The impacts of parity on lung function data (LFD) of healthy females aged 40 years and more issued from an upper middle income country (Algeria): A comparative study.

BACKGROUND: Studies evaluating the impacts of parity on LFD of healthy females presented controversial conclusions. AIM: To compare the LFD of healthy females broken down according to their parities.
METHODS: A medical questionnaire was administered and anthropometric data were determined. Two groups [G1 (n = 34): ≤ 6; G2 (n = 32): > 6] and three classes [C1 (n = 15): 1-4; C2 (n = 28): 5-8; C3 (n = 23): 9-14] of parities were identified. LFD (plethysmography, specific airway resistance (sRaw)] were determined. Student's t-test and ANOVA test with post-Hoc test were used to compare the two groups' and the three classes' data.
RESULTS: G1 and G2 were age and height matched; however, compared to G1, G2 had a lower body mass index (BMI). C1, C2 and C3 were height, weight and BMI matched; however, compared to C2, C3 was older. G1 and G2 had similar values of FEV1, forced- and slow- vital capacities (FVC, SVC), maximal mid-expiratory flow (MMEF), forced expiratory flow at x% of FVC (FEFx%), peak expiratory flow (PEF), expiratory and inspiratory reserve volumes (ERV, IRV, respectively), inspiratory capacity (IC), sRaw, FEV1/FVC, FEV1/SVC, and residual volume/total lung capacity (RV/TLC). The three classes had similar values of MMEF, FEFx%, PEF, thoracic gas volume (TGV), ERV, IRV, FEV1/FVC, FEV1/SVC and RV/TLC. Compared to G1, G2 had higher TGV (2.68±0.43 vs. 3.00±0.47 L), RV (1.80±0.29 vs. 2.04±0.33 L) and TLC (4.77±0.62 vs. 5.11±0.67 L). Compared to C1, C2 had higher FEV1 (2.14±0.56 vs. 2.47±0.33 L), FVC (2.72±0.65 vs. 3.19±0.41 L), SVC (2.74±0.61 vs. 3.24±0.41 L), TLC (4.47±0.59 vs. 5.10±0.58 L), IC (1.92±0.41 vs. 2.34±0.39 L) and sRaw (4.70±1.32 vs. 5.75±1.18 kPa*s). Compared to C1, C3 had higher TLC (4.47±0.59 vs. 5.05±0.68 L) and RV (1.75±0.29 vs. 2.04±0.30 L).
CONCLUSION: Increasing parity induced a tendency towards lung-hyperinflation.

Introduction

Respiratory aging, which would start from the age of 35–40 [1], can be estimated from lung function data (LFD), recognized as predictors of mortality and morbidity [2]. Indeed, the American thoracic and the European respiratory societies (ATS/ERS) recommended the use of LFD to diagnose any respiratory defect, even before any clinical manifestation [3]. In a healthy and asymptomatic population, the decline in LFD is associated with a high risk of cardiopulmonary diseases and all other causes of death [4]. Since the different aspects of LFD’ decline are still inescapable [5], and since the determination of numerous factors of LFD’ decline is ongoing, their analysis is necessary to formulate strategies to prevent lung-aging, especially in females without clinical symptoms [6].

In practice, once lung function test quality has been validated, the succeeding step consists in comparisons of measured/determined LFD with data generated from reference equations based on healthy subjects [3]. On the one hand, these equations are based on the subject’s ethnicity and included as influencing factors sex and some anthropometric data [eg, age, height, weight and body mass index (BMI)] [3, 7, 8]. On the other hand, LFD’ influencing factors are numerous and are not limited to the aforementioned characteristics, which explain only 70% of their variance [9]. According to the literature, the influence of different characteristics/factors on the variance of the forced vital capacity (FVC) is ± 30% for sex, 20% for height, 10% for group ethnic, 8% for age, 3% for technical factors, 2% for weight, and the remaining 30% for other factors [eg, air pollution, climatic conditions, altitude, socioeconomic-level, schooling-level, physical-activity level, thoracic diameter, nutritional status] [9, 10]. Among the remaining LFD influencing factors, parity has been proposed in some studies [6, 7, 11–22]. On the one hand, contrary to high income countries such as European and North American ones, parity is a particular issue in low- and lower-middle-income countries such as African ones [23]. For example, during 2015, while the European and the Asian parity means were respectively, 1.616 and 2.173, that of Africa was 4.589 [23] (S1 File). Moreover, in some African countries, the 2015 mean values of parity were higher than six [eg, 6.365, 6.202, 6.145 and 6.050, respectively, in Chad, Somalia, Democratic Republic of Congo and Mali] [23] (S1 File). To the best of the authors’ knowledge, few studies, published between 1999 and 2018, have raised the impact of parity on healthy females’ LFD [USA (n = 1 [11]), Tunisia (n = 3 [6, 7, 12]), Nigeria (n = 2 [14, 16]), Brazil (n = 1) [15]] with contradictory results. On the one hand, some studies concluded that high parity was associated with positive effects on LFD of American [, larger forced expiratory volume in 1 s (FEV1) and FVC [11]] or of Nigerian [, increases in FEV1 and FVC [14], even across all females positions [16]] In the other hand, some other studies concluded that high parity was associated with negative effects on LFD of Tunisian [, reduction in peak flow rate [7], a tendency towards a proximal obstructive ventilatory defect (OVD) [6] and acceleration of lung-aging [12, 13]], or of Brazilian aged < 25 years [eg, lower maximal mid-expiratory flow (MMEF) and peak expiratory flow (PEF) [15]]. Moreover, a North-African study concluded that compared to aging by one year, the parity increase of one unit, caused a greater LFD’ decline [, FEV1 declines were 23 and 33 mL, respectively, per year of age and when parity increases by one unit [6]].

In view of the above divergence between studies, the main aim of the present study was to compare the LFD of healthy North-African females broken down according to their parities into two groups [G1: parity ≤ 6; G2: parity > 6] and three classes [C1: parity ≤ 4; C2: 5 ≤ parity ≤ 8; C3: parity ≥ 9]. The second aim was to determine the relationship between parity and some LFD.

Population and methods

This present study is part of a project involving four parts. The first, which was recently published [24], aimed at testing the applicability of the global lung initiative (GLI-2012) norms on a sample of healthy adults living in Algiers. The second, recently published [10], aimed to test the applicability of the Eastern Algeria plethysmographic norms [8] on a sample of healthy adults living in Algiers. The third part is the objective of this study. The fourth part, will be the establishment, according to recent international recommendations [25], of plethysmographic norms specific to the population of northern Algeria. For the above reasons, a large part of the methodology of this study has already been the object of previous descriptions [10, 24].

Study design

It was a comparative study performed in the Department of Pneumology, Phtisiology and Allergology at the Rouiba Hospital, Algiers. The study was conducted in compliance with the ‘Ethical principles for medical research involving Human subjects of the Helsinki Declaration (https://www.wma.net/wp-content/uploads/2016/11/ethics_manual_arabic.pdf; last visit: September 25th 2019). The study was approved by the Rouiba Hospital (Algiers) Medical Council and Ethics Committee (approval number: 0601/2014). Written informed consent was obtained from all participants who were not charged any costs for the accomplished tests.

Sample size

The null hypothesis [26] was H0: m1 = m2, and the alternative one was Ha: m1 = m2 + d, where “d” is the difference between two means and n1 and n2 are the sample sizes for the two groups (G1 and G2) of females, such N = n1 + n2. The sample size was estimated using the following formula [26]:

“Zα/2” is the normal deviate at a level of significance = 1.64 (0.10 level of significance);

“Z1-β” is the normal deviate at 1-β% power with β% of type II error (0.84 at 80% statistical power);

“R” (= n1/n2) is the ratio of sample size required for two groups (R = 1 gives the sample size distribution as 1:1 for two groups);

“s” and “d” are the pooled standard-deviation (SD) and difference of total lung capacity (TLC) means of two groups. These two values were obtained from a Tunisian study including females aged ≥ 60 years [6] where TLC means of two groups of females (parity < 4 vs. parity ≥ 4) were, respectively, 5.01 and 4.62 L, with a common SD equal to 0.92 L. The sample size for the study was 68 (34 females in each group).

Population: Inclusion, non-inclusion and exclusion criteria

The target population consisted of a group of healthy adults aged ≥ 18 years. These adults were selected by convenience sampling among visitors and the acquaintances of hospitalized patients in the aforementioned Department. The population was relatively homogeneous and considered as belonging to the middle class with an elevated human development index of 0.75 [27]. The latter is a measure of the average quality of life of a country's population, ranging from 0 to 1, and takes into account three dimensions of human development (life expectancy, years of schooling, and income).

Only healthy females aged ≥ 40 years with at least one parity and presenting technically acceptable and reproducible plethysmographic maneuvers were included in this study. The following non-inclusion criteria were applied: acute or chronic diseases of the respiratory system [, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, tuberculosis] or previous hospitalization for pulmonary or thoracic problems; cardiac diseases that may affect the respiratory system [, heart failure, arrhythmia, unstable angina or myocardial infarction, uncontrolled high blood pressure]; current-smoker or ex-smoker of more than one pack-year; leanness and obesity stage 2 and more; and high physical-activity level [, sports practice > 5 h/week [6]].

The total population was divided into four groups: a group for the development of plethysmographic norms specific to northern Algeria’ population (n = 491, 49.7% females), a group for the validation of the GLI-2012 spirometric norms (n = 300, 50.0% females) [24], a group for the validation of the Eastern Algeria plethysmographic norms (n = 453, 51.7% females) [8], and this study group (n = 66 females).

Collected data

Clinical data were collected using the ATS questionnaire [28], widely described elsewhere [8, 10, 24]. Parity, defined as the number of offspring a female has borne, was introduced in three forms: numerical (unit), two groups [G1 (parity ≤ 6); G2 (parity > 6)] and three classes [C1: 1 ≤ parity ≤ 4; C2: 5 ≤ parity ≤ 8; C3: parity ≥ 9] [17, 29–31]. Menopausal status was determined using the stages of reproductive aging workshop classification [32]. Females were classified into premenopausal (regular or irregular menses) or postmenopausal (lack of menses for over one year or hysterectomy).

The decimal age was calculated from the date of measurement and the date of birth. Standing height (m) and weight (kg) were recorded and BMI (kg/m2) was calculated. Obesity status was categorized into leanness (BMI < 18.5), normal weight (18.5 ≤ BMI ≤ 24.9), overweight (25.0 ≤ BMI ≤ 29.9), and obesity stages 1 (30.0 ≤ BMI ≤ 34.9), 2 (35.0 ≤ BMI ≤ 39.9) and 3 (BMI > 40.0) [33].

Plethysmographic measurements

LFD were determined by one qualified person (AK in the authors’ list) via a plethysmograph (Body-box 5500, MediSoft, Belgium). The latter was calibrated each morning. The following data were determined: flow-volume curve’ data [FVC (L), FEV1 (L), PEF (L/s), MMEF (L/s), forced expiratory flow when x% FVC remains to be exhaled (FEFx%, L/s)], volumes and capacities [expiratory reserve volume (ERV, L), inspiratory reserve volume (IRV, L), inspiratory capacity (IC, L), slow vital capacity (SVC, L), residual volume (RV, L), TLC (L), thoracic gas volume (TGV, L)], ratios (FEV1/FVC, FEV1/SVC, RV/TLC, absolute values), and specific airway resistance (sRaw, kPa*s).

The plethysmographic measurements were performed according to the international recommendations [34, 35], widely described elsewhere [8, 10, 24, 36], and the reproducibility and acceptability criteria were respected [34, 35]. The acceptability and reproducibility of the FVC maneuvers were described elsewhere [24]. Regarding the TGV repeatability, at least three values were obtained so that the difference between the highest and the lowest TGV values divided by the mean was ≤ 0.05 [35]. The TGV average value was selected [35].

Statistical analysis

Qualitative and quantitative data were expressed by their mean±SD and relative frequencies. Student’s t-test and Chi-square test were used to compare, respectively, the two groups’ of parity quantitative and qualitative data. An analysis of variance with post-Hoc test was carried out for the three parity classes’ quantitative data. The Pearson Chi-square test was used to compare the obesity and menopause statuses of the three parity classes. When applicable, significant differences between percentages were tested using the McNemar test. Determination-coefficient (r2 = square of the Pearson product-moment correlation-coefficient) evaluated the associations between parity, and plethysmographic and anthropometric data. “r2” was considered as “clinically significant” when it was > 0.30 [37]. Hedge's TLC value was used for effect size measurement [38]. An effect size of ≤ 0.2 was described as a small effect, around 0.5 as medium effect, around 0.8 as a large effect, and more than 1.30 as very large effect [38]. All mathematical computations and statistical procedures were performed using Statistica software (Statistica Kernel version 6; Stat Software. France). Significance was set at 0.05 level.

Results

Among the 244 females included in the whole project, 121 were excluded from this study (97 were under 40 years of age and 24 were nulliparous). The parity’ mean±SD of the remaining 123 females aged ≥ 40 with at least one parity was 6.4±3.5. Based on this data, two groups were randomly chosen to be age- and height- matched [G1 (parity ≤ 6) (n = 34), G2 (parity > 6) (n = 32)]. Fig 1 presents the mean age of the 66 females divided according to their parities. Females with parity equaling 6 (n = 10), 5 (n = 9), 4, 9 and 10 (n = 7 each) dominated the distribution. All together their represented 60.6% of the total sample.

Fig 1

Mean age of the 66 females broken down according to their parities (numerical data).

Table 1 exposes the data of the females divided into two groups of parities. The two groups were age- and height- matched, and included similar percentages of menopaused females. Compared to the G1, the G2 was lighter, had a significantly lower BMI, and included a lower percentage of females with obesity stage 1. The two groups had similar values of the flow-volume curve’ data, sRaw and ratios. Compared to the G1, the G2 had significantly higher TGV, RV and TLC. The TLC effect size was medium (Hedges’ unbiased d = +0.521).

Table 1

Characteristics and plethysmographic data of the total sample and of females divided into two groups (G) of parities: G1 (parity ≤ 6) and G2 (parity > 6).

		Total sample (n = 66)	G1 (n = 34)	G2 (n = 32)	p
Parity, anthropometric data, obesity and menopause status
Parity	numerical	7±3	4±1	10±2	0.00001
Age	Years	60±9	58±9	62±8	0.0649
Height	m	1.56±0.05	1.55±0.06	1.56±0.05	0.6530
Weight	kg	70±10	73±10	67±9	0.0271*
BMI	kg/m2	28.8±3.7	30.0±3.60	27.6±3.4	0.0073*
Obesity status	Normal weight	12 (18.2)	4 (11.8)	8 (25.0)	0.1648
	Overweight	27 (40.9)	11 (32.3)	16 (50.0)	0.1438
	Obesity stage 1	27 (40.9)	19 (55.9)	8 (25.0)	0.0107**
Menopause	Yes	58 (87.9)	28 (82.3)	30 (93.8)	0.1526
Flow-volume curve’ data
FEV1	L	2.33±0.42	2.32±0.49	2.33±0.34	0.9331
FVC	L	3.01±0.53	2.97±0.59	3.04±0.47	0.6001
MMEF	L/s	3.03±0.61	3.11±0.71	2.95±0.46	0.2925
FEF25%	L/s	0.89±0.44	0.92±0.41	0.86±0.46	0.6167
FEF50%	L/s	3.22±0.90	3.31±0.95	3.12±0.85	0.3987
FEF75%	L/s	5.18±1.02	5.30±1.16	5.05±0.86	0.3089
PEF	L/s	5.72±1.16	5.87±1.38	5.56±0.87	0.2796
Volumes and capacities
SVC	L	3.05±0.53	3.01±0.57	3.09±0.49	0.5457
TGV	L	2.83±0.47	2.68±0.43	3.00±0.47	0.0053*
RV	L	1.91±0.33	1.80±0.29	2.04±0.33	0.0026*
TLC	L	4.94±0.66	4.77±0.62	5.11±0.67	0.0349*
ERV	L	0.88±0.37	0.82±0.35	0.93±0.38	0.2351
IRV	L	1.55±0.42	1.60±0.46	1.50±0.37	0.3776
IC	L	2.17±0.43	2.19±0.48	2.16±0.38	0.8005
Airway resistances
sRaw	kPa*s	5.47±1.26	5.34±1.343	5.60±1.17	0.3906
Ratios
FEV1/FVC	absolute value	0.77±0.04	0.78±0.04	0.77±0.03	0.1801
FEV1/SVC	absolute value	0.76±0.05	0.77±0.05	0.76±0.05	0.2686
RV/TLC	absolute value	0.39±0.05	0.38±0.06	0.40±0.04	0.1743

BMI: body mass index. ERV: expiratory reserve volume. FEF: forced expiratory volume at x% of FVC. FEV: forced expiratory volume in 1 s. FVC: forced vital capacity. IC: inspiratory capacity. IRV: inspiratory reserve volume. MMEF: maximal mid-expiratory flow. PEF: peak expiratory flow. RV: residual volume. sRaw: specific resistance airway. SVC: slow vital capacity. TGV: thoracic gas volume. TLC: total lung capacity. Quantitative data were mean±SD. Qualitative data (obesity and menopause status) were number (%).

*p (student test) < 0.05: G1 vs. G2.

**p (Chi-2 test) < 0.05: G1 vs. G2.

Table 2 exposes the data of the females divided into three classes of parities (C1: 1–4; C2: 5–8; C3: 9–14). The three classes were height-, weight-, BMI- and obesity status- matched; however, compared to C2, C3 was older. Compared to the C2, the C1 and the C3 included higher percentages of menopaused females. The three classes had similar values of MMEF, FEFx%, PEF, TGV, ERV, IRV and ratios. Compared to the C1, the C2 had significantly higher FEV1, FVC, SVC, TLC, IC and sRaw. Compared to the C1, the C3 had significantly higher TLC and RV.

Table 2

Characteristics and plethysmographic data of the females divided into three classes (C) of parities: C1 (parity ≤ 4); C2 (5 ≤ parity ≤ 8) and C3 (9 ≤ parity ≤ 14).

		C1 (n = 15)	C2 (n = 28)	C3 (n = 23)	p
Parity, anthropometric data, obesity and menopause status
Parity	numerical	3±1	6±1	10±1	0.0000*abc
Age	Years	61±8	56±10	64±6	0.0062*c
Height	m	1.56±0.06	1.56±0.05	1.55±0.05	0.7454
Weight	kg	71±10	72±10	67±9	0.0961
BMI	kg/m2	29.4±4.2	29.6±3.7	27.6±3.2	0.1264
Obesity status	Normal weight	3 (20.0)	4 (14.3)	5 (21.7)	0.2054
	Overweight	4 (26.7)	10 (35.7)	13 (56.4)
	Obesity stage 1	8 (53.3)	14 (50.0)	5 (21.7)
Menopause	Yes	15 (100.0)	20 (71.4)	23 (100.0)	0.0021**ac
Flow-volume curve’ data
FEV1	L	2.14±0.56	2.47±0.33	2.27±0.37	0.0301*a
FVC	L	2.72±0.65	3.19±0.41	2.96±0.50	0.0167*a
MMEF	L/s	2.93±0.75	3.17±0.65	2.93±0.41	0.2788
FEF25%	L/s	0.84±0.44	1.02±0.52	0.77±0.26	0.1209
FEF50%	L/s	3.14±1.06	3.45±0.86	2.99±0.80	0.1822
FEF75%	L/s	5.03±1.19	5.33±1.08	5.09±0.84	0.5758
PEF	L/s	5.56±1.55	5.91±1.11	5.58±0.93	0.5121
Volumes and capacities
SVC	L	2.74±0.61	3.24±0.41	3.02±0.53	0.0115*a
TGV	L	2.64±0.41	2.83±0.46	2.97±0.50	0.1054
RV	L	1.75±0.29	1.90±0.33	2.04±0.30	0.0223*b
TLC	L	4.47±0.59	5.10±0.58	5.05±0.68	0.0050*ab
ERV	L	0.83±0.33	0.90±0.34	0.87±0.43	0.8214
IRV	L	1.37±0.43	1.66±0.41	1.54±0.40	0.0856
IC	L	1.92±0.41	2.34±0.39	2.15±0.42	0.0075*a
Airway resistances
sRaw	kPa*s	4.70±1.32	5.75±1.18	5.62±1.16	0.0227*a
Ratios
FEV1/FVC	absolute value	0.78±0.04	0.77±0.03	0.77±0.03	0.5511
FEV1/SVC	absolute value	0.77±0.04	0.76±0.05	0.75±0.05	0.4862
RV/TLC	absolute value	0.39±0.07	0.37±0.05	0.41±0.04	0.0719

For abbreviations, see Table 1. Quantitative data were mean±SD. Qualitative data (obesity and menopause status) were number (%).

*p (analysis of variance) < 0.05: comparison between the 3 classes. Tukey test: C1 vs. C2; C1 vs. C3; C2 vs. C3.

**p (Pearson Chi-square) < 0.05: comparison between the 3 classes. Mac-Nemar test: C1 vs. C2; C1 vs. C3; C2 vs. C3.

Table 3 presents the “r2” between parity, and anthropometric and plethysmographic data. No “clinically significant” correlation was found between anthropometric or plethysmographic data, and parity of the total sample, G2, C2 or C3 (all “r2” were < 0.30). In the G1, a positive “clinically significant” correlation was found between parity and SVC. In C1, a negative “clinically significant” correlation was found between parity and age, and positive “clinically significant” correlations were found between parity and FEV1, FVC, MMEF, FEF75%, PEF, SVC, TGV and ERV.

Table 3

Determination coefficient (r2) between anthropometric and plethysmographic data, and parity.

		Total sample (n = 66)	Groups (G)		Classes (C)
			G1	G2	C1	C2	C3
Anthropometric data
Age	years	0.0265	0.0269*b	0.1500*b	0.6889*a	0.0079	0.0363
Weight	kg	0.0447	0.0164	0.0029	0.0162	0.0323	0.0238
BMI	kg/m2	0.0524	0.0014	0.0172	0.1098	0.1160	0.1288
Plethysmographic data
FEV1	L	0.0085	0.2286*b	0.2292*b	0.3094*a	0.0084	0.1292
FVC	L	0.0076	0.2699*b	0.1699*b	0.3130*a	0.0008	0.1849*b
MMEF	L/s	0.0032	0.1092	0.0334	0.3115*a	0.0938	0.0254
FEF25%	L/s	0.0178	0.0423	0.1667	0.0943	0.0019	0.1915*b
FEF50%	L/s	0.0106	0.0711	0.0895	0.1865	0.0135	0.0221
FEF75%	L/s	0.0001	0.1120	0.0005	0.3489*a	0.1167	0.0005
PEF	L/s	0.0001	0.1504*b	0.0022	0.4056*a	0.0778	0.0100
SVC	L	0.0094	0.3009*a	0.1630*b	0.3067*a	0.0045	0.1540
TGV	L	0.0958*b	0.0600	0.0092	0.3008*a	0.1633*b	0.0092
RV	L	0.1094*b	0.0104	0.0001	0.0142	0.1103	0.0099
TLC	L	0.0624*b	0.2800*b	0.0868	0.2492	0.0623	0.1235
ERV	L	0.0043	0.0300	0.1013	0.3823*a	0.0857	0.0476
IRV	L	0.0003	0.2195*b	0.0036	0.0692	0.0944	0.0899
IC	L	0.0039	0.2759*b	0.0395	0.1119	0.0335	0.0726
sRaw	kPa*s	0.0194	0.0789	0.0071	0.2085	0.0063	0.0504
FEV1/FVC	absolute value	0.0292	0.0011	0.0209	0.0793	0.0979	0.0407
FEV1/SVC	absolute value	0.0183	0.0008	0.0085	0.2067	0.0407	0.0004
RV/TLC	absolute value	0.0194	0.1340*b	0.1671*b	0.2185	0.0363	0.1007

For abbreviations, see Table 1. G1 (n = 34): parity ≤ 6. G2 (n = 32): parity > 6. C1 (n = 15): 1 ≤ parity ≤ 4. C2 (n = 28): 5 ≤ parity ≤ 8. C3 (n = 23): 9 ≤ parity ≤ 14.

*p < 0.05: significant r2. Correlations were: Clinical significant: “r2” ≥ 0.30; Non clinical significant: “r2” < 0.30.

Discussion

The main results of the present study were that the two groups of parities had similar flow-volume curve’ data values, sRaw and ratios; and that the three classes of parities had similar values of MMEF, FEFx%, PEF, TGV, ERV, IRV and ratios. However, compared to the G1, the G2 had higher TGV, RV and TLC; compared to the C1, the C2 had higher FEV1, FVC, SVC, TLC, IC and sRaw; and compared to the C1, the C3 had higher TLC and RV. The clinical significance of this study is clear: high parity is associated with a tendency towards lung-hyperinflation and two females of similar age and height, but of two different parities, have different lung static volumes.

The respiratory phenomenon highlighted in this study may be an evidence of a more general aging phenomenon related to multiparity [39]. The link between parity and longevity is widely discussed in the scientific literature in terms of "selection pressure" [39]. Above all, it is the lung which both generates and undergoes the repercussions of the multiple physio-pathological episodes of the female life. Indeed, it is known that multiparity has adverse health effects, with a high risk of heart disease and renal cancer [40, 41]. Gestation is probably an event that, when repeated, may have consequences for LFD. In females, such study is needed in order to better understand some specific factors contributing in their lifelong LFD’ loss. It should be noted that, while the total fertility rate in Algeria declined from 1951 to 2015 (from 7.279 to 2.839 or 3.100 children [42]), it remained still higher in some other African countries [23] (S1 File). To the best of the authors’ knowledge, the impacts of parity on healthy females’ LFD has been treated in only a few publications [6, 7, 11–16], largely described in the S2 File.

Methodology discussion

Discussion related to the study design, the applied inclusion and non-inclusion criteria, the choice of the cutoff of six parities, and some LFD influencing factors is highlighted in the S3 File.

This study presents four limitations related to the non-identification of the schooling-level, socioeconomic-level, physical-activity level, and number of caesareans. The first three factors, recognized as LFD’ influencing factors [6, 11, 43, 44], may differ between the two groups and the three classes of parities, and therefore can explain the tendency towards lung-hyperinflation observed in the G2, C2 and C3. First, compared to females with a high schooling-level, those with a low level had higher parity [20] and lower LFD [6]. However, LFD differences concerned only peripheral flows such as PEF (increase by 254 mL/s) and FEF25% (increase by 150 mL/s) [6]. Secondly, in high-income countries, compared to females with a high socioeconomic-level, those with a low one had higher parity [20], lower LFD [43, 44], and a tendency towards a distal OVD [44]. Moreover, in Polish females with COPD, the FEV1 decline’ acceleration with increased parity (≥ 4) was accounted for by the low socioeconomic-level of the latter [20]. However, it seemed that North-African females’ LFD weren’t influenced by the socioeconomic-level [6]. Thirdly, physical-activity level was positively correlated with some LFD (eg, FEV1, FVC, FEV1/SVC, PEF and FEF50%) [6]. Yet, no correlation existed with static lung volumes (eg, TGV, RV, TLC) [6]. Moreover, in this study, it can be speculated that included females were sedentary since only females with low physical-activity levels were included. At least, it was better to report the number of caesarians for each female and to study its correlation with LFD. In fact, caesarean section induced a decrease in abdominal muscle strength [45], which can influence the needed forced expiratory maneuvers during the plethysmographic test. A specific study about the above mentioned issue will be of a great interest in the respiratory field.

Results discussion

LFD are very interesting markers used to define the respiratory system’s ageing, since their declines are a predictor of mortality [46]. But is-it possible to distinguish between “normal aging” in relation to the natural wear of the respiratory system and “pathological aging”, which is characterized by increased, above-normal, deterioration of this system? The contribution of physiology is fundamental in this context [6]. The impacts of parity on the LFD of healthy females has been treated in few publications [6, 7, 11–16], especially bearing on those aged ≥ 40 years [6, 7, 11–13] (S2 File). Moreover, among the aforementioned studies, only one determined plethysmographic LFD [6]. Other studies evaluated the impacts of parity on respiratory muscle strength [17, 21] and physical function [18, 30] of healthy females, and some others included females with chronic diseases [eg, COPD [20], protease inhibitor phenotype [19], diabetes [31] and sleep-apnea syndrome [29]]. This study showed that the G2 compared to the G1, and C2 or C3 compared to C1, had a tendency towards lung-hyperinflation. The latter, a major concern in the management of some chronic respiratory diseases [36, 47], leads to an increase in the relaxation volume due to the reduction of lung elastic retraction forces [48]. Lung-hyperinflation has deleterious clinical, functional and radiological consequences that make it a major source of impaired quality of life [48, 49].

This study’s main results are intermediate among those reported in literature (S2 File). On the one hand, findings related to FEV1 and FVC (compared to the C1, the C2 had significantly higher FEV1, FVC and sRaw (Table 2)) are partially similar to those obtained in some studies [11, 14, 16]. First, it seems that younger American females (< 50 years) with parity ≥ 1, compared to nulliparous ones, had larger FEV1 and FVC [11] (S2 File). Secondly, it appears that increased parity (primigravida, nullipara, primipara, para2 and para3) favorably affects the LFD of Nigerians, with increases in both FEV1 and FVC [14]. Thirdly, as parity increases (primigravida, nullipara, primipara, para2 and para3), Nigerians’ FVC and FEV1 also increased across all studied positions [16]. Fourthly, a North-African study showed that high parity leads to a decrease in total airway conductance [6]. On the other hand, the present study findings related to FEV1 FVC and peripheral airway flows (Table 2) are partially opposite with these of others concluding that multiparity negatively impacts LFD [6, 7, 12, 13, 15] (S2 File). First, a study including females aged ≥ 60 years [7], concluded that compared to females with a parity ≤ 4, those with a parity > 4 had lower FEV1, FEV1/FVC, MMEF and PEF. Secondly, another study including females aged ≥ 40 years [6], concluded that multiparity leads to a tendency towards an OVD with a decrease in FEV1/FVC. Thirdly, compared to Brazilian nulliparous females aged < 25 years, those with a parity ≥ 1 had lower MMEF during the first trimester and lower PEF during the third trimester [15]. Fourthly, it appears that parity accelerated lung-aging, with an increase of one parity rising the estimated lung-age by 1.2 years [12, 13]. Finally, findings related to TGV, RV and TLC (Tables 2 and 3) are totally opposite with these of the only study that evaluated static volumes [6] (S2 File). While this study’s findings suggested that multiparity is associated with a tendency towards lung-hyperinflation (Tables 2 and 3), a Tunisian study showed that the two groups (≤ 3; > 4) and the three classes (0–2; 3–4; > 5) of parities had similar TGV, VR and TLC data (expressed as percentage of predicted values), meaning the lack of a trend towards lung-hyperinflation [6].

The present study correlations between parity and LFD (Table 3) are intermediate between those reported in the literature [6, 7, 11] (S2 File). On the one hand, similar to this study, where no correlation was found between the parities of the total sample, G2, C2 and C3, and LFD (Table 3), one study also reported no correlation between the parity (mean not reported) and the flow-volume curve data (ie, FVC, FEV1, MMEF, PEF) [7]. Moreover, another study reported no correlation between parity (mean: 4±2) and static lung volumes (ie, TGV, TLC, RV) [6], and reported negative but not “clinically significant” correlations between parity and FVC, FEV1, PEF, FEF75%, FEF50%, MMEF and SVC (all “r2” were < 0.30) (S2 File). In addition, positive but not “clinically significant” correlations were noted between parity of 397 Caucasians (mean not reported) and FEV1 (S2 File) [11]. On the other hand, similar to this study, where “clinically significant” correlations were found between parity and G1’ SVC and C1’ some LFD (Table 3), another study identified a negative “clinically significant” correlation between parity and FEV1/SVC (r2 = 0.5334) [6]. Since parity wasn’t correlated either to weight or to BMI (Table 3), its impact on LFD appears to be independent from those two parameters.

The discrepancy between reported results in literature may be due to some different obstetric/anthropometric characteristics of the included females (S2 File): different parity means [4±2 [6], 5±3 [12, 13], 6±3 (this study)], different age ranges [21–28 [16], 18–92 [11], 19–90 [12, 13], 40–74 (this study), 45–90 [6], 60–96 [7]], different applied cutoff for parities [1 [11, 15], 3 [6], 4 [7], 6 (this study)], different groups of parities [n = 2 [6, 7, 11, 15], n = 3 [6], n = 4 [15], n = 5 [14, 16]].

How to explain the impacts of parity on LFD?

During healthy pregnancy, respiratory function is affected through both biochemical and mechanical pathways [50, 51]. Throughout gravidity, spirometry remains within normal ranges (ie; unchanged FVC, FEV1, and FEV1/FVC, unchanged or a modest increase of PEF [50-52]). Conversely, lung volumes endure for most variations: ERV progressively declines during the second half of gestation since RV decreases [50-52]. TGV then diminishes while IC rises in the same degree in order to conserve stable TLC [50-52]. Bronchial resistance rises whereas respiratory conductance decreases during gestation [50-52]. Total pulmonary and airways resistances have a tendency to decline in late gestation as a result of hormonally induced relaxation of tracheobronchial tree smooth muscles [51]. What happens with increasing parity? With increasing parity, the rise in TGV, RV and TLC (Tables 1 and 2), and therefore the tendency towards lung-hyperinflation, can be interpreted as an aging index of the ventilatory mechanics, or as an indirect sign towards an OVD and/or an expiratory muscle weakness [36, 53]. The tendency towards lung-hyperinflation can be explained by at least the four following hypothesizes:

Anatomical changes: during gestation, the progressive increase of the uterus volume is the main reason for lung volume and chest wall changes (eg, elevation of the diaphragm, altered thoracic shape) [50–51, 54]. The diaphragm elevation induced two phenomena: i) earlier closure of the lower airways with consequent reduction of TGV and ERV; ii) shorter chest height, but increase of the other thoracic dimensions in order to maintain constant TLC [50-52]. Gestation is also accompanied by changes in the mucosa of the upper and lower airways with the appearance of inflammatory phenomena [54, 55]. Thus, the effects of these changes, can accumulate with repeated gestations. Chest circumference may increase and hypotrophy of the respiratory muscles may develop. This will explain the decline of the maximal inspiratory pressure with high parity (S2 File) [56].

Hormonal changes: during gestation, the physiological adaptation of hormonal (progesterone, estrogen and prostaglandins) profiles is the foremost cause of ventilatory changes in respiratory function [50, 51]. Progesterone modifies the airways’ smooth muscle tone inducing a bronchodilator effect [50, 51]. Estrogen upsurges the number and the sensitivity of progesterone receptors within several nervous areas (eg, hypothalamus, medulla, and central neuronal respiratory-related areas) [50, 51]. Prostaglandin F2α rises airway resistance by bronchial smooth muscle constriction, whereas a bronchodilator effect can be a consequence of prostaglandins E1 and E2 [51]. The aforementioned hormonal changes are related to LFD variations [50, 57]. With repeated gestations, it can be speculated that hormonal changes persist and accumulate. During the ageing process, aging-induced hormonal changes can modify LFD [58] (eg, elderly female’ cortisol secretion determined the rate of the lung-aging [59]). Since gestation is experienced as a stressful situation, hormonal changes can increase in multiparous females.

Biochemical changes: the natural damage of elastin with age, contributing to the LFD’ decline, is less accelerated in females with a moderate deficiency in protease inhibitor and having a high parity [60]. This has been attributed to an improvement in elastin turnover in these females with high parity [60]. This finding has not been proven in females with normal protease inhibitor phenotype and high parity [60].

Bronchial hyperreactivity: with gestation, there is a decrease in bronchodilator factors (β2-adrenergic receptors and adenylyl-cyclase activity) in favor of an increase in bronchoconstrictor ones (prostaglandin F2α and cyclic guanosine monophosphatectively) [55]. These effects can accumulate with repeated gestations and partially explain the tendency towards lung-hyperinflation.

In conclusion, high parity is associated with a tendency towards lung-hyperinflation. In females, parity should be considered, along with sex and anthropometric data, as a major determinant of LFD.

Entity, Code, Year, “Estimates, 1950–2015: Demographic Indicators—Total fertility (live births per woman) (live births per woman)”.

(DOCX)

Click here for additional data file.

Studies evaluating the effects of parity on lung function data (LFD) of healthy females: Designs and results.

(DOCX)

Click here for additional data file.

Appendix: Discussion.

(DOCX)

Click here for additional data file.

Spirometric data of the 66 Algerian females.

Data are “Excel file”.

(XLSX)

Click here for additional data file.

21 Aug 2019

PONE-D-19-16514

The impacts of parity on lung function data (LFD) of healthy females aged 40 years and more issued from an upper middle income country (Algeria): a comparative study

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Reviewer #1: Overall this is a well written paper using sound methodologies. There are a few issues, however, in its current form.

Major comments:

While the authors spend a significant amount of time attempting to explain why they chose parity less than or equal to 6 as their definition of low parity, it still seems like it includes a high number. The authors mention in their introduction that parity is high in Africa but give reference to numbers which would be otherwise considered in the “low parity group,”( i.e everyone less than 6). Also in the results section they mention previous studies and different parity cutoffs which are all lower than the current study.

- Why not divide into 3 groups? 1-4, 5-8, 9-12 for instance.

- Can there be more information on the health of the females. You mention education, access to food and education, and that the average was 0.75. Then you mention in the discussion that SL, SEL, PAL cannot be identified. Why was this? Is this information included in the study?

- Higher parity can be associated with lower economic status. How do you adjust for that in your study?

Minor comments:

- “Since the different aspects of LFD’ decline are still inescapable [5], and since, the determination of numerous factors of LFD’ decline is not yet closed” – I don’t understand what closed means

- “while the total fertility rate in Algeria declined from 1951 to 2015 (from 7.279 to 2.839 or 3.100 children [42]), it remained still higher in some author African countries” -> I think you mean “other”

Reviewer #2: RE: PONE-D-19-16514 -- Parity and ageing of the respiratory system

Studies evaluating the impacts of parity on lung function data (LFD) of healthy females present controversial conclusions. Respiratory aging, can be estimated by lung function data (LFD), recognized as predictors of mortality and morbidity. These relationships are based on the subjects’ ethnicity and are included as influencing factors [eg, gender, age, height, weight and body mass index (BMI)].

Parity has been proposed as an additional influence in some studies. Contrary to European and North American studies, parity is of particular impact in low- and lower middle-income countries such as in Africa. In several African countries, recent values of parity were higher than six. A few studies, published between 1999 and 2018, raised the impacts of parity on healthy females’ LFD [USA (n=1), Tunisia (n=3), Nigeria (n=2) and Brazil (n=1)] with conflicting results. Some studies concluded that high parity was positively associated LFD while others concluded that it was associated with negative effects on LFD.

Thus, the purpose of this investigation was to compare lung function data (LFD) of two groups of healthy females divided according to their parities, and to determine the relationship between parity and LFD.

Methods. A medical questionnaire was administered and anthropometric data were determined. Parity was introduced as numeric and as dichotomous [G1 ≤ 6 parity; G2 >6 parity]. LFD (plethysmography, specific airway resistance (sRaw)] was performed. Correlation-coefficient (r) and Student’s t-test were used, respectively, to evaluate therelationships between parity and LFD (absolute values) and to compare the two groups’ mean±SD quantitative data.

Main results: Compared to GI, G2 had a lower mean body mass index (30.vs. 27.6) and a higher parity (4 vs. 10). G1 and G2 had similar values of forced expiratory volume in 1 s (FEV1), forced- and low- vital capacity (FVC, SVC), maximal mid-expiratory flow, forced expiratory flow at x% of FVC, peak expiratory flow, expiratory and inspiratory reserve volumes, inspiratory capacity, sRaw, FEV1/FVC, FEV1/SVC, and residual volume/total lung capacity (RV/TLC). Compared to G1, G2 had significantly higher thoracic gas volume, RV and TLC. In the total sample, significant positive correlations were found between parity and TGV (r=0.31), RV (r=0.33) and TLC (r=0.25).

The authors concluded that increasing parity induces a tendency towards lung-hyperinflation.

General comments:

A key goal of this study should be to describe and explain the differences between high and low parity women, and explain the differences found between the two cohorts and the mechanisms that would explain the findings. Instead, the authors launch into a lengthy disquisition of why lung function testing is obtained in general, how lung function changes with age and other factors (smoking, environment, etc), how cohort values are compared to controls, and a detailed description of differences in lung function amongst European, American and northern (the Sahel) and sub-Saharan African ethnic groups. This is interesting material but has little to do with the main purpose of the study which was ostensibly to assess the effects of parity on lung function (and what is implied in the title of the paper). The authors should have primarily focused on this topic. The rest of their discussion is better suited for a textbook or monograph on the epidemiology of lung function.

Not only that, but the paper is needlessly prolonged by repeating in the discussion much of what’s already stated in the introduction. The explanation for the changes in LFD is only briefly explained in a paragraph ending on p. 23. Instead of placing most of this information in the supplementary material it should be included as part of the main discussion – that is the main point of the paper.

Specific comments:

The paper needs grammatical and stylistic corrections. I will list a few:

1. Pages and lines should be numbered – makes changes easily traceable.

2. The authors should reconsider the weightedness and clinical importance of their correlation coefficients. From a clinically relevant standpoint, the correlation coefficient should be squared: an r-squared value of >0.3 is considered to be clinically relevant. Thus r=0.3 becomes 0.09, which is not clinically meaningful; r=0.4 becomes 0.16, also not relevant. In other words, what may be statistically significant may not be clinically significant or relevant.

3. Intro., l. 8, “…next line: “…ongoing...” instead of “… not yet closed…”

4. Next line: Instead of “…guaranteed...”, state “…has been validated…”

5. Intro, next page, l. 5: Chad is repeated in same sentence.

6. Same page, l. 7: For Tunisia there are 4 references cited, not 3.

7. Intro, last paragraph, l. 1: “In view of…” instead of “…in front of…”

8. Under plethysmographic measurements, l. 1; should read “Lung volume data were determined by… plethysmography (Body-box 5500…)".

9. Under discussion, last para, last line: “… still higher in other African countries.”

10. Under Methodology discussion, l. 8: “…who reported being healthy…”

11. Same section, next 2 pages: Beginning with “The non-inclusion criteria were respected.” all the way through the next page, ending with “… can’t be explained by their menopause status” should be deleted, as it is repetitious from the introduction and also not relevant to the discussion itself.

12. Results discussion, last 2 pages: Beginning with “The present study correlations…”, the authors just regurgitate what is already listed in the supplementary tables – this information should be transferred to the results section and not repeated here. Rather, the authors should expand on and explain their findings from a physiological standpoint, that is, how are the findings explained. This has much to do with physiologic differences of the thoracic cage between men and women and how pregnancy affects these mechanical properties during pregnancy and with repeated pregnancies. This would add a unique aspect to their discussion because there is not much information on the effects of multiparity on respiratory mechanics.

13. Again, these r-values should be squared to determine if they are truly clinically significant – many of the LFD changes will turn out to be not significant or relevant to parity.

14. Last page, last para.: This brief paragraph should be greatly expanded to explain the effects of multiparity on respiratory function (here, not in the supplement), particularly in regards to the lung hyperinflation – how is this event linked to changes in the thoracic cage? In fact, this expanded discussion should nearly completely replace the bloated epidemiologic data from different countries listed by the authors. Pregnancy likely affects the fundamental changes that occur in the respiratory system in a common way, with only subtle differences amongst ethnic/national groups.

In short, the information provided here is interesting, and relatively new and should be reported, but in a greatly revised form. It can be presented in a cleaner, more concise manner with greater emphasis placed on the physiologic explanations rather than just reporting epidemiologic data from different countries. The latter aspect can be considerably shortened. Finally, the clinical relevance of statistically significant correlations should be re-considered in a clinically relevant manner.

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25 Sep 2019

TO THE ACADEMIC EDITOR

Dear EDITOR,

Thank you for giving us the chance to review and improve our paper. Please find below the responses to the two reviewers questions/suggestions. Sincerely yours.

TO REVIEWER #1

Dear Reviewer,

Thank you for your comments. Please find below the responses to your questions/suggestions.

Sincerely,

REMARK N°1

Overall this is a well written paper using sound methodologies. There are a few issues, however, in its current form.

CORRECTIVE ACTION

All your suggestions were applied.

REMARK N°2 a

*While the authors spend a significant amount of time attempting to explain why they chose parity less than or equal to 6 as their definition of low parity, it still seems like it includes a high number. The authors mention in their introduction that parity is high in Africa but give reference to numbers which would be otherwise considered in the “low parity group,”( i.e everyone less than 6).

**Also in the results section they mention previous studies and different parity cutoffs which are all lower than the current study. Why not divide into 3 groups? 1-4, 5-8, 9-12 for instance.

RESPONSE

*Needed changes were applied over all the paper.

**We have takin into account your suggestion to divide the population into three 3 classes:

Parity 1-4: n=15

Parity 5-8: n=28

Parity 9-14: n=23

CORRECTIVE ACTION

*The following sentence was deleted from the “Introduction” “[eg, 2.570, 3.229, 4.673, 4.927, 5.374 and 5.749, respectively, in Middle-, Southern-, Northern-, Eastern-, Sub-Saharan-, and Middle- Africa]”.

**In the “Methods” section, we have added that our population was divided into two groups (Table 1) and into three classes (Table 2) of parity.

*We have also applied all needed changes in the text (Methods, Results, Discussion, Tables).

REMARK N°2 b

Can there be more information on the health of the females. You mention education, access to food and education, and that the average was 0.75. Then you mention in the discussion that SL, SEL, PAL cannot be identified. Why was this? Is this information included in the study?

RESPONSE

In the manuscript (L185-187), we have noted that “The population was relatively homogeneous and considered as belonging to the middle class with an elevated human development index of 0.75 [27].” The information was retrieved from the following reference (ref 27): Human development index in Algeria. Therefore, SL, SEL, PAL weren’t objectively determined.

CORRECTIVE ACTION

Education (schooling level) was addressed as a limitation study (L303-306): “First, compared to females with a high schooling-level, those with a low level had higher parity [20] and lower LFD [6]. However, LFD differences concerned only peripheral flows such as PEF (increase by 254 mL/s) and FEF25% (increase by 150 mL/s) [6].”

REMARK N°2 c

Higher parity can be associated with lower economic status. How do you adjust for that in your study?

RESPONSE

We agree with your remark. The association between high parity and lower socioeconomic level was highlighted as a study limitation (L306-311).

CORRECTIVE ACTION

The following sentence is noted in the paper (L306-311): “Secondly, in high-income countries, compared to females with a high socioeconomic-level, those with a low one had higher parity [20], lower LFD [43, 44], and a tendency towards a distal OVD [44]. Moreover, in Polish females with COPD, the FEV1 decline’ acceleration with increased parity (≥ 4) was accounted for by the low socioeconomic-level of the latter [20]. However, it seemed that North-African females’ LFD weren’t influenced by the socioeconomic-level [6].”

REMARK N°3 a

Since the different aspects of LFD’ decline are still inescapable [5], and since, the determination of numerous factors of LFD’ decline is not yet closed” – I don’t understand what closed means

RESPONSE

The sentence was corrected (as suggested by the 2nd reviewer: please see his remark 9c)

CORRECTIVE ACTION

“ongoing” replaced “not yet closed” L110.

REMARK N°3 b

while the total fertility rate in Algeria declined from 1951 to 2015 (from 7.279 to 2.839 or 3.100 children [42]), it remained still higher in some author African countries” -> I think you mean “other”

RESPONSE

Correction done.

CORRECTIVE ACTION

Please see L292

TO REVIEWER #2

Dear Reviewer,

Thank you for your comments. Please find below the responses to your questions/suggestions. Sincerely yours.

REMARK N°1

Studies evaluating the impacts of parity on lung function data (LFD) of healthy females present controversial conclusions. Respiratory aging, can be estimated by lung function data (LFD), recognized as predictors of mortality and morbidity. These relationships are based on the subjects’ ethnicity and are included as influencing factors [eg, gender, age, height, weight and body mass index (BMI)].

Parity has been proposed as an additional influence in some studies. Contrary to European and North American studies, parity is of particular impact in low- and lower middle-income countries such as in Africa. In several African countries, recent values of parity were higher than six. A few studies, published between 1999 and 2018, raised the impacts of parity on healthy females’ LFD [USA (n=1), Tunisia (n=3), Nigeria (n=2) and Brazil (n=1)] with conflicting results. Some studies concluded that high parity was positively associated LFD while others concluded that it was associated with negative effects on LFD.

Thus, the purpose of this investigation was to compare lung function data (LFD) of two groups of healthy females divided according to their parities, and to determine the relationship between parity and LFD.

Methods. A medical questionnaire was administered and anthropometric data were determined. Parity was introduced as numeric and as dichotomous [G1 ≤ 6 parity; G2 >6 parity]. LFD (plethysmography, specific airway resistance (sRaw)] was performed. Correlation-coefficient (r) and Student’s t-test were used, respectively, to evaluate the relationships between parity and LFD (absolute values) and to compare the two groups’ mean±SD quantitative data.

Main results: Compared to GI, G2 had a lower mean body mass index (30.vs. 27.6) and a higher parity (4 vs. 10). G1 and G2 had similar values of forced expiratory volume in 1 s (FEV1), forced- and low- vital capacity (FVC, SVC), maximal mid-expiratory flow, forced expiratory flow at x% of FVC, peak expiratory flow, expiratory and inspiratory reserve volumes, inspiratory capacity, sRaw, FEV1/FVC, FEV1/SVC, and residual volume/total lung capacity (RV/TLC). Compared to G1, G2 had significantly higher thoracic gas volume, RV and TLC. In the total sample, significant positive correlations were found between parity and TGV (r=0.31), RV (r=0.33) and TLC (r=0.25).

The authors concluded that increasing parity induces a tendency towards lung-hyperinflation.

RESPONSE

No corrective action is needed in this stage. Please note that we have applied all your asked corrections.

REMARK N°2a

A key goal of this study should be to describe and explain the differences between high and low parity women, and explain the differences found between the two cohorts and the mechanisms that would explain the findings.

Instead, the authors launch into a lengthy disquisition of why lung function testing is obtained in general, how lung function changes with age and other factors (smoking, environment, etc), how cohort values are compared to controls, and a detailed description of differences in lung function amongst European, American and northern (the Sahel) and sub-Saharan African ethnic groups.

This is interesting material but has little to do with the main purpose of the study which was ostensibly to assess the effects of parity on lung function (and what is implied in the title of the paper).

The authors should have primarily focused on this topic. The rest of their discussion is better suited for a textbook or monograph on the epidemiology of lung function.

RESPONSE

Several changes were performed in the Discussion section.

CORRECTIVE ACTION

*The paper is now primarily focused on the effects of parity on lung function data.

**Several parts from the “Methodology discussion” subsection was moved to the S3 File.

REMARK N°2b

Not only that, but the paper is needlessly prolonged by repeating in the discussion much of what’s already stated in the introduction.

The explanation for the changes in LFD is only briefly explained in a paragraph ending on p. 23. Instead of placing most of this information in the supplementary material it should be included as part of the main discussion – that is the main point of the paper.

RESPONSE

Several changes were performed in the Discussion.

CORRECTIVE ACTION

The answer to the following question “How to explain the impacts of parity on LFD?” is moved from the S3 File to the main manuscript (L381-428).

REMARK N°3a

Pages and lines should be numbered – makes changes easily traceable.

CORRECTIVE ACTION

Pages and lines are added.

REMARK N°3b

The authors should reconsider the weightiness and clinical importance of their correlation coefficients. From a clinically relevant standpoint, the correlation coefficient should be squared: an r-squared value of >0.3 is considered to be clinically relevant. Thus r=0.3 becomes 0.09, which is not clinically meaningful; r=0.4 becomes 0.16, also not relevant. In other words, what may be statistically significant may not be clinically significant or relevant.

RESPONSE

All your suggestions were applied.

CORRECTIVE ACTION

*In the ‘statistical analysis” subsection, the following sentence was added (L239-241): “Determination-coefficient (r2 = square of the Pearson product-moment correlation-coefficient) evaluated the associations between parity, and plethysmographic and anthropometric data. “r2” was considered as “clinically significant” when it was > 0.30 [37]”

**Table 3 exposes the “Determination coefficient (r2) between anthropometric and plethysmographic data, and parity.” Only “clinically significant” correlations were considered.

***All required changes were applied in the main manuscript.

REMARK N°3c

Intro., l. 8, “…next line: “…ongoing...” instead of “… not yet closed…”

RESPONSE

Agree with you

CORRECTIVE ACTION

Done L110.

REMARK N°3d

Next line: Instead of “…guaranteed...”, state “…has been validated…”

RESPONSE

Agree with you

CORRECTIVE ACTION

Done L112.

REMARK N°3e

Intro, next page, l. 5: Chad is repeated in same sentence.

RESPONSE

Agree with you

CORRECTIVE ACTION

The second ‘Chad” was deleted (L129).

REMARK N°3f

Same page, l. 7: For Tunisia there are 4 references cited, not 3.

RESPONSE

References 12 (Spirometric “Lung Age” estimation for North African population. Egyptian Journal of Chest Diseases and Tuberculosis. 2014;63(2):491-503) and 13 (Estimated lung age in healthy North African adults cannot be predicted using reference equations derived from other populations. Egyptian Journal of Chest Diseases and Tuberculosis. 2013;62(4):789-804) are derived from the same project and described the same population.

CORRECTIVE ACTION

Only reference 12 was kept.

REMARK N°3g

Intro, last paragraph, l. 1: “In view of…” instead of “…in front of…”

RESPONSE

Agree with your suggestion.

CORRECTIVE ACTION

Done L143.

REMARK N°3h

Under plethysmographic measurements, l. 1; should read “Lung volume data were determined by… plethysmography (Body-box 5500…)".

RESPONSE

Agree with your suggestion.

CORRECTIVE ACTION

The following sentence was added (L218-219): “LFD were determined by one qualified person (AK in the authors’ list) via a plethysmograph (Body-box 5500, MediSoft, Belgium). The latter was calibrated each morning.”

REMARK N°3i

Under discussion, last para, last line: “… still higher in other African countries.”

RESPONSE

Agree with your suggestion.

CORRECTIVE ACTION

Done L292.

REMARK N°3k

Under Methodology discussion, l. 8: “…who reported being healthy…”

RESPONSE

Agree with your suggestion.

CORRECTIVE ACTION

Note: the “Methodology discussion“ subsection was moved to the S3 File.

REMARK N°3l

Same section, next 2 pages: Beginning with “The non-inclusion criteria were respected.” all the way through the next page, ending with “… can’t be explained by their menopause status” should be deleted, as it is repetitious from the introduction and also not relevant to the discussion itself.

RESPONSE

We have considered your suggestion and we agree with it.

CORRECTIVE ACTION

In order to shorten the manuscript, all the long sentence “The non-inclusion criteria were respected……… can’t be explained by their menopause status” was moved to the S3 File.

REMARK N°3m

*Results discussion, last 2 pages: Beginning with “The present study correlations…”, the authors just regurgitate what is already listed in the supplementary tables – this information should be transferred to the results section and not repeated here.

**Rather, the authors should expand on and explain their findings from a physiological standpoint, that is, how are the findings explained. This has much to do with physiologic differences of the thoracic cage between men and women and how pregnancy affects these mechanical properties during pregnancy and with repeated pregnancies.

***This would add a unique aspect to their discussion because there is not much information on the effects of multiparity on respiratory mechanics.

RESPONSE

We have taken into account all your suggestions.

CORRECTIVE ACTION

.In order to improve the scientific quality of our paper, we have added a new table (S2 File) which exposes the main results of the seven studies including healthy females and evaluating the effects of parity on lung function data. We hope that this table will facilitate the interpretation of our data taking into account those of the literature.

*We have avoided redundancy between text and tables.

**In the revised version, we tried to explain our findings from a physiological standpoint. For that reason, we have added the following sentence (L381-428) related to how pregnancy affects the mechanical properties during pregnancy and with repeated pregnancies.

“How to explain the impacts of parity on LFD?

During healthy pregnancy, respiratory function is affected through both biochemical and mechanical pathways [50, 51]. Throughout gravidity, spirometry remains within normal ranges (ie; unchanged FVC, FEV1, and FEV1/FVC, unchanged or a modest increase of PEF [50-52]). Conversely, lung volumes endure for most variations: ERV progressively declines during the second half of gestation since RV decreases [50-52]. TGV then diminishes while IC rises in the same degree in order to conserve stable TLC [50-52]. Bronchial resistance rises whereas respiratory conductance decreases during gestation [50-52]. Total pulmonary and airways resistances have a tendency to decline in late gestation as a result of hormonally induced relaxation of tracheobronchial tree smooth muscles [51]. What happens with increasing parity? With increasing parity, the rise in TGV, RV and TLC (Tables 1 and 2), and therefore the tendency towards lung-hyperinflation, can be interpreted as an aging index of the ventilatory mechanics, or as an indirect sign towards an OVD and/or an expiratory muscle weakness [36, 53]. The tendency towards lung-hyperinflation can be explained by at least the four following hypothesizes:

1) Anatomical changes: during gestation, the progressive increase of the uterus volume is the main reason for lung volume and chest wall changes (eg, elevation of the diaphragm, altered thoracic shape) [50-51, 54]. The diaphragm elevation induced two phenomena: i) earlier closure of the lower airways with consequent reduction of TGV and ERV; ii) shorter chest height, but increase of the other thoracic dimensions in order to maintain constant TLC [50-52]. Gestation is also accompanied by changes in the mucosa of the upper and lower airways with the appearance of inflammatory phenomena [54, 55]. Thus, the effects of these changes, can accumulate with repeated gestations. Chest circumference may increase and hypotrophy of the respiratory muscles may develop. This will explain the decline of the maximal inspiratory pressure with high parity (S2 File) [56].

2) Hormonal changes: during gestation, the physiological adaptation of hormonal (progesterone, estrogen and prostaglandins) profiles is the foremost cause of ventilatory changes in respiratory function [50, 51]. Progesterone modifies the airways’ smooth muscle tone inducing a bronchodilator effect [50, 51]. Estrogen upsurges the number and the sensitivity of progesterone receptors within several nervous areas (eg, hypothalamus, medulla, and central neuronal respiratory-related areas) [50, 51]. Prostaglandin F2α rises airway resistance by bronchial smooth muscle constriction, whereas a bronchodilator effect can be a consequence of prostaglandins E1 and E2 [51]. The aforementioned hormonal changes are related to LFD variations [50, 57]. With repeated gestations, it can be speculated that hormonal changes persist and accumulate. During the ageing process, aging-induced hormonal changes can modify LFD [58] (eg, elderly female’ cortisol secretion determined the rate of the lung-aging [59]). Since gestation is experienced as a stressful situation, hormonal changes can increase in multiparous females.

3) Biochemical changes: the natural damage of elastin with age, contributing to the LFD’ decline, is less accelerated in females with a moderate deficiency in protease inhibitor and having a high parity [60]. This has been attributed to an improvement in elastin turnover in these females with high parity [60]. This finding has not been proven in females with normal protease inhibitor phenotype and high parity [60].

4) Bronchial hyperreactivity: with gestation, there is a decrease in bronchodilator factors (β2-adrenergic receptors and adenylyl-cyclase activity) in favor of an increase in bronchoconstrictor ones (prostaglandin F2α and cyclic guanosine monophosphatectively) [55]. These effects can accumulate with repeated gestations and partially explain the tendency towards lung-hyperinflation.”

***We hope that the actual “Discussion” section is acceptable.

REMARK N°3n

Again, these r-values should be squared to determine if they are truly clinically significant – many of the LFD changes will turn out to be not significant or relevant to parity.

RESPONSE

Agree with your suggestion.

CORRECTIVE ACTION

As previously highlighted, all needed changes were applied (please see our answer to your Remark 9b).

REMARK N°3o

Last page, last para.: This brief paragraph should be greatly expanded to explain the effects of multiparity on respiratory function (here, not in the supplement), particularly in regards to the lung hyperinflation – how is this event linked to changes in the thoracic cage? In fact, this expanded discussion should nearly completely replace the bloated epidemiologic data from different countries listed by the authors. Pregnancy likely affects the fundamental changes that occur in the respiratory system in a common way, with only subtle differences amongst ethnic/national groups.

RESPONSE

Totally agree with your suggestion.

CORRECTIVE ACTION

*The old short paragraph was greatly expanded to explain the effects of multiparity on respiratory function.

**The paragraph aiming to answer the following question “How to explain the impacts of parity on LFD?” was moved to the main manuscript (L381-428).

REMARK N°3p

In short, the information provided here is interesting, and relatively new and should be reported, but in a greatly revised form. It can be presented in a cleaner, more concise manner with greater emphasis placed on the physiologic explanations rather than just reporting epidemiologic data from different countries. The latter aspect can be considerably shortened. Finally, the clinical relevance of statistically significant correlations should be re-considered in a clinically relevant manner.

RESPONSE

All your suggestions were accepted and applied.

CORRECTIVE ACTION

*The paper was deeply revised.

**We tried to shorten our paper.

***Physiologic explanations are advanced in the main paper.

****The clinical relevance of statistically significant correlations should were re-considered in a clinically relevant manner.

Submitted filename: Responses to reviewers.docx

Click here for additional data file.

29 Oct 2019

The impacts of parity on lung function data (LFD) of healthy females aged 40 years and more issued from an upper middle income country (Algeria): a comparative study

PONE-D-19-16514R1

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Much of the material in the appendix has been appropriately transferred to the main text.

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1 Nov 2019

PONE-D-19-16514R1

The impacts of parity on lung function data (LFD) of healthy females aged 40 years and more issued from an upper middle income country (Algeria): a comparative study

Dear Dr. Ben Saad:

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If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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