother’s use of antibiotics while breastfeeding, child’s use of antibiotics and allergy medications, and child’s infections and respiratory illnesses (allergies, sneezing/ runny nose, hay fever, itchy rash, eczema, bronchitis, bronchiolitis, pneumonia, croup, ear infection, strep throat, sinus infection, respiratory syncytial virus, and tonsillitis).
Analysis of the effect of prenatal exposure to acetaminophen was conducted with logistic regression models using SAS 9.1 Proc Logistic (SAS Institute, Inc., Cary, NC). Odds ratios (ORs) were estimated for asthma, associated with different categories of acetaminophen use, compared with never use. For each combination of exposure and outcome, the unadjusted OR and adjusted OR were obtained, adjusting for potential confounders from pregnancy, the perinatal period, and early childhood. Covariates were initially selected for inclusion in the model by identifying those significantly associated with both the exposure and the outcome at P≤.10. Final adjusted models were constructed using a backward elimination statistical procedure that includes only those covariates resulting in a change of 10% or greater in the parameter estimate of acetaminophen exposure. The study was able to detect at least a 52% increased risk of asthma with 90% power.