Asthma in a prospective cohort of rural pregnant women from Sri Lanka: Need for better care during the pre-conceptional and antenatal period.

OBJECTIVES: To describe the epidemiology and the effect of asthma on pregnancy outcomes in pregnant women from a rural geography.
METHODS: We conducted a prospective cohort study in Anuradhapura district, Sri Lanka enrolling all eligible pregnant women registered in the maternal care program. An interviewer-administered questionnaire-based symptom analysis and clinical assessment was conducted in the first and second trimesters.
RESULTS: We recruited 3374 pregnant women aged 15-48 years at conception. Self-reported physician-diagnosed asthma prevalence was 6.6% (n = 223) with only 41.7% (n = 93) on regular medical follow-up for asthma. The prevalence of wheeze reduced from pre-pregnancy (67.0%) to the first (46.4%) and second trimesters (47.7%; p<0.01). Of the 73 asthmatic women who did not have wheeze in the last 3 months preceding pregnancy, new-onset wheeze was reported by 6(8.2%) and 12(16.4%) in the first and second trimester, respectively. Pregnant women who sought medical care for asthma in the private sector had a lower likelihood of developing new-onset wheeze in the first trimester (p = 0.03; unadjusted OR = 0.94;95%CI 0.89-0.99). Thirty-four (33.3%) pregnant women had at least one hospital admission due to exacerbation of wheeze during the first and second trimester. The prevalence of low birth weight (16.0%) was higher among pregnant asthmatic women.
CONCLUSION: This study reports the high prevalence of asthma and asthma-associated pregnancy outcomes in women from a rural geography signifying the importance of targeted management.

Introduction

Asthma is the most common chronic disease complicating pregnancy [1]. It commonly manifests as frequent episodes of wheezing, dyspnoea and nocturnal cough. Anatomical and physiological changes of pregnancy such as the increases in uterine size, intra-abdominal pressure and the subcostal angle results in reduced total lung volume and functional residual capacity [2]. Furthermore, hormonal changes of pregnancy result in increased sensitivity of the respiratory centre to carbon dioxide, increased minute ventilation and tidal volume [3]. In addition, changes in immunological functions, nutritional factors and female fetus are known to affect the control of asthma in pregnant women [4]. In vitro studies have demonstrated increased production of pro-inflammatory cytokines and activation of inflammatory pathways in pregnancy that may contribute to exacerbation of asthma [5]. Furthermore, significant differences in the plasma protein patterns of asthmatic and non-asthmatic pregnant women and increased levels of circulating immune cells have been demonstrated [6,7]. Although, the exact mechanism is unknown, these changes are implicated in worsening of asthma symptoms during pregnancy [8].

Poor asthma control and frequent asthma exacerbations during pregnancy are associated with adverse foetal, maternal and pregnancy outcomes such as low birth-weight, preterm birth, congenital malformations, and increased perinatal mortality [9]. Importantly, current evidence suggests that well-controlled asthma during pregnancy reduces the risk of adverse pregnancy outcomes. If asthma symptoms are adequately controlled, babies born to asthmatic mothers may achieve growth and development similar to that of babies born to non-asthmatic mothers [10]. Current evidence supports patient education, objective asthma control assessment, regular follow-up and active asthma management during pregnancy to improve asthma symptom control and to minimize adverse pregnancy outcomes [11].

However, adequate information on the prevalence of asthma among pregnant women from rural geographic regions of low and middle-income countries, control of asthma during pregnancy and the effect of asthma control on pregnancy outcomes is severely lacking. Asthma prevalence significantly varies according to the geography with a higher prevalence of severe asthma in low-income countries [12]. Against this background, this study aims to assess the epidemiology of asthma in pregnancy and the effect of asthma control on pregnancy outcome in a diverse cohort of pregnant women from geographically the largest district in Sri Lanka, which has one of the best maternal healthcare programmes in the region.

Methods

This study was conducted as part of a large prospective cohort study of pregnant women: Rajarata Pregnancy Cohort (RaPCo) [13]. All eligible pregnant women registered with the maternal care program (almost 100% of pregnant mothers are registered with the routine program) and were residing in Anuradhapura district and having a period of gestation less than 12 weeks were invited to the study (Fig 1). The study cohort included pregnant women presented to the program from July to September 2019. Baseline assessment was done in 226 special clinics conducted over 71 days for this purpose, which was coupled with the routine investigation process to maximize participation. Informed written consent was obtained before recruiting participants for the study. Assent and informed consent from the accompanying parent/ guardian were obtained for the research participants who are aged less than 18 years. Medically trained data collectors completed interviewer-based questionnaires to collect data on symptomatology and conducted clinical examination in all research participants. Data collection was conducted in the first and second trimester for each participant. All recruited pregnant women were invited to visit the clinic around 24–28 weeks for the mid-pregnancy assessment. Participants (n = 2) with comorbid significant 2D echo-cardiogram findings (pulmonary hypertension and ostium secundum atrial septal defect with right to left shunt) were excluded from the analysis to eliminate the role of cardiac dysfunction on the symptoms.

Fig 1

Flow chart of the research.

An interviewer-administered questionnaire to assess demographic factors, physical health status, symptoms of asthma and treatment seeking behaviour was used in this study after obtaining informed written consent. A positive response to the question “Have you ever been diagnosed and confirmed as having asthma?” was considered as self-reported physician-diagnosed asthma (hereafter referred to as asthma). Asthma status in participants without documented evidence was confirmed following probing for a history of inhaler use, nebulization, exacerbating factors and hospitalization. A positive response to the question “Have you experienced shortness of breath in the last three months?” was considered dyspnoea and a positive response to the question “Was the shortness of breath increased with exertion?” is considered exertional dyspnoea. A positive response to the question “Have you experienced wheezing in the last three months?” was considered wheeze and a positive response to the question “Was the wheezing increased with exertion in the last three months?” was considered exertional wheeze. New-onset of symptoms was defined as an asthmatic participant who did not have a particular symptom during the last three months preceding pregnancy and developing the symptom during the first or second trimester.

Data analysis was conducted using SPSS beta version (IBM, Armonk, NY, USA) statistical software. Univariate analysis was performed to analyse the effect of housing conditions and domestic fuel source on pre-existing asthma in pregnant women. Bivariate analysis was performed to assess significant associations of asthma control during pregnancy with socio-demographic factors, patient characteristics, exposure to allergens, risk factors for asthma, health-seeking behaviour and patient education. Chi-square test for proportions was used to compare the estimates during pre-pregnancy, first trimester and second trimester with a significant level of 0.05. Odds ratio was calculated with 95% confidence interval to quantify the associations between symptoms of asthma and for pregnancy outcomes (low birth weight and preterm delivery). In addition, for pregnancy outcomes, the relative risk was computed with 95% confidence interval.

Ethical approval for the study was granted by the Ethics Review Committee of Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka (ERC/ 2019/ 07).

Results

We collected data from 3374 pregnant women aged 15 to 48 years at conception. Of the 3374 participants, 221 was selected as the asthmatic cohort (2 research participants with significant findings on 2D echocardiogram were excluded). Out of the 221 research participants with asthma, mid-pregnancy assessment at 24–28 weeks is available for 107 participants. The pregnancy outcomes—birthweight and preterm delivery—were assessed using hospital birth records. Table 1 shows the profile of study participants. The prevalence of asthma was 6.6% (n = 223; 95%CI 5.8%–7.5%) with 22.9% (n = 51) participants having documented evidence of a diagnosis of asthma (Table 2). The majority sought medical care for asthma in the private sector (n = 86; 46.7%), followed by the government sector (n = 84; 45.7%). Only 41.7% (n = 93) of the asthmatic pregnant women reported regular medical follow-up for asthma. Of the 223 pregnancies, 28.3% (n = 63) were unplanned with 2.3% (n = 5) due to contraceptive failure.

Table 1

Demographic characteristics and housing conditions of asthmatic pregnant women without comorbid cardiac conditions (n = 221) and non-asthmatic pregnant women recruited to the study (N = 3151).

	Asthmatic		Non-asthmatic
Characteristic	Number	Prevalence (%)	Number	Prevalence (%)
Ethnicity
Sinhalese	205	92.8	2731	86.7
Moor	12	5.4	369	11.7
Other	4	1.8	51	1.6
Religion
Buddhism	199	90.0	2704	85.8
Islam	14	6.3	388	12.3
Other	8	3.6	59	1.9
Highest education level at school
Up to or less than grade 10	26	11.7	351	11.2
Grade 11	99	44.8	1548	49.4
Grade 12–13	96	43.5	1232	39.3
Post-school educational qualifications
Certificate course	57	26.3	675	21.7
Degree	26	12.0	295	9.5
Age at conception (years)
Less than 20	14	6.3	240	7.6
20–24	39	17.7	645	20.5
25–29	72	32.6	1096	34.8
30–34	67	30.3	751	23.8
35–39	25	11.3	350	11.1
40–44	4	1.9	66	2.1
More than 44	0	0	3	0.1
Number of bedrooms in the house
One	19	8.6	244	7.8
Two	56	25.5	698	22.4
Three	83	37.7	1137	36.5
Four or more	62	28.3	1036	33.3
Number of other people sharing the bedroom
One	86	40.0	1184	39.2
Two	75	34.9	1257	41.7
Three or more	54	25.1	576	19.1
Major fuel source for cooking
Firewood	109	49.5	1549	49.7
Liquid petroleum gas	107	48.6	1480	47.5
Other	4	1.9	87	2.8
Walls are made up of
Clay bricks	166	75.1	2369	75.2
Cement blocks	49	22.2	682	21.6
Other	6	2.8	100	3.2
Roof is made up of
Asbestos sheets	136	61.5	2019	64.1
Roofing tiles	68	30.8	908	28.8
Other	17	7.8	224	7.1
Floor is
Cemented	114	52.1	1589	51.0
Tile	48	21.9	615	19.8
Concrete	38	17.4	663	21.3
Other	19	8.7	246	7.9

Table 2

Prevalence and the incidence of asthma symptoms during first and second trimester in a cohort of pregnant women (N = 3374).

Factor	Number	Per 1000 pregnant women	95% confidence interval
			Upper	Lower
Prevalence of a history of physician-diagnosed asthma	223	66.1	57.9	75.0
Prevalence of asthmatics on regular treatment	51	15.1	11.3	19.8
Incidence of new-onset dyspnoea in the first trimester*	16	4.7	2.7	7.7
Incidence of new-onset dyspnoea in the second trimester*	16	4.7	2.7	7.7
Incidence of new-onset wheezing in first trimester*	6	1.8	0.6	3.9
Incidence of new-onset dyspnoea in second trimester*	12	3.6	1.8	6.2
Incidence of exacerbation(s) of wheeze requiring hospitalization	34	10.1	7.0	14.1

*New onset is defined as an asthmatic patient who did not have a particular symptom during the last three months preceding the pregnancy developing the symptom.

The prevalence of non-cardiac origin dyspnoea increased from the last three months before pregnancy 20.4% (n = 45; 95%CI 15.3%–26.3%) to the first (n = 51, 23.3%) and second trimester (n = 30, 28.3%) (p>0.11) (Table 3). The total number of patients complaining of daily dyspnoea increased from pre-pregnancy (n = 8, 19.5%) to the first trimester (n = 17, 35.4%, p = 0.10). None of the study participants with asthma reported a frequency of dyspnoea symptoms more than once a week in the second trimester (Fig 2). In most study participants with asthma who had dyspnoea in the last three months preceding pregnancy (n = 30, 93.8%), the frequency of dyspnoea symptoms was unchanged from pre-pregnancy to the first trimester (Table 4).

Table 3

Symptomatology of asthma among self-reported physician-diagnosed asthmatic pregnant women without significant comorbid cardiac conditions in 2D echocardiogram (n = 221).

Symptom	Last 3 months prior to pregnancy		During first trimester		During second trimester
	Number	%	Number	%	Number	%
Dyspnoea	45	20.4	51	23.3	30	28.3
Frequency of dyspnoea
Once a month	9	22.0	5	10.4	19	82.6
2–4 times a month	11	26.8	11	22.9	4	17.4
Several times a     week	13	31.7	15	31.3	0	0
Daily	8	19.5	17	35.4	0	0
Dyspnoea after exercise	34	81.0	35	72.9	16	69.6
Wheeze	148	67.0	102	46.4	51	47.7
Frequency of wheeze
Once a month	48	35.0	26	27.1	24	55.8
2–4 times a month	39	28.5	27	28.1	6	14.0
Several times a week	33	24.1	28	29.2	5	11.6
Daily	17	12.4	15	15.6	8	18.6
Wheeze after exercise	92	64.8	69	69.7	35	72.9

Fig 2

Variation of the frequency dyspnoea and wheeze from the last three months before pregnancy to the second trimester among self-reported physician-diagnosed asthmatic women without significant cardiac comorbidities in 2D echocardiogram (n = 221).

Table 4

The change in the frequency of symptoms of wheeze and dyspnoea among pregnant women with self-reported physician-diagnosed asthma without significant comorbid cardiac conditions in 2D echocardiogram (n = 221).

Time period	Increased		Unchanged		Decreased
	n	%	n	%	n	%
Pre-conceptional to first trimester
Wheeze	53	25.4	147	70.3	9	4.3
Dyspnoea	1	3.1	30	93.8	1	3.1
First trimester to second trimester
Wheeze	22	23.4	46	48.9	26	27.7
Dyspnoea	9	47.4	2	10.5	8	42.1
Pre-conceptional to second trimester
Wheeze	38	40.9	34	36.6	21	22.6
Dyspnoea	9	50.0	3	16.7	6	33.3

The prevalence of wheeze among asthma patients without comorbid cardiac conditions was 67.0% (n = 148, 95%CI 60.3–73.1). There is a significant reduction of wheezing in the first (n = 102, 46.4%) and second trimesters (n = 51, 47.7%) compared to the pre-conceptional period (p<0.01). Interestingly, 67.9% (n = 36) of the study participants who reported an increase in the frequency of wheezing from pre-pregnancy to the first trimester had an unplanned pregnancy. Of the 73 (33.0%) participants who did not have wheezing episodes during the last three months preceding pregnancy, new-onset wheeze was reported in the first and second trimester by 8.2% (n = 6) and 16.4% (n = 12), respectively. Demographic characteristics of study participants with new onset dyspnoea and wheeze or an increase in the symptom frequency of dyspnoea and wheeze are presented in supplementary information (S1 Table). A total of 34 (33.3%) pregnant women had at least one hospital admission due to exacerbation of wheeze during the first and second trimester.The pregnant women who sought medical care for asthma at the private sector had a lower likelihood of developing new-onset wheeze in the first trimester (unadjusted OR = 0.51; 95%CI 0.44–0.59; p = 0.03). None of the study participants with asthma reported a past history of habitual cigarette smoking and 20.3% (n = 40) reported that at least one family member smoked cigarettes at home. Of these 40 study participants, wheezing in the last three months preceding pregnancy, first trimester and the second trimester was reported by 62.5% (n = 25, p = 0.50), 46.2% (n = 18, p = 0.97) and 40.0% (n = 10, p = 0.39) asthmatic pregnant women, respectively. Using firewood for cooking (p = 0.93, unadjusted OR 0.99; 95%CI 0.75–1.30), having an asbestos roofing (p = 0.36, unadjusted OR 1.14; 95%CI 0.86–1.51), having brick walls (p = 0.84, unadjusted OR 1.0; 95%CI 0.75–1.42) and having a cemented floor (p = 0.88, unadjusted OR 0.98l 95%CI 0.75–1.29) were not associated with self-reported physician-diagnosed asthma in this cohort of pregnant women from rural Sri Lanka.

Of the 221 pregnant asthmatics, birthweight and preterm delivery data was obtained from hospital records for 187 and 189 participants, respectively. There were 30 (16.0%) low birthweight (LBW) deliveries and 23 (11.1%) were preterm deliveries (Table 5). Increase in the frequency of symptoms from pre-pregnancy to the second trimester for wheezing (RR 2.37, 95%CI 0.84–6.66) or dyspnoea (RR 6.4, 95%CI 0.55–74.89) was not associated with LBW. Increased frequency of wheezing in the same period was not associated with preterm delivery as well (RR 2.32, 95%CI 0.61–8.90). Sex of the foetus was not associated with the increasing frequency of symptoms. The prevalence of anaemia in the first trimester among pregnant asthmatic women was 14.5% (n = 32) with the range of haemoglobin from 8.7 to 14.9 g/ dL. Comorbid anaemia in first trimester among pregnant asthmatic women did not further increase the risk of low birthweight (RR 0.90; 95%CI 0.29–2.8) or preterm delivery (RR 0.26; 95%CI 0.03–2.0) in this cohort.

Table 5

Variation in the prevalence of low birthweight and preterm delivery among pregnant women with self-reported physician-diagnosed asthma depending on the change in symptomatology (n = 221).

Change in symptomatology	Low birthweight		Preterm delivery		Relative risk	95% confidence interval
	n	%	n	%
Increase in the frequency wheezing of
from pre-pregnancy to first trimester	9	20.5	5	11.1	1.05	0.36–3.11
from pre-pregnancy to second trimester	11	30.6	6	16.2	2.32	0.61–8.90
from first trimester to second trimester	6	27.3	2	9.1	0.75	0.15–3.83
Increase in the frequency of dyspnoea
from pre-pregnancy to first trimester	0	0	0	0	0.92	0.82–1.03
from pre-pregnancy to second trimester	4	44.4	2	22.2	2.29	0.17–30.96
from first trimester to second trimester	2	22.2	1	11.1	1.00	0.53–18.91

Discussion

The prevalence of asthma in pregnancy reported in our study (6.6%, 95%CI 5.8–7.5) is within the current reported global mean prevalence of 4–12%, though wide variations are reported in large national and multicentre studies conducted in other countries [14,15]. To the best of authors knowledge, we report for the first time the prevalence of asthma among pregnant Sri Lankan women.

In this cohort, a third of women who had an exacerbation were hospitalized: a number much larger than the estimated 20% that require interventions with only 6% requiring hospitalization [16]. Furthermore, among pregnant asthmatic women, approximately one in four reported an increase in the frequency of wheezing from pre-pregnancy to the first trimester and from the first trimester to the second trimester. More than one in ten pregnant asthmatic women (11.7%) developed new onset dyspnoea during the second trimester. These findings could be proxy indicators of poorly managed asthma during pregnancy in this study population. Furthermore, those who were under care at the private sector had a lower likelihood of developing new-onset wheeze, most probably due to the higher likelihood of specialist follow-up at private sector which is associated with better control of asthma symptoms [17].

Current evidence suggest that among asthmatic pregnant women, almost a third each had worsened, unchanged or improved asthmatic symptoms during pregnancy a finding which is almost similar to our study [18]. However, the significant reduction in the prevalence of wheeze from pre-pregnancy to the first and second trimesters could be because the majority (58.4%) of asthmatic pregnant women were not on medical treatment prior to getting pregnant.

Using firewood for cooking, which is associated with asthma [19,20], is commonly practiced in rural Sri Lanka: almost half of the households in this cohort use firewood as the major fuel source (49.7%). However, in the current study a significant difference in asthma among households using firewood as the major fuel source and the households using other sources of fuel—mostly liquid petroleum gas (47.5%)–was not observed. This observation may be due to firewood commonly been as a secondary fuel source, which was not assessed in this study, especially for boiling water and cooking [21]. Similarly, having an asbestos roofing is known to be associated with asthma [22]. However, in the current study the housing conditions such as the materials used for roofing, walls and the floor, did not associate with asthma or increased symptom frequency among known asthmatics. This finding highlights the crucial need to conduct further investigations to clearly understand the causative and contributory factors to bronchial asthma among pregnant women from rural geographies.

According to the national statistics of the Family Health Bureau of Sri Lanka, the prevalence of low birth-weight in Sri Lanka for the year 2019 was 12.3%, which is the highest recorded percentage since 2015 [23]. Our study shows that the prevalence of low birth-weight (16.0%) is higher in pregnant women with asthma compared to the national level prevalence which is consistent with current medical literature [24]. This may be attributable to the reduced foetal growth resulting of the hypoxia caused by chronic maternal suboptimal pulmonary function and inflammation associated with asthma [25]. Although not observed in this study sample, current evidence suggests that the incidence of preterm delivery is significantly higher among asthmatic women with inadequate symptom control compared to asthmatic women who had adequate symptom control during pregnancy [26].

Available evidence suggests that asthma in pregnancy could lead to increased risk of low birth-weight, small for gestation age, preterm delivery, congenital malformations, neonatal hospitalization and neonatal death for babies of asthmatic pregnant women [9,24]. This increased risk was associated with the severity of asthma and frequent asthma exacerbations [27]. The wide confidence intervals across the null value in our study indicates that a larger sample is required to assess the effect of asthma on these selected pregnancy outcomes. Although, anaemia is independently associated with increased risk of low birthweight [28] and preterm delivery [29], comorbid anaemia did not further increase the risk of low birthweight and preterm delivery in this cohort.

Pregnancy-related complications of asthma are dependent on the changing asthma symptom severity during pregnancy and maybe mitigated by tailored treatment aimed at asthma symptom management during pregnancy [30]. Women with controlled asthma during pregnancy has normal placental function comparable to non-asthmatic women indicating that well-controlled maternal asthma is crucial in improving the health outcomes of the children of asthmatic women [31]. Our study clearly indicates that symptoms of asthma is not considered as an important health condition by the pregnant women living in this rural community and also the management of asthma during pregnancy is not optimal as showed by the number of hospital admissions. More focus on medical conditions complicating pregnancy is required in countries like Sri Lanka where the maternal mortality and morbidities are increasingly common due to these conditions.

Limitations

The asthma diagnosis was based on self-reporting and only 22.6% of participants had documented evidence of asthma. Self-reported physician-diagnosed asthma is a lower level of evidence compared to asthma diagnosed with objective lung function assessment. Although 41.6% of the asthmatics were on regular medical treatment, adequate documented evidence of asthma medication of individuals was not properly available. Therefore, the effect of asthma medication on symptomatology could not be assessed in this study. We assessed the presence of cigarette smoker(s) in the household, however, further detailed examination of the degree of passive cigarette smoke exposure was not carried out. Similarly, the level of exposure to domestic risk factors were not assessed in this study. Furthermore, ideally, multivariable analysis and determination of the adjusted odds ratio for each factor should be conducted to assess the association with self-reported physician-diagnosed asthma. However, due to the small number of pregnant asthmatic women the authors did not conduct a regression analysis. In the current study, due to the disruptions caused by island-wide lockdown procedures and other COVID 19 pandemic prevention regulations, data collection in the third trimester was disrupted. Therefore, the authors do not have data on pregnancy induced hypertension, preeclampsia, eclampsia, gestational diabetes mellitus and other comorbid conditions that may contribute to low birthweight or prematurity in the offspring.

Conclusion

This study reports the high prevalence of asthma and asthma-associated pregnancy outcomes in women from a rural geography signifying the importance of targeted management of asthma. Prioritizing asthma management at pre-conceptional period and early identification and management of asthma during the pregnancy is required to minimize the high rate of hospital admissions and exacerbations observed in this rural cohort of pregnant asthmatic women.

Demographic characteristics of patients who reported increased frequency or new onset dyspnoea or wheeze in the first and second trimester.

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10 May 2022

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Reviewer #1: In this article, the authors evaluate a prospective cohort of pregnant women for the incidence and prevalence of asthma in a rural population in the Anuradhapura district of Sri Lanka. The work is generally technically sound. My comments are as follows.

Introduction

The physiologic changes you describe during pregnancy (decreased TLC, decreased FRC, increased minute ventilation and Vt) are generally associated with restrictive lung disease, and yet you suggest (in line 102) that these factors may be implicated in impacting asthma control. Instead, the sentences that follow (lines 102-108) are those that are implicated in asthma associated with pregnancy. Therefore, I would suggest that sentence should be edited for clarity.

Methods

It would be useful to clarify the reason patients with co-morbid significant 2D echo findings were excluded and/or define which findings would or would not prompt exclusion.

Do you mean to say (in line) that you performed multivariate analysis? If not, why did you only include bivariate analysis?

Can you clarify why RR and OR were both calculated for pregnancy outcomes?

Results

In table 2, you have two rows listing the factor “Incidence of new-onset dsypnoea in the in the second trimester”. Please clarify

In tables 3-4, can you demonstrate some statistical measure of the change in symptoms over time from pre-pregnancy to first trimester to second trimester (? Regression or Mann-Kendall)

Could table 5 go in an appendix?

In table 6, please represent the RR and Cis in the table.

Discussion

Some women with asthma improve clinically during pregnancy. Did you see this? If so, could you also address that observation (i.e. history of asthma with symptoms in the 3 months prior to pregnancy that improved in the 1st/2nd trimester).

Reviewer #2: There is no novelty in this manuscript, it just describe the situation pertaining to the asthma and pregnancy, not even followed up to the third trimester.

Diagnosis of asthma through the questionnaires without documentary evidence (only 22.9%) would have been introduced selection bias to the study. Author should pay a much attention when labelling asthmatic and non-asthmatic. Dyspnea due to other reason, need to taken into the consideration: heart failure, COPD, pneumonia or psychologic problem.

Other risk factors for asthma were not investigated: pollen, pollutants, smoking,

Need details of passive smoking

Table 2 : raw number 5 and 7 are similar, raw number 7 would be "wheezing"

How examiners were calibrated, trained were not described.

Inter examiner variability of diagnosis with clinical examination

I am not sure that all pregnant mothers were included for the study or what were the inclusion and exclusion criteria.

To complete the study all pregnant mothers should have been followed up to the termination of pregnancy.

Reviewer #3: The authors have conducted a meticulous study and reports significant results. A few corrections and clarifications are mentioned.

In the abstract and main text, it is best to stick to a similar format when reporting both numbers and percentages. If the number is within brackets such as in line 82 maintain a similar format throughout (line 171, 185 in results section also uses 2 different formats in the same section).

In the abstract under methods, line 76, the word ‘study’ should be included after ‘prospective cohort’.

It is not clear whether new onset wheeze was reported in 6 out of what population in the abstract (mentioned in the text as 73).

It is good practice to mention the lost to follow up patients in the beginning of the results section and describe the final study population, mentioning Figure 01. In line 226 it is mentioned ‘out of 221’ the proportion of LBW and preterm deliveries. However, Figure 01 states that 114 and 32 patients were lost to follow up. If so, how were the birth outcomes of all 221 assessed?

The prevalence of asthma was mentioned as 223 in line 171 and Table 02 but in Table 01 and Table 03 it is 221. In line 226, also it is mentioned as 221 pregnant asthmatics. As two were excluded due to cardiac conditions it is clearer to mention so in the beginning of the results section.

Did 53 asthma patients not seek treatment (223-84-86)? If so, how were they diagnosed? (in methods section it is mentioned that physician reported, use of inhalers, nebulization, hospitalizations and exacerbating factors were used and table 02 indicates all 223 were physician diagnosed asthma)

Table 02 and Table 06 also needs to be cited in text.

Use either simple ‘p’ or ‘P’ throughout the text for better uniformity when reporting p value.

Adjust the sentence in line 246 to better reflect the meaning.

In line 267, mention that asbestos is reported as having an association or known to. Currently it conveys that your study shows that there’s an association which is then contraindicated by the next statement.

Reviewer #4: It is a comprehensive and descriptive study, helping with having a picture of basic pregnancy care and infering problems that could be addressed in the future.

Problems with sample size and data completeness. Shaky asthma diagnosis. Good starting point for future studies but with problems in their methodology making assumptions difficult.

**********

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Reviewer #1: No

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Reviewer #3: No

Reviewer #4: No

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24 May 2022

Journal requirements

Comment: Thank you for your information. We note your study included pregnant participants under the age of 18. Please ensure you have stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent.

Response: We have included the following statement on obtaining assent and parental/guardian’s consent for participants under the age of 18.

“Assent and informed consent from the accompanying parent/ guardian were obtained for the research participants who are aged less than 18 years.”

Comment: Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Response: We edited the manuscript according to the PLOS ONE style requirements including titles, file names, graphs and tables.

Comment: You indicated that you had ethical approval for your study. In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent.

Response: The methods section of the manuscript has the following statement on obtaining informed written consent.

“Informed written consent was obtained before recruiting participants to the study.” 140-141

Comment: Please note that funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Response: The information about the funding agency was removed from the acknowledgement section. 369-371

Comment: Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement.

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

Response: Kindly keep the current funding statement.

“Authors SA and TA received funding for this research project. This research was supported by the Accelerating Higher Education Expansion and Development (AHEAD) Operation of the Ministry of Higher Education, Sri Lanka funded by the World Bank. The funding agency had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. The authors wish to acknowledge the funding agency (grant identifier: DOR STEM HEMS [6026-LK/8743-LK]).”

Comment: Please note that in order to use the direct billing option the corresponding author must be affiliated with the chosen institute.

Response: The corresponding author Suneth Buddhika Agampodi is affiliated with the Section of Infectious Diseases, Department of Internal Medicine, School of Medicine, Yale University 43-48

Reviewer 1

The authors appreciate the constructive and insightful comments of the reviewer and has edited the manuscript accordingly. We believe that the comments improved the quality and the clarity of the manuscript.

Comment: The physiologic changes you describe during pregnancy (decreased TLC, decreased FRC, increased minute ventilation and Vt) are generally associated with restrictive lung disease, and yet you suggest (in line 102) that these factors may be implicated in impacting asthma control. Instead, the sentences that follow (lines 102-108) are those that are implicated in asthma associated with pregnancy. Therefore, I would suggest that sentence should be edited for clarity.

Response: The authors agree that this sentence should be edited to improve clarity. The sentence was edited as follows “In addition, changes in immunological functions, nutritional factors and female fetus are known to affect the control of asthma in pregnant women” 105-107

Comment: It would be useful to clarify the reason patients with co-morbid significant 2D echo findings were excluded and/or define which findings would or would not prompt exclusion.

Response: The authors agree with the reviewer and has amended the manuscript as follows “Participants (n=2) with comorbid significant 2D echo-cardiogram findings (pulmonary hypertension and ostium secundum atrial septal defect with right to left shunt) were excluded from the analysis to eliminate the role of cardiac dysfunction on the symptoms. 147-150

Comment: Do you mean to say (in line) that you performed multivariate analysis? If not, why did you only include bivariate analysis?

Response: This study was conducted as a part of a large cohort study. The study sample is the recruited study participants during data collection period.

Therefore, the number of cases in each analysis (e.g., increased dyspnoea in a given trimester) was not adequate to perform multivariate analysis.

However, the authors agree with the comment and have mentioned it as a limitation.

“Furthermore, ideally, multivariable analysis and determination of the adjusted odds ratio for each factor should be conducted to assess the association with self-reported physician-diagnosed asthma. However, due to the small number of pregnant asthmatic women the authors did not conduct a regression analysis.” 352-355

Comment: Can you clarify why RR and OR were both calculated for pregnancy outcomes?

Response: The authors thank the reviewer for the comment. This was a typing mistake and it has been corrected as follows.

“Comorbid anaemia in first trimester among pregnant asthmatic women did not further increase the risk of low birthweight (RR 0.90; 95%CI 0.29-2.8) or preterm delivery (RR 0.26; 95%CI 0.03-2.0) in this cohort.” 263-272

Comment: In table 2, you have two rows listing the factor “Incidence of new-onset dsypnoea in the in the second trimester”. Please clarify

Response: The authors agree with the reviewer and added the following footnote as requested.

* New-onset of symptoms (dyspnoea/wheeze) was defined as development of a particular symptom during the pregnancy in an individual who did not have the particular symptom last three months before pregnancy 202

Comment: In tables 3-4, can you demonstrate some statistical measure of the change in symptoms over time from pre-pregnancy to first trimester to second trimester (? Regression or Mann-Kendall)

Comment: Authors also agree with the comment. However, since we only have 3 time points (pre-pregnancy, first trimester and second trimester), we did not apply Mann-Kendall test.

Comment: Could table 5 go in an appendix?

Response: The authors moved Table 5 to supplementary information as suggested by the reviewer and renamed Table 6 as Table 5. 235

Comment: In table 6, please represent the RR and Cis in the table.

Response: The relative risk and the 95% confidence interval were provided for Table 5 (former table 6) as suggested by the reviewer. 275-278

Comment: Some women with asthma improve clinically during pregnancy. Did you see this? If so, could you also address that observation (i.e. history of asthma with symptoms in the 3 months prior to pregnancy that improved in the 1st/2nd trimester).

Response: Authors agree with the comment of the reviewer. In table 4 and Fig 2, we provided the details of the changes in the symptoms including the number and percentage of research participants who had improvement in their symptoms from pre-pregnancy to first and second trimesters. It was also discussed in the discussion section. 213-215 and 222-225

Reviewer 2

Comment: There is no novelty in this manuscript, it just describe the situation pertaining to the asthma and pregnancy, not even followed up to the third trimester.

Response: This cohort study is the first reported evidence on asthma among pregnant Sri Lankan women. Furthermore, the aim of this manuscript is to describe the situation pertaining to asthma among pregnant Sri Lankan women. Authors acknowledge that follow up in the third trimester would have generated more evidence for asthma in pregnant women. However, due to the COVID 19 pandemic situation and the island-wide curfew and other restrictions imposed to curtail the pandemic, the authors were unable to collect data from research participants in the third trimester. Following relaxation of travel restrictions, authors collected information on the pregnancy outcomes.

Comment: Diagnosis of asthma through the questionnaires without documentary evidence (only 22.9%) would have been introduced selection bias to the study. Author should pay a much attention when labelling asthmatic and non-asthmatic.

Response: The authors have included the following statement on diagnosis of asthma and its limitations in the limitations section.

“The asthma diagnosis was based on self-reporting and only 22.6% of participants had documented evidence of asthma. Self-reported physician-diagnosed asthma is a lower level of evidence compared to asthma diagnosed with objective lung function assessment. Although 41.6% of the asthmatics were on current medical treatment, adequate documented evidence of asthma medication of individuals was not properly available.” 344-348

Comment: Dyspnea due to other reason, need to taken into the consideration: heart failure, COPD, pneumonia or psychologic problem.

Response: We mentioned that any participant with significant findings in 2D echocardiogram were not included in the study.

Furthermore, detailed clinical history taking and examinations were carried out by medically trained data collectors to exclude other diseases as mentioned in the methods section. 147-150 and 143-145

Comment: Other risk factors for asthma were not investigated: pollen, pollutants, smoking, Need details of passive smoking

Response: The authors have included the following statement on passive smoking in the results section.

“None of the study participants with asthma reported a past history of habitual cigarette smoking and 40 (20.3%) reported that at least one family member smoked cigarettes at home.”

Further, we have acknowledged this limitation in the limitations section.

“We assessed the presence of cigarette smoker(s) in the household, however, further detailed examination of the degree of passive cigarette smoke exposure was not carried out.” 244-246 and 349-351

Comment: Table 2: raw number 5 and 7 are similar, raw number 7 would be "wheezing"

Response: Raw number 5 represent the participants who did not have wheeze during the last three months before pregnancy and developed wheeze in the first trimester. This includes participants who required hospital admission for symptom control and those that didn’t.

Whereas raw number 7 represent the participants who developed wheezing episodes that required hospital admission.

Comment: How examiners were calibrated, trained were not described. Inter examiner variability of diagnosis with clinical examination

Response: Medically trained data collectors were used for data collection and clinical examination in the cohort study. “An interviewer-administered questionnaire to assess demographic factors, physical health status, symptoms of asthma and treatment seeking behaviour was used in this study after obtaining informed written consent. A positive response to the question “Have you ever been diagnosed and confirmed as having asthma?” was considered as self-reported physician-diagnosed asthma (hereafter referred to as asthma). Asthma status in participants without documented evidence was confirmed following probing for a history of inhaler use, nebulization, exacerbating factors and hospitalization.”

The detailed protocol is published as mentioned in the methods section.

“This study was conducted as part of a large prospective cohort study of pregnant women: Rajarata Pregnancy Cohort (RaPCo).[13]”

Reference: Agampodi TC, Wickramasinghe ND, Prasanna RIR, Irangani MKL, Banda JMS, Jayathilake PMB, et al. The Rajarata Pregnancy Cohort (RaPCo): study protocol. BMC Pregnancy Childbirth. 2020;20: 374. doi:10.1186/s12884-020-03056-x 152-158

Comment: I am not sure that all pregnant mothers were included for the study or what were the inclusion and exclusion criteria

Response: The authors have stated the following in the methods section.

“This study was conducted as part of a large prospective cohort study of pregnant women: Rajarata Pregnancy Cohort (RaPCo).[13] All eligible pregnant women registered with the maternal care program (almost 100% of pregnant mothers are registered with the routine program) and were residing in Anuradhapura district and having a period of gestation less than 12 weeks were invited to the study (Fig 1). The study cohort included pregnant women presented to the program from July to September 2019.”

A detailed protocol paper is already published by the authors (reference 13).

Reference: Agampodi TC, Wickramasinghe ND, Prasanna RIR, Irangani MKL, Banda JMS, Jayathilake PMB, et al. The Rajarata Pregnancy Cohort (RaPCo): study protocol. BMC Pregnancy Childbirth. 2020;20: 374. doi:10.1186/s12884-020-03056-x

133-138

Reviewer 3

The authors wish to appreciate the constructive and insightful comments of the reviewer. We believe that these comments improved the quality of the manuscript and we have edited the manuscript accordingly.

Comments: The authors have conducted a meticulous study and reports significant results. A few corrections and clarifications are mentioned.

In the abstract and main text, it is best to stick to a similar format when reporting both numbers and percentages. If the number is within brackets such as in line 82 maintain a similar format throughout (line171, 185 in results section also uses 2 different formats in the same section).

Response: Authors appreciate the encouraging and constructive remarks of the reviewer.

The authors agree with the reviewer about maintaining uniformity. Therefore, we edited as suggested.

“Self-reported physician-diagnosed asthma prevalence was 6.6% (n=223) with only 41.7% (n=93) on regular medical follow-up for asthma.”

“The prevalence of asthma was 6.6% (n=223; 95%CI 5.8%–7.5%) with 22.9% (n=51) participants having documented evidence of a diagnosis of asthma (Table 2).”

“Only 41.7% (n=93) of the asthmatic pregnant women reported regular medical follow-up for asthma.”

“Of the 223 pregnancies, 28.3% (n=63) were unplanned with 2.3% (n=5) due to contraceptive failure.”

“Interestingly, 67.9% (n=36) of the study participants who reported an increase in the frequency of wheezing from pre-pregnancy to the first trimester had an unplanned pregnancy.”

“by 8.2% (n=6) and 16.4% (n=12), respectively.”

“habitual cigarette smoking and 20.3% (n=40) reported that at least one family member smoked”

‘reported by 62.5% (n=25, p=0.50),”

“pregnancy, first trimester and the second trimester was reported by 62.5% (n=25, p=0.50), 46.2% (n=18, p=0.97) and 40.0% (n=10, p=0.39)”

83-85, 186-188, 189-190, 190-191, 228-229, 233, 244-245, 247 and 248

Comment: In the abstract under methods, line 76, the word ‘study’ should be included after ‘prospective cohort’.

Response: We corrected the manuscript as suggested.

“We conducted a prospective cohort study in Anuradhapura district, Sri Lanka” 78

Comment: It is not clear whether new onset wheeze was reported in 6 out of what population in the abstract (mentioned in the text as 73).

Response: We amended the sentence as suggested by the reviewer for clarity.

“Of the 73 asthmatic women who did not have wheeze in the last 3 months preceding pregnancy, new-onset wheeze was reported by 6(8.2%) and 12(16.4%) in the first and second trimester, respectively” 86-88

Comment: It is good practice to mention the lost to follow up patients in the beginning of the results section and describe the final study population, mentioning Figure 01.

Response: Authors agree with the reviewer and edited the manuscript as suggested.

“Of the 3374 participants, 221 was selected as the asthmatic cohort (2 research participants with significant findings on 2D echocardiogram were excluded). Out of the 221 research participants with asthma, mid-pregnancy assessment at 24-28 weeks is available for 107 participants. The pregnancy outcomes - birthweight and preterm delivery - were assessed using hospital birth records.” 181-186

Comment: In line 226 it is mentioned ‘out of 221’ the proportion of LBW and preterm deliveries. However, Figure 01 states that 114 and 32 patients were lost to follow up. If so, how were the birth outcomes of all 221 assessed?

Response: We included the valid percentage (LBW/189). We edited the sentence to be more meaningful as suggested.

“Of the 221 pregnant asthmatics, birthweight and preterm delivery data was obtained from hospital records for 187 and 189 participants, respectively. There were 30 (16.0%) low birthweight (LBW) deliveries and 23 (11.1%) were preterm deliveries (Table 5).” 254-256

Comment: The prevalence of asthma was mentioned as 223 in line 171 and Table 02 but in Table 01 and Table 03 it is221. In line 226, also it is mentioned as 221 pregnant asthmatics. As two were excluded due to cardiac conditions it is clearer to mention so in the beginning of the results section.

Response: The authors included the following sentence in the first paragraph of the results section as suggested.

“Of the 3374 participants, 221 was selected as the asthmatic cohort (2 research participants with significant findings on 2D echocardiogram were excluded).” 181-183

Comment: Did 53 asthma patients not seek treatment (223-84-86)? If so, how were they diagnosed? (in methods section it is mentioned that physician reported, use of inhalers, nebulization, hospitalizations and exacerbating factors were used and table 02 indicates all 223 were physician diagnosed asthma)

Response: We used self-reported physician diagnosed asthma to identify patients with asthma. During data collection, further questioning on the use of inhalers, nebulization, hospitalization and exacerbating factors were used to clarify whether the participants reporting physician diagnosed asthma actually had asthma.

Of the 223 (including the two participants with significant comorbid cardiac conditions) 93 were on regular medical follow up for asthma. Others sought medical care only if they suffer an acute asthma exacerbation.

For clarity, we changed the term “current medical follow up” to “regular medical follow up” 84, 190, 347

Table 2

Comment: Table 02 and Table 06 also needs to be cited in text.

Response: Table 2 is cited in line 182 and Table 6 (renamed as Table 5 following the suggestion of one reviewer to move former table 5 to supplementary information) is cited in line 237

188, 256

Comment: Use either simple ‘p’ or ‘P’ throughout the text for better uniformity when reporting p value.

Response: As suggested, the authors changed to “p” for uniformity throughout the text. 90, 206, 208, 229, 244

Comment: Adjust the sentence in line 246 to better reflect the meaning.

Response: The sentence was edited to better reflect the meaning as suggested by the reviewer.

“In this cohort, a third of women who had an exacerbation were hospitalized: a number much larger than the estimated 20% that require interventions with only 6% requiring hospitalization” 286-288

Comment: In line 267, mention that asbestos is reported as having an association or known to. Currently it conveys that your study shows that there’s an association which is then contraindicated by the next statement.

Response: The authors edited the sentence as suggested by the reviewer.

“Similarly, having an asbestos roofing is known to be associated with asthma” 307-308

Reviewer 4

The authors appreciate the encouraging and constructive comments of the reviewer. We edited the manuscript accordingly.

Comment: It is a comprehensive and descriptive study, helping with having a picture of basic pregnancy care and infering problems that could be addressed in the future.

Response: Authors appreciate the encouraging comments of the reviewer.

Comment: Problems with sample size and data completeness.

Response: The authors agree with the reviewer and acknowledge the impact of the COVID-19 pandemic and the restrictions imposed to curtail the pandemic limited the opportunities for data collection. 356-361

Comment: Shaky asthma diagnosis.

Response: Authors agree with the reviewer and acknowledge the limitations in using self-reported asthma. We have included this as a limitation of the study. 344-348

Comment: Good starting point for future studies but with problems in their methodology making assumptions difficult.

Response: Authors agree that further studies are needed to understand the impact of asthma on pregnant women from rural geographies.

Submitted filename: Response letter.docx

Click here for additional data file.

30 May 2022

Asthma in a prospective cohort of rural pregnant women from Sri Lanka: need for better care during the pre-conceptional and antenatal period

PONE-D-21-40055R1

Dear Dr. Agampodi,

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Additional Editor Comments (optional):

Reviewers' comments:

7 Jul 2022

PONE-D-21-40055R1

Asthma in a prospective cohort of rural pregnant women from Sri Lanka: need for better care during the pre-conceptional and antenatal period

Dear Dr. Agampodi:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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