Preconceptional exposure to oral contraceptive pills and the risk of wheeze, asthma and rhinitis in children

Abstract

Background

The prevalence of maternal oral contraceptive pills (OCP) use and that of childhood asthma are high in western countries. The aim of this study is to examine the association of OCP use with childhood wheeze and allergic diseases in Japan.

Methods

Relevant data were extracted from a hospital based birth cohort study named as Tokyo-Childrens Health, Illness and Development Study (T-CHILD) of which questionnaire conducted during pregnancy included maternal history and duration of OCP use. To identify wheeze and allergic diseases in the children, the questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC) was used. Logistic regression models were applied to estimate those association and adjustments were made for maternal history of allergy, maternal education level, maternal age at pregnancy, maternal BMI, maternal smoking during pregnancy, mode of delivery, gestational age at delivery, daycare attendance, number of previous live births, and gender of child.

Results

OCP use was associated with ever wheeze (adjusted odds ratio [aOR], 1.62; 95% confidence interval [CI], 1.10–2.40), current wheeze (aOR, 1.59; 95% CI, 1.01–2.50), ever asthma (aOR, 1.65; 95% CI, 1.02–2.65), and ever rhinitis (aOR, 1.90; 95% CI, 1.30–2.80). Compared with no prior OCP use, using OCP for more than three months statistically increased the odds of ever wheeze (P = 0.012), current wheeze (P = 0.035), and ever rhinitis (P = 0.002).

Conclusions

Our findings suggest that maternal OCP use has a role in the development of wheeze, asthma and rhinitis in children. Extended use of OCP is likely to increase the risk of wheeze and rhinitis.

Keywords

Asthma; Birth cohort; Oral contraceptives; Rhinitis; Wheeze

Abbreviations

OCP, oral contraceptive pills; ISAAC, the International Study of Asthma and Allergies in Childhood; BMI, Body Mass Index; DOHaD, Developmental Origins of Health and Disease

Introduction

First wave of allergic epidemic occurred in westernized countries including Japan drew attention mainly on asthma and its prevalence has reached high plateau in recent decades,¹ followed by second wave from developing countries. Although Japan has been a top runner of this undesirable race in the Asia-Pacific region, now prevalence of allergic diseases such as asthma, atopic eczema, and rhinoconjunctivitis among young schoolchildren have become high in many countries in this region.^2 and 3 Environmental changes elicited by rapid industrialization and affluent life might have interacted genetic function resulting in the epidemic of asthma and allergic diseases.⁴

The emerging concept of Developmental Origins of Health and Disease (DOHaD) hypothesis suggests that various environmental exposures during preconceptional and postconceptional period for embryo and fetus may contribute to development of non-communicable diseases for children.^5 and 6 The cause and development of allergy are complicated and need further investigation.

In western affluent countries, oral contraceptive pills (OCP) use has become common and an association of OCP use with childhood wheeze and asthma was reported in several studies from western countries, although conclusions were mixed.^{7, 8 and 9} The aim of our study was to elucidate the relationship between OCP use and childhood asthma and allergic disease in Japan located outside region of western countries.

We examined whether a history of maternal OCP use and the duration of the usage before pregnancy were associated with wheeze and allergic features in five-year-old children.

Methods

Study design was a hospital based prospective birth cohort study, which was named as Tokyo-Childrens Health, Illness and Development study (T-CHILD study).^10 and 11 We recruited 1701 pregnant women at the first antenatal visit at the National Center for Child Health and Development (NCCHD) in Tokyo Japan between 2003 and 2005. Among neonates born from these women, a total of 1550 newborn babies and their mothers were registered in this cohort from March 2004 to August 2006. Baseline data were collected from questionnaires answered by mothers during pregnancy and their medical charts. Outcome data of children at 5 years old were obtained from the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire which was translated into Japanese and validated through the process of back translation under cooperation of the sterling committee members. The definitions of outcomes and exposures are described in Table 1. Potential confounders were maternal history of allergy (asthma, atopic dermatitis, or allergic rhinitis), maternal education level, maternal age at delivery, maternal body mass index (BMI) at recruitment, maternal smoking during pregnancy, caesarean section, gestational age at delivery, number of previous live births, daycare attendance at age of one and gender.

Table 1. Definitions of outcomes and exposures.

Outcomes of children at five years old
Wheeze ever	a positive answer to the question at five years old of the children: “Has your child ever had wheezing or whistling in the chest at any time in the past?”
Wheeze current	a positive answer to the question at five years old of the children: “Has your child ever had wheezing or whistling in the past 12 months?”
Asthma ever	a positive answer to the question at five years old of the children: “Have you ever had asthma?”
Asthma current	a positive answer to the question at five years old of the children: “Has your child ever been diagnosed by a doctor as having asthma in the past 12 months?”
Rhinitis ever	a positive answer to the question at five years old of the children: “Has your child ever had a problem with sneezing, or a runny, or blocked nose when he/she DID NOT have a cold or the flu?”
Rhinitis current	a positive answer to the question at five years old of the children: “In the past 12 months, has your child had a problem with sneezing, or a runny, or blocked nose when he/she DID NOT have a cold or the flu?”
Eczema ever	a positive answer to the question at five years old of the children: “Have your child ever had eczema?”
Eczema current	a positive answer to the question at five years old of the children: “Has your child had this itchy rash at any time in the past 12 months?” and “Has this itchy rash at any time affected any of the following places: the folds of the elbows, behind the knees, in front of the ankles, under the buttocks, or around the neck, ears or eyes?”
Exposures of COP
Past history of OCP use	a positive answer to the question of the base line data, “Have you ever used the pill?”.
Duration of OCP use	a positive answer to the question of the base line data, “How long have you ever used the pill totally?” and it was classified into three groups, (not use, OCP 1–6 months use and OCP >6 months use).

Data from surveys conducted at pregnancy and children at age of five were used for analysis of the current study. Data of Twins and those with missing values were not included for analysis.

For statistical analysis, the differences in patient characteristics between OCPs and non-OCPs groups were tested using the chi-square test and t-test for category variables and continuous variables, respectively. Univariate and multivariate logistic regression analyses were used to analyze the association between maternal OCP use and allergic diseases in children. The potential confounders were included in multivariate models to obtain the adjusted odds ratios (aORs). We also performed a trend test for duration of OCP use with the logistic model by treating duration of OCP, the ordered variable, as continuous variables. All associations based on models were presented with odds ratios with 95% confidence intervals (CI). Statistical analyses were conducted using SPSS Version 22.0 (IBM Corp. Armonk, NY, USA), with a P-value of <0.05 defined as being statistically significant.

Results

We obtained the data of 980 children without missing variables. The comparison of subjects analyzed in our study with those who were excluded revealed that a difference only in parity (see Table 2). Table 3-1 and Table 3-2 showed the characteristics of the participants according to OCP users and duration of OCP users. There were statistically significant differences for maternal age at pregnancy, number of previous live births, type of delivery and childs gender and daycare attendance in background characteristics between OCP use group and non-OCP use group. Of the children, 28.2% had a history of ever wheeze and 15.9% had current wheeze, and 14.6% had ever asthma and 10.2% had current asthma, at five years old. Among the mothers, 13.8% had a past history of OCP use and 6.2% used OCP for more than three months in total.

Table 2. Comparison between the characteristics of participants included in the analysis and those of lost follow up.

	Data used for analysis			Data not used for analysis			P
	n	N	%	n	N	%
Maternal characteristics
OCP use (yes)	135	980	13.8	65	475	13.7	0.962
Maternal history of allergy (yes)	547	980	55.8	227	417	54.4	0.653
Level of education
Middle school or high school	98	980	10	42	411	10.2	0.901
Body mass index at pregnancy (≧25)	46	980	4.7	27	480	5.6	0.443
Smoking during pregnancy	22	980	2.2	16	476	3.4	0.210
Maternal age at pregnancy (≧35)	407	980	41.5	188	479	39.2	0.405
Number of previous live births (≧1)	424	980	43.3	263	479	54.9	<0.001
Caesarean section	216	980	22	104	475	21.9	0.950
Gender (Male)	500	980	51	261	480	54.4	0.228
Daycare (yes)	206	980	21	62	319	19.4	0.544
Weeks of gestation, median (IQR)	39 (38, 40)			39 (38, 40)			0.120†

†. Mann–Whitney test. IQR, Interquartile range25th, 75th.

Table 3-1. Characteristics of the participants according to OCP users.

	OCP (no)		OCP (yes)		P
	n = 845		n = 135
	n	%	n	%
Maternal history of allergy					0.292
Yes	466	55.1	81	60.0
No	379	44.9	54	40.0
Level of education					0.089
Middle school or high school	79	9.3	19	14.1
College, university or graduate school	766	90.7	116	85.9
Body mass index at pregnancy					0.771
<25	806	95.4	128	94.8
≧25	39	4.6	7	5.2
Smoking during pregnancy (yes)					0.985†
Yes	19	2.2	3	2.2
No	826	97.8	132	97.8
Maternal age at pregnancy (≧35 years old)					0.009
<35	508	60.1	65	48.1
≧35	337	39.9	70	51.9
Number of previous live births (≧1)					0.02
0	467	55.3	89	65.9
≧1	378	44.7	46	34.1
Type of delivery					0.012
Caesarean section	175	20.7	41	30.4
Vaginal delivery	670	79.3	94	69.6
Childs characteristics
Gender					0.001
Male	413	48.9	87	64.4
Female	432	51.1	48	35.6
Daycare					0.132
Yes	171	20.2	35	25.9
No	674	79.8	100	74.1
Weeks of gestation, median (interquartile range25%, 75%)	39 (38, 40)		39 (38, 40)		0.201‡
Allergy outcomes at 5 years old
Ever wheeze	223	16.4	53	39.3	0.002
Current wheeze	124	14.7	32	23.7	0.008
Ever asthma	115	13.6	28	20.7	0.029
Current asthma	80	9.5	20	14.8	0.057
Ever atopic dermatitis	206	24.4	30	22.2	0.586
Current atopic dermatitis	189	22.4	28	20.7	0.673
Ever rhinitis	301	35.6	70	51.9	<0.001
Current rhinitis	81	9.6	16	11.9	0.413

†. Fisher exact test.

‡. Mann–Whitney test.

Table 3-2. Characteristics of OCP users according to duration of OCP use.

	OCP (no)		OCP (yes)				P
			<3 months		≥3months
	n = 845		n = 74		n = 61
	n	%	n	%	n	%
Maternal history of allergy							0.561
Yes	466	55.1	45	60.8	36	59.0
No	379	44.9	29	39.2	25	41.0
Level of education							0.169
Middle school or high school	79	9.3	9	12.2	10	16.4
College, university or graduate school	766	90.7	65	87.8	51	83.6
Body mass index at pregnancy							0.758
<25	806	95.4	71	95.9	57	93.4
≧25	39	4.6	3	4.1	4	6.6
Smoking during pregnancy (yes)							0.787†
Yes	19	2.2	1	1.4	2	3.3
No	826	97.8	73	98.6	59	96.7
Maternal age at pregnancy (≧35 years old)							0.021
<35	508	60.1	33	44.6	32	52.5
≧35	337	39.9	41	55.4	29	47.5
Number of previous live births (≧1)							0.042
0	467	55.3	46	62.2	43	70.5
≧1	378	44.7	28	37.8	18	29.5
Type of delivery							0.035
Caesarean section	175	20.7	24	32.4	17	27.9
Vaginal delivery	670	79.3	50	67.6	44	72.1
Childs characteristics
Gender							0.003
Male	413	48.9	49	66.2	38	62.3
Female	432	51.1	25	33.8	23	37.7
Daycare							0.029
Yes	171	20.2	14	18.9	21	34.4
No	674	79.8	60	81.1	40	65.6
Weeks of gestation, median (interquartile range25%, 75%)	39 (38, 40)		39 (38, 40)		39 (38, 40)		0.413‡
Allergy outcomes at 5 years old
Ever wheeze	223	26.4	27	36.5	26	42.6	0.006
Current wheeze	124	14.7	16	21.6	16	26.2	0.022
Ever asthma	115	13.6	16	21.6	12	19.7	0.088
Current asthma	80	9.5	13	17.6	7	11.5	0.083
Ever atopic dermatitis	206	24.4	19	25.7	11	18	0.505
Current atopic dermatitis	189	22.4	17	23	11	18	0.722
Ever rhinitis	301	35.6	38	51.4	32	52.5	0.001
Current rhinitis	81	9.6	8	10.8	8	13.1	0.648

†. Fisher exact test.

‡. Kruskal–Wallis test.

Table 4 showed the association of maternal OCP use before pregnancy with childhood wheeze and allergic outcomes. In the adjusted analysis, maternal OCP was associated with an increased risk of ever wheeze (aOR, 1.62; 95% CI, 1.10–2.40), current wheeze (aOR, 1.59; 95% CI, 1.01–2.50), ever asthma (aOR, 1.65; 95% CI, 1.02–2.65) and ever rhinitis (aOR, 1.90; 95% CI, 1.30–2.80).

Table 4. Associations of OCP use before pregnancy with allergy outcomes in children at 5 years old.

	Crude OR (95% CI)				Adjusted OR (95% CI)†
	OR	Lower	Upper	P	OR	Lower	Upper	P
Ever wheeze	1.80	1.24	2.63	0.002	1.62	1.10	2.40	0.015
Current wheeze	1.81	1.16	2.81	0.008	1.59	1.01	2.50	0.046
Ever asthma	1.66	1.05	2.63	0.031	1.65	1.02	2.65	0.040
Current asthma	1.66	0.98	2.82	0.059	1.64	0.95	2.84	0.077
Ever atopic eczema	0.89	0.57	1.37	0.587	0.87	0.55	1.35	0.523
Current atopic eczema	0.91	0.58	1.42	0.673	0.88	0.56	1.39	0.593
Ever rhinitis	1.95	1.35	2.81	<0.001	1.90	1.30	2.80	0.001
Current rhinitis	1.27	0.72	2.24	0.414	1.07	0.60	1.94	0.813

†. ORs adjusted for maternal history of allergy (asthma, atopic dermatitis, or allergic rhinitis), maternal education level, maternal age at pregnancy, maternal BMI, maternal smoking during pregnancy, mode of delivery, gestational age at delivery, previous live birth, day care and gender of child.

Table 5 showed the association of OCP use duration before pregnancy with childhood wheeze and allergic outcomes. In adjusted analysis, a usage of OCP of more than three months statistically was associated with an increased risk of ever wheeze (P = 0.012), current wheeze (P = 0.035), and ever rhinitis (P = 0.002) among five-year-old children compared to no OPC use and 1 day–3 months OCP use.

Table 5. Associations of OCP use before pregnancy with wheeze and allergy outcomes in children at 5 years old.

	Crude OR (95% CI)				Adjusted OR (95% CI)†
	OR	Lower	Upper	P	OR	Lower	Upper	P
Ever wheeze
1 day–2 months	1.60	0.97	2.64	0.063	1.45	0.87	2.42	0.151
≥3 months	2.07	1.22	3.52	0.007	1.85	1.08	3.18	0.026
P trend				0.002				0.012
Current wheeze
1 day–2 months	1.60	0.89	2.88	0.114	1.41	0.78	2.57	0.258
≥3 months	2.07	1.13	3.77	0.018	1.82	0.98	3.38	0.058
P trend				0.007				0.035
Ever asthma
1 day–2 months	1.75	0.97	3.15	0.062	1.66	0.91	3.03	0.100
≥3 months	1.56	0.80	3.01	0.191	1.63	0.83	3.21	0.159
P trend				0.055				0.057
Current asthma
1 day–2 months	2.04	1.07	3.87	0.030	1.97	1.02	3.82	0.044
≥3 months	1.24	0.55	2.82	0.608	1.23	0.53	2.86	0.623
P trend				0.169				0.204
Ever atopic eczema
1 day–2 months	1.07	0.62	1.85	0.804	1.06	0.61	1.84	0.846
≥3 months	0.68	0.35	1.34	0.265	0.66	0.33	1.30	0.228
P trend				0.386				0.33
Current atopic eczema
1 day–2 months	1.04	0.59	1.82	0.905	1.01	0.57	1.80	0.969
≥3 months	0.76	0.39	1.50	0.432	0.74	0.37	1.46	0.381
P trend				0.526				0.454
Ever rhinitis
1 day–2 months	1.91	1.18	3.07	0.008	1.89	1.15	3.11	0.013
≥3 months	1.99	1.18	3.36	0.010	1.92	1.11	3.31	0.019
P trend				0.001				0.002
Current rhinitis
1 day–2 months	1.14	0.53	2.47	0.733	0.99	0.45	2.18	0.982
≥3 months	1.42	0.65	3.10	0.373	1.17	0.53	2.62	0.696
P trend				0.358				0.739

†. ORs adjusted for maternal history of allergy (asthma, atopic dermatitis, or allergic rhinitis), maternal education level, maternal age at pregnancy, maternal BMI, maternal smoking during pregnancy, mode of delivery, gestational age at delivery, previous live birth, day care and gender of child.

Discussion

Our results supported the hypothesis that maternal history of OCP use before pregnancy is associated with increased respiratory allergic disease signs in the first five years of life. Moreover, longer time use of OCP was associated with an increased risk of such conditions. Strength of our study was the study design of which evidence level is higher than trans-sectional case-control studies ever reported. Especially this prospective birth cohort consisted of general population not focusing on children with high risk of allergy.

A Norwegian birth cohort study examined the influence of two types of OCPs (estrogen-progestin combined pills and progestin-only pills) and found that progestin-only pills use was slightly associated with wheeze in children at 6–8 months old (aOR, 1.19; 95% CI, 1.05–1.34).⁹ Meanwhile, a Jamaican cohort study, not evaluating the types of OCP, reported that maternal OCP use was associated with asthma or wheeze in children at 11–12 years old (aOR, 1.81; 95% CI, 1.25–2.61).⁷ On the other hand, a German case-control study, not evaluating the types of OCP as well, did not show an association between OCP use and asthma/allergic rhinitis, but showed an association with atopic eczema among children aged 5–14 years instead, as noted by Frye et al.¹² Another case-control study in the UK demonstrated that OCP use within 6 months of conception was associated with asthma (aOR, 1.16; 95% CI, 1.06–1.27).⁸ As to the association between OCP use and allergic outcomes of young adults, young women in German cohort study had the inverse association between OCP use and new-onset asthma and allergic rhinitis after puberty.¹³ Regarding hormone replacement therapy, another cohort study reported that postmenopausal women in the US who used hormones increased the risk of asthma compared to those who never used.¹⁴ A controversial impact of OCPs as well as hormone replacement therapy on wheeze/allergy implies that the dose and type of OCP used and the duration and timing of the usage may influence the development of wheeze and allergy in children and adults. Comparative study with USA and France found OCP use was not the first choice for contraceptive method in Japan.¹⁵ The prevalence of allergic diseases in western countries was higher than that in non-western countries according to the large scale international epidemiological study.¹⁶ The prevalence of OCP use in western countries was also much higher than that in Japan.¹⁷ If the prevalence of OCP use influences the prevalence of offsprings childhood asthma and allergic outcomes, the more Japanese populations use OCP, the higher the prevalence of wheeze and allergic diseases may be.

At present, the underlying mechanisms of wheeze and allergic diseases development caused by OCPs are still unclear. A recent study revealed that an interaction among genetic variants in the GATA 3, OCP use and DNA-methylation increased asthma prevalence in post-puberty women,¹⁸ suggesting that OCP use before pregnancy may cause epigenetic changes such as DNA-methylation. According to the Developmental Origins of Health and Disease (DOHaD) theory,^{5, 6 and 19} it is speculated these epigenetic alterations before conception may be passed on to the embryo leading to the development of wheeze and allergic diseases in their childhood age, although there has been no evidence that preconceptional OCP use had epigenetic influence on the gametocyte, so far. The emerging concept of DOHaD hypothesis implies that an exposure of the female gametocyte or the fetus to various environmental factors may contribute to the development of non-communicable diseases in children. Besides preconceptional exposure to OCP, prenatal exposure to acetaminophen was reported to be associated with wheeze of children at age of 5 years.²⁰ Exposures to various medication not only during pregnancy but also even before conception should be considered as candidates of risk factors to be explored to prevent the development to childhood allergic diseases.

There were several limitations in this study. We could not evaluate the influence of different types of OCPs, because in Japan, only estrogen-progestin pills were available to be prescribed before and during the recruitment of pregnant women to this birth cohort study. Furthermore, exact doses and timing of OCP used by participants was impossible to be detected since enrollment of participants for the birth cohort study was done after confirmed their pregnancy. Another limitation was that lost to follow-up rate in this study was 35%, and the number of previous live births was the only variable which showed statistical difference between subjects, but it gave no influence on our conclusion even after adjustment. To minimize the influence of confounders, a randomized controlled trials is the best to provide the highest evidence, but they can not be permitted to be carried out from ethical point of view to evaluate the risk of preconceptional OCP use. One of the other limitations of our study was that we measured childhood outcomes not directly by a physician but by a questionnaire. Indeed, various birth cohort studies have used validated questionnaires to evaluate outcomes. Single-center recruitment in Tokyo was also the other limitation of our study. Although participants in the cohort might not be representative of whole Japanese population, we could found the statistically significant association between preconceptional OCP use and childhood wheeze and allergic outcomes after adjusting for the confounders in our study.

In summary, our prospective birth cohort study suggested that maternal OCP use was a risk of the development of childhood wheeze and some allergic outcomes in their offspring. More than three-months usage of OCP increased the risk of asthma and related allergic outcomes.

Conflict of interest

The authors have no conflict of interest to declare.

Authors' contributions

KYH, MF, TS, MN, FK, HS and YO designed the study. KYH, MF, TS, MN, and YO contributed to data collection. LY performed the statistical analysis. KYH, MF, TS, MN, FK, HS and YO contributed to the interpretation of the results. KYH wrote the first draft of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

We deeply thank the mothers and children who participated in the T-CHLD study. We would like to thank Dr. Julian Tang of the Department of Education for Clinical Research, National Center for Child Health and Development, for proofreading, and rewriting part of this manuscript. This study was supported in part by Health and Labour Sciences Research Grants from the Ministry of Health, Labour, and Welfare of Japan (No. 09158522) and by the Grant of National Center for Child Health and Development (20A-1).

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