Drug use for gastrointestinal symptoms during pregnancy: A French nationwide study 2010–2018

Antoine Meyer; Marion Fermaut; Jérôme Drouin; Franck Carbonnel; Alain Weill

doi:10.1371/journal.pone.0245854

. 2021 Jan 22;16(1):e0245854. doi: 10.1371/journal.pone.0245854

Drug use for gastrointestinal symptoms during pregnancy: A French nationwide study 2010–2018

Antoine Meyer ^1,^2,^3,^*, Marion Fermaut ⁴, Jérôme Drouin ¹, Franck Carbonnel ^2,³, Alain Weill ¹

Editor: Angela Lupattelli⁵

PMCID: PMC7822332 PMID: 33481904

Abstract

Purpose

To describe drug prescription for gastrointestinal symptoms during pregnancy.

Methods

Using the French national health database, we identified pregnancies ending with a birth between April 2010 and December 2018, in France. We studied prescription of antacids, antispasmodics, antinauseants, laxatives and antidiarrheals during pregnancy, between two trimesters before and two trimesters after delivery. We also assessed hospitalization for gastrointestinal symptoms during pregnancy.

Results

Among 6,365,471 pregnancies, 4,452,779 (74.0%) received at least one gastrointestinal drug during pregnancy; 2,228,275 (37.0%) received an antacid, 3,096,858 (51.5%) an antispasmodic, 1,861,731 (31.0%) an antinauseant, 919,116 (15.3%) a laxative and 617,808 (10.3%) an antidiarrheal. Prescription of proton pump inhibitors doubled from 12.2% in 2010 to 26.0% in 2018, while domperidone use decreased from 18.3% in 2010 to 2.2% in 2018. In addition, prescription of antacids increased from 7.0% during the trimester before pregnancy to 11.8% during the 1^st trimester, 17.0% during the 2^nd trimester and 23.4% during the 3^rd trimester. Antispasmodic use was 10.6% during the trimester before pregnancy, 23.1% during the 1^st trimester, 25.2% during the 2^nd trimester and 24.0% during the 3^rd trimester. Prescription of antinauseant drugs increased from 5.0% during the trimester before pregnancy to 25.7% during the 1^st trimester, then decreased to 6.4% during the 2^nd trimester and 3.2% during the 3^rd trimester. Nausea/vomiting was the most common cause of hospitalization for gastrointestinal symptoms or diseases during pregnancy, although it accounted for only 1.0% of pregnancies.

Conclusions

Approximately three-quarters of women use drugs for gastrointestinal symptoms during pregnancy in France. Prescription of gastrointestinal drugs during pregnancy should be the subject of more detailed risk-benefit assessment and recommendations.

Background and aims

Thalidomide was used as an antinauseant medication during pregnancy until its teratogenic effect was demonstrated in the 1960s. This scandal led to an increased awareness of the safe use of drugs during pregnancy [1]. Yet, data on the safety of drugs used during pregnancy (for women and offspring) is often lacking as pre-marketing clinical trials exclude pregnant women. Observational studies are therefore essential to study the efficacy and safety drugs in pregnant women and their offspring. For instance, a French nationwide study on recent data confirmed that valproic acid, a treatment for epilepsy, cause birth defects and delayed cognitive development [2, 3].

Despite the concerns about the safety of medication use during pregnancy, many women take medication during pregnancy, but with considerable variability according to geographical region and over time [4, 5]. In recent years, between 58% and 97% of women take at least one medication during pregnancy, depending on the country [4–7]. Gastrointestinal symptoms are common during pregnancy: 50 to 90% of pregnant women experience nausea and 30–80% experience heartburn [8, 9]. No study has specifically assessed the use of the various classes of gastrointestinal drugs during pregnancy, as these drugs are often grouped into a single category of gastrointestinal drugs [4, 6, 7, 10, 11]. Drug use studies in pregnancy are useful to identify the most frequently used drugs and thereby decide which drug safety studies should be prioritized.

The aim of the present study was to describe drug use for gastrointestinal symptoms during pregnancy in a large-scale, population-based, nationwide study between 2010 and 2018 using the French national health data system, in a partnership between clinicians, French national health insurance (Caisse Nationale d’Assurance Maladie) and the French National Agency for Medicines and Health Products Safety (Agence Nationale de Sécurité du Médicament).

Materials and methods

Data source

The French national health data system (Système National des Données de Santé, SNDS) covers more than 99% of the French population (around 66,000,000 people). Each person is identified by a unique, anonymous number. The SNDS contains all outpatient information (demographics, drugs dispensed, and procedures) and all inpatient information (expensive drugs dispensed, procedures performed during hospital stays, and diagnoses) [12]. Studies based on this database have produced meaningful results in recent years [13–17].

We adapted an algorithm previously developed and used [16, 18] to identify pregnancies ending between April 1, 2010 and December 31, 2018 among women aged 15 to 49 in the SNDS (S1 Table). The pregnancy end date was the date of delivery, or, when missing, the date of admission for pregnancy completion. The pregnancy start date was calculated using gestational age at the end of pregnancy, or, when missing, the date of the last menstrual period entered by the physician at the end of pregnancy [19].

Study population

All pregnancies ending with a birth—either livebirth—between April 2010 and December 2018 were included. A stillbirth was the delivery of a dead fetus after 22 weeks of amenorrhea (referred to as weeks thereafter). We excluded pregnancies with elective or therapeutic abortions, spontaneous abortions, ectopic pregnancies and hydatidiform moles and other abnormal products of conception (blighted ovum and nonhydatidiform moles), because to study drug exposure throughout pregnancy, pregnancies that last three trimesters are needed. Pregnant women with no healthcare record in the SNDS database during the 2 years preceding the pregnancy were excluded. These women may have lived outside of France or their outpatient data may have been unavailable in the SNDS (less than 1% of the French population).

Drug exposure and hospitalizations

We studied each drug dispensed for gastrointestinal symptoms including: antacids, antispasmodics, antinauseants, laxatives, antidiarrheals and other drugs for functional gastrointestinal disorders. Details on International Non-Proprietary name and Anatomical Therapeutic Chemical Classification are given in S2 Table. For each pregnancy, seven trimesters were studied: two trimesters before the beginning of pregnancy (Trim-2: day −182 to day −92; Trim-1: day −91 to day −1), each trimester of pregnancy (Trim1: day 0 i.e. fertilisation to day 90; Trim2: day 91 to day 181; Trim3: day 182 to delivery −1) and two trimesters after the end of pregnancy (Trim+1: delivery to delivery + 91; Trim+2: delivery + 92 to delivery + 182). A pregnancy trimester was considered to be exposed to a drug when this drug was dispensed at least once during this trimester. We also grouped these drugs into a single category to study the rate of pregnant women using at least one gastrointestinal drug. Additionally, we looked at the dispensing rates of drugs in the Anatomical Therapeutic Chemical (ATC) classes A02 to A09 to allow more reliable comparison with published data.

We also studied the most common reasons for hospitalization for a gastrointestinal symptom or disease between two trimesters before and two trimesters after pregnancy, including: nausea/vomiting, cholestasis, proctological disease (fissure, fistula, abscess, hemorrhoids), appendicitis and biliary diseases (S3 Table).

Maternal and pregnancy characteristics

Baseline maternal characteristics included: age, Complementary Universal Health Insurance status (free access to health care for people with low income), a deprivation index expressed in quintiles that was developed in France as the first component of a principal component analysis of 4 socioeconomic variables [20], and income (general health insurance scheme: none, <€2,000/month, ≥€2,000/month; and agricultural/self-employed scheme) calculated from the woman's salary during the three months before maternity leave. Gravidity (1^st pregnancy, 2^nd pregnancy,…) was defined as the pregnancy number in a woman during the study period. Assisted reproduction was defined as any of the following procedures performed in France during the two months preceding pregnancy: ovarian stimulation, oocyte retrieval, artificial insemination or in vitro fertilization. The clinical setting of termination of pregnancy was recorded: university hospital, general hospital, private hospital, or outpatient procedure.

Pregnancy characteristics included type of delivery (cesarean or vaginal), vital status at birth (livebirth or stillbirth), prematurity (births occurring before 37 weeks were considered to be preterm and those occurring before 32 weeks were considered to be very preterm) and birth weight for gestational age (below the 10^th percentile and above the 90^th percentile of the gestational age computed in the national pregnancy cohort were considered small and large for gestational age, respectively). Birth weight was available for those infants in whom linkage between mother and child data was available (78.5% of pregnancies with delivery).

Statistical analysis

The unit of analysis was a pregnancy, i.e. all of a patient's pregnancies were included in the analysis. We first described maternal characteristics at the beginning of pregnancy and pregnancy characteristics for each pregnancy: median and interquartile range (IQR) for continuous variables and proportions for categorical variables. Medication dispensing during pregnancy over time was then described for pregnancy ending between April 2010 and December 2018: crude numbers and percentages of exposed pregnancies by year of pregnancy end. Medication dispensing and hospitalizations before, during and after pregnancy was described for pregnancies ending between April 2010 and June 2018: crude numbers and percentages of exposed pregnancies by trimester. A sensitivity analysis was performed and excluded pregnancies of less than 37 weeks.

All analyses were performed with SAS® software version 9.4 (SAS Institute, North Carolina, USA). The French public institution which conducted this study has permanent access to the SNDS database in application of the provisions of Articles R. 1461–12 et seq. of the French Public Health Code and the French data protection authority decision CNIL-2016-316. No informed consent was therefore required. This research did not receive any funding.

Results

Study population

Among approximately 32 million women in France, 4,546,505 completed a pregnancy between April 1, 2010 and December 31, 2018. A total of 8,796,626 pregnancies were identified among these women. The following pregnancies were excluded: 1,687,516 elective/therapeutic abortions, 339,553 spontaneous abortions, 96,073 ectopic pregnancies, 110,902 hydatidiform moles or other abnormal products of conception and 197,111 with no prior outpatient health care utilization during the 2 years before pregnancy. A total of 6,365,471 pregnancies ending with delivery were therefore included (S1 Fig). The annual number of pregnancies decreased slightly from 763,069 in 2011 to 682,065 in 2018 (S2 Fig).

Maternal and pregnancy characteristics

Maternal and pregnancy characteristics are presented in Table 1. Median age at the beginning of pregnancy was 29 years (IQR: 26–33), 809,034 (12.7%) women had Complementary Universal Health Insurance cover, 2,508,345 (39.4%) had no income and 174,174 (2.7%) had undergone assisted reproduction. Pregnancies ended with 1,273,816 (20.0%) cesarean sections, 32,677 (0.5%) stillbirths, 352,817 (5.5%) preterm births, 73,135 (1.2%) very preterm births and the mean birth weight was 3.29 kg (IQR: 2.98–3.61).

Table 1. Demographic data and pregnancy characteristics (in thousands).

	Total	Age at the beginning of pregnancy (years)
		15–24	25–34	35–49
	N, thousands (%)	N, thousands (%)	N, thousands (%)	N, thousands (%)
Number of pregnancies	6 365	1 155	4 108	1 103
Age (years)^¶	29.0 [26.0–33.0]	22.0 [20.0–24.0]	29.0 [27.0–32.0]	37.0 [36.0–39.0]
Income
General health scheme: No income	2 508 (39.4)	571 (49.5)	1 479 (36.0)	458 (41.6)
General health scheme: < €2,000/month	1 856 (29.2)	441 (38.2)	1 181 (28.8)	234 (21.2)
General health scheme: ≥ €2,000/month	1 603 (25.2)	89 (7.7)	1 185 (28.8)	329 (29.9)
Agricultural and self-employed scheme	398 (6.3)	54 (4.7)	263 (6.4)	81 (7.4)
Deprivation index
Quintile 1 (less deprived)	1 204 (19.8)	114 (10.7)	816 (20.6)	274 (26.0)
Quintile 2	1 208 (19.9)	174 (16.3)	820 (20.7)	214 (20.4)
Quintile 3	1 191 (19.6)	210 (19.7)	786 (19.8)	195 (18.6)
Quintile 4	1 179 (19.4)	243 (22.8)	759 (19.2)	178 (16.9)
Quintile 5 (more deprived)	1 297 (21.3)	326 (30.5)	782 (19.7)	190 (18.1)
Complementary Universal Health Insurance^§	809 (12.7)	281 (24.4)	403 (9.8)	125 (11.4)
Gravidity (Apr 1, 2010—Dec 31, 2018)
1st pregnancy	3 863 (60.7)	798 (69.1)	2 431 (59.2)	634 (57.5)
2nd pregnancy	1 858 (29.2)	268 (23.3)	1 256 (30.6)	334 (30.3)
3rd and more pregnancy	645 (10.1)	88 (7.7)	421 (10.3)	135 (12.3)
Assisted reproduction	174 (2.7)	6 (0.5)	112 (2.7)	56 (5.1)
Place of end of pregnancy
University hospital	1 172 (18.4)	209 (18.1)	733 (17.8)	230 (20.9)
General hospital	3 529 (55.5)	698 (60.5)	2 261 (55.1)	570 (51.7)
Private hospital	1 656 (26.0)	248 (21.4)	1 108 (27.0)	301 (27.3)
Outpatient	9 (0.1)	1 (0.1)	6 (0.2)	2 (0.2)
Multiple pregnancy	62 (1.3)	7 (0.8)	40 (1.3)	15 (1.7)
Cesarean section	1 274 (20.0)	184 (15.9)	788 (19.2)	302 (27.4)
Pregnancy outcome
Livebirth	6 333 (99.5)	1 148 (99.4)	4 089 (99.5)	1 095 (99.3)
Stillbirth	33 (0.5)	7 (0.6)	19 (0.5)	7 (0.7)
Pregnancy term
Term birth (≥37 weeks)	5 940 (93.3)	1 071 (92.7)	3 852 (93.8)	1 017 (92.2)
Preterm birth (<37 weeks)	353 (5.5)	68 (5.9)	214 (5.2)	70 (6.4)
Very preterm birth (<32 weeks)	73 (1.2)	15 (1.3)	42 (1.0)	16 (1.4)
Birth weight (kg)^¶	3.29 [2.98–3.61]	3.24 [2.93–3.55]	3.30 [3.00–3.62]	3.30 [2.97–3.63]
Birth weight for gestational age
Small for gestational age (<P10)	492 (9.8)	106 (11.7)	302 (9.4)	84 (9.7)
Appropriate (P10-P90)	4 010 (80.2)	731 (80.5)	2 600 (80.6)	680 (78.7)
Large for gestational age (>P90)	497 (10.0)	71 (7.8)	326 (10.1)	100 (11.6)

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¶Quantitative variable, median [interquartile range].

§Free access to health care for people with low income. P10/P90: 10th/90th percentile.

Drug exposure

Among all pregnancies with delivery, 4,452,779 (74.0%) received at least one gastrointestinal drug during pregnancy; 2,228,275 (37.0%) pregnancies were exposed to an antacid, 3,096,858 (51.5%) to an antispasmodic, 1,861,731 (31.0%) to an antinauseant, 919,116 (15.3%) to a laxative and 617,808 (10.3%) to an antidiarrheal (Table 2). The antispasmodic phloroglucinol was by far the most commonly prescribed drug (51.0% of all pregnancies). These rates of drug exposure during pregnancy were consistent over ages at the beginning of pregnancy and excluding pregnancies of less than 37 weeks (S3 Fig and S4 Table). However, drug use was slightly higher in more deprived pregnancies than in less deprived pregnancies (76.0% vs 72.3% for at least one gastrointestinal drug use), and this applied to most of the drugs studied (S4 Fig).

Table 2. Drug exposure before, during and after pregnancy (thousands).

	Number of pregnancies, thousands (%)
	Trim-2	Trim-1	Trim1	Trim2	Trim3	Trim123	Trim+1	Trim+2
Number of pregnancies	6,015	6,015	6,015	6,015	5,985	6,015	6,015	6,015
Antacids	448 (7.4)	420 (7.0)	711 (11.8)	1,022 (17.0)	1,400 (23.4)	2,228 (37.0)	469 (7.8)	363 (6.0)
Locally-acting	115 (1.9)	104 (1.7)	449 (7.5)	674 (11.2)	808 (13.5)	1,541 (25.6)	107 (1.8)	97 (1.6)
Histamine 2 blocker	11 (0.2)	10 (0.2)	21 (0.3)	45 (0.7)	78 (1.3)	118 (2.0)	7 (0.1)	7 (0.1)
Proton pump inhibitor	379 (6.3)	360 (6.0)	371 (6.2)	465 (7.7)	753 (12.6)	1,188 (19.7)	396 (6.6)	303 (5.0)
Antispasmodics	644 (10.7)	635 (10.6)	1,387 (23.1)	1,513 (25.2)	1,434 (24.0)	3,097 (51.5)	1,355 (22.5)	514 (8.5)
Mebeverine	10 (0.2)	10 (0.2)	4 (0.1)	1 (0.0)	1 (0.0)	6 (0.1)	4 (0.1)	5 (0.1)
Trimebutine	85 (1.4)	84 (1.4)	45 (0.8)	21 (0.3)	9 (0.2)	72 (1.2)	73 (1.2)	63 (1.0)
Pinaverium	12 (0.2)	12 (0.2)	4 (0.1)	1 (0.0)	0 (0.0)	5 (0.1)	4 (0.1)	7 (0.1)
Phloroglucinol	534 (8.9)	527 (8.8)	1,346 (22.4)	1,499 (24.9)	1,427 (23.8)	3,065 (51.0)	1,293 (21.5)	435 (7.2)
Alverine	57 (1.0)	58 (1.0)	26 (0.4)	7 (0.1)	3 (0.0)	34 (0.6)	22 (0.4)	37 (0.6)
Others	11 (0.2)	10 (0.2)	8 (0.1)	3 (0.1)	1 (0.0)	12 (0.2)	4 (0.1)	6 (0.1)
Antinauseants	321 (5.3)	298 (5.0)	1,548 (25.7)	385 (6.4)	191 (3.2)	1,862 (31.0)	156 (2.6)	249 (4.1)
Metoclopramide	50 (0.8)	42 (0.7)	805 (13.4)	170 (2.8)	83 (1.4)	971 (16.1)	22 (0.4)	35 (0.6)
Domperidone	162 (2.7)	149 (2.5)	511 (8.5)	114 (1.9)	56 (0.9)	634 (10.5)	84 (1.4)	110 (1.8)
Metopimazine	122 (2.0)	117 (2.0)	492 (8.2)	118 (2.0)	58 (1.0)	622 (10.3)	54 (0.9)	111 (1.8)
5-HT3 antagonists	0 (0.0)	0 (0.0)	7 (0.1)	3 (0.0)	1 (0.0)	8 (0.1)	1 (0.0)	1 (0.0)
Others	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.0)	1 (0.0)
Laxatives	141 (2.4)	132 (2.2)	370 (6.2)	381 (6.3)	353 (5.9)	919 (15.3)	438 (7.3)	127 (2.1)
Lubricant	8 (0.1)	8 (0.1)	13 (0.2)	8 (0.1)	5 (0.1)	25 (0.4)	18 (0.3)	9 (0.1)
Bulk	19 (0.3)	18 (0.3)	35 (0.6)	31 (0.5)	20 (0.3)	76 (1.3)	28 (0.5)	16 (0.3)
Osmotic	108 (1.8)	101 (1.7)	315 (5.2)	325 (5.4)	234 (3.9)	741 (12.3)	356 (5.9)	98 (1.6)
Enema	30 (0.5)	27 (0.5)	59 (1.0)	59 (1.0)	126 (2.1)	226 (3.8)	93 (1.5)	23 (0.4)
Others	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Antidiarrheals	275 (4.6)	263 (4.4)	287 (4.8)	230 (3.8)	141 (2.4)	618 (10.3)	158 (2.6)	244 (4.1)
Loperamide	98 (1.6)	93 (1.5)	72 (1.2)	52 (0.9)	32 (0.5)	151 (2.5)	47 (0.8)	76 (1.3)
Racecadotril	110 (1.8)	106 (1.8)	45 (0.7)	20 (0.3)	10 (0.2)	74 (1.2)	54 (0.9)	101 (1.7)
Diosmectite	120 (2.0)	115 (1.9)	205 (3.4)	180 (3.0)	112 (1.9)	473 (7.9)	85 (1.4)	113 (1.9)
Ursodeoxycholic acid	2 (0.0)	2 (0.0)	1 (0.0)	2 (0.0)	21 (0.3)	22 (0.4)	2 (0.0)	2 (0.0)
All gastrointestinal drugs	1,197 (19.9)	1,147 (19.1)	2,625 (43.6)	2,452 (40.8)	2,603 (43.5)	4,453 (74.0)	2,003 (33.3)	1,006 (16.7)
ATC A02-A09	1,208 (20.1)	1,158 (19.3)	2,630 (43.7)	2,457 (40.8)	2,608 (43.6)	4,456 (74.1)	2,018 (33.5)	1,018 (16.9)

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Medication dispensing before, during and after pregnancy was described for pregnancies ending between April 2010 and June 2018: crude numbers and percentages of exposed pregnancies by trimester. As other drugs for functional gastrointestinal disorders represented <0.1% for each trimester, they were not reported. ATC: Anatomical Therapeutic Chemical.

Drug exposure over time

The percentage of women who received at least one gastrointestinal drug during pregnancy varied little over time (75.2% in 2010 to 72.0% in 2018). However, exposure to several drugs changed over the study period (Fig 1). Antacid use increased from 34.0% in 2010 to 39.0% in 2018 mainly due to increased use of proton pump inhibitors from 12.2% in 2010 to 26.0% in 2018, while the use of locally-acting antacids and histamine 2 blockers decreased slightly from 27.1% and 2.4% in 2010 to 24.0% and 1.3% in 2018, respectively (Fig 2). Antinauseant drug use decreased from 37.8% in 2010 to 25.2% in 2018, mainly due to decreased use of domperidone (18.3% in 2010 to 2.2% in 2018), while 5-HT3 antagonists use increased from 0.02% in 2010 to 0.4% in 2018 (S5 Fig). Antispasmodic and laxative exposure did not change from 2010 to 2018 (S6 and S7 Figs). Antidiarrheal drug use decreased slightly from 11.7% in 2010 to 8.9% in 2018, mainly due to decreased use of diosmectite (9.3% in 2010 to 6.4% in 2018) (S8 Fig).

Drug exposure before, during and after pregnancy

All drug exposures varied during the course of the pregnancy. Antacid use increased from 7.0% during the trimester before pregnancy to 11.8% during the 1^st trimester, 17.0% during the 2^nd trimester and 23.4% during the 3^rd trimester. Antispasmodic use increased from 10.6% during the trimester before pregnancy to 23.1% during the 1^st trimester, 25.2% during the 2^nd trimester and 24.0% during the 3^rd trimester. Antinauseant use increased from 5.0% during the trimester before pregnancy to 25.7% during the 1^st trimester, and then decreased to 6.4% during the 2^nd trimester and 3.2% during the 3^rd trimester. Laxative use increased from 2.2% during the trimester before pregnancy to 6.2% during the 1^st trimester, 6.3% during the 2^nd trimester and 5.9% during the 3^rd trimester (Table 2 and Fig 3). These variations in exposure during the course of pregnancy were consistent over age at the beginning of pregnancy, deprivation index and excluding pregnancies lasting less than 37 weeks (S2 and S3 Figs and S4 Table).

Hospitalizations

Nausea/vomiting was the most common cause of hospitalization for gastrointestinal symptoms or diseases during pregnancy, although it accounted for only 1.0% of pregnancies, mainly during the 1^st trimester (0.7%). Hospitalization for cholestasis occurred in 0.3% of pregnancies, mainly in the 3^rd trimester (0.3%). The other causes of hospitalization each represented less than 0.2% of pregnancies (Table 3).

Table 3. Hospitalizations before, during and after pregnancy (thousands).

	Number of pregnancies, thousands (%)
	Trim-2	Trim-1	Trim1	Trim2	Trim3	Trim123	Trim+1	Trim+2
Number of pregnancies	6 015	6 015	6 015	6 015	5 985	6 015	6 015	6 015
Nausea/vomiting	1 (0.0)	0 (0.0)	45 (0.7)	10 (0.2)	9 (0.2)	60 (1.0)	0 (0.0)	0 (0.0)
Cholestasis	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.0)	18 (0.3)	19 (0.3)	10 (0.2)	0 (0.0)
Proctologic disease	3 (0.1)	3 (0.0)	1 (0.0)	1 (0.0)	7 (0.1)	9 (0.2)	8 (0.1)	4 (0.1)
Appendicitis	3 (0.0)	2 (0.0)	2 (0.0)	1 (0.0)	0 (0.0)	3 (0.0)	3 (0.0)	2 (0.0)
Biliary tract disease	6 (0.1)	5 (0.1)	2 (0.0)	2 (0.0)	1 (0.0)	5 (0.1)	14 (0.2)	14 (0.2)

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Hospitalizations before, during and after pregnancy was described for pregnancies ending between April 2010 and June 2018: crude numbers and percentages of exposed pregnancies by trimester.

Discussion

This population-based, nationwide study of 6,365,471 pregnancies in France from 2010 to 2018 shows that, during pregnancy, approximately three-quarters of women use drugs for gastrointestinal symptoms: approximately one-half of pregnancies are exposed to antispasmodics, and one-third are exposed to antacids and antinauseants. From 2010 to 2018, the use of proton pump inhibitors doubled, while the use of histamine 2 blockers decreased. Prescription of antacids increased during the course of pregnancy, while antinauseants were mainly prescribed during the first trimester. Hospitalizations for gastrointestinal diseases were rare, most commonly because of vomiting in 1.0% of pregnancies.

We found that approximately three-quarters of women used drugs for gastrointestinal symptoms during pregnancy. This rate is higher than those reported elsewhere: 4 to 13% in Italy [5, 11], 6% in Ireland [21], 7% in British Columbia [10], 9% in Sweden [7], 8 to 34% in the United States of America [6, 22] and 44% in a worldwide web-based study [23]. Gastrointestinal drug use was already high in 1996 in France, as 69% of women took at least one drug during pregnancy [24, 25]. However, the comparison between countries might be biased by differences in terms of recording of the use, availability and reimbursement of drugs, as well as treatment traditions [26]. Gastrointestinal drugs are widely used in France apart from the context of pregnancy. In 2016, 45% of patients between the ages of 18 and 34 years used at least one gastrointestinal drug, 19% used at least one antacid, 16% used antispasmodics, 7% used antinauseants, 3% used laxatives and 8% used antidiarrheal drugs [27]. These drugs were therefore used more frequently during pregnancy. In addition, the type of drug used during pregnancy is not the same around the world; for example, in some countries, H1 anti-histamines are used as a first line of treatment for nausea while this drug class is not used in France for this indication [28]. We found that drug use was only 5% higher in more deprived pregnancies than in less deprived pregnancies (76.0% vs 72.3% for at least one gastrointestinal drug use); other studies have reported a similar trend, but with more marked differences (around 30%) [23, 29, 30].

Domperidone use decreased from 18.3% in 2010 to 2.2% in 2018, which can be explained by the publication of two studies in 2010 that showed that domperidone prolongs the QT interval, and may cause life-threatening arrhythmias [31, 32]. Metopimazine use decreased in 2015 due to a drug company stock shortage [33].

As pre-marketing clinical trials exclude pregnant women, observational studies are therefore essential to study the efficacy and safety drugs in pregnant women and their offspring. Prescription of proton pump inhibitors doubled between 2010 and 2018 in pregnant women. This increase is of the same order of magnitude as that observed in the general population [34–36]. The efficacy of proton pump inhibitors for the relief of heartburn during pregnancy has not been demonstrated [37] and these drugs should be reserved to women not relieved by lifestyle modification [9, 38]. Several studies [9, 39–41] on the safety of use of proton pump inhibitors during pregnancy are reassuring. However, a recent meta-analysis including 26 observational studies suggested that these drugs were associated with an increased risk of congenital malformations (OR 1.28; 95%CI: 1.09–1.52) [42]. Moreover, toxic effects on animal embryos and fetuses are observed with high doses of omeprazole [43]. The two drugs most commonly used for nausea during pregnancy are dopamine antagonists: metoclopramide and metopimazine. Although metoclopramide has been shown to be effective and safe during pregnancy [9, 28, 44], this is not the case for metopimazine. French recommendations indicate that the use of metopimazine should only be considered after failure of other validated treatments, including metoclopramide and 5-HT3 antagonists [45]. Altogether, these data suggest that a more detailed risk-benefit assessment of prescription during pregnancy is necessary, particularly for proton pump inhibitors and metopimazine which are frequently used during pregnancy.

This study has certain limitations. First, like previously published studies based on the SNDS databases, algorithms rather than clinical data were used to identify pregnancies [2, 16]. Nevertheless, the validity of endpoints such as pregnancy outcomes, maternal age, type of delivery, pregnancy duration and birth weight has previously been demonstrated [16, 19, 46]. Second, over-the-counter drugs or drugs prescribed but not reimbursed (e.g. doxylamine) are not included in the SNDS, leading to underestimation of already high rates. Third, a dispensed drug does not mean that it has been used. However, studying dispensed drugs and not prescriptions avoids primary non-compliance, i.e., that the patient does not redeem the prescription.

The present study also has a number of major strengths. First, it is based on a large and unselected cohort of women with a pregnancy during recent years. Second, the SNDS is a comprehensive database for drug dispensing, covering more than 99% of the French population (around 66,000,000 people).

In conclusion, this large-scale population-based study shows that approximately three-quarters of women are exposed to drugs for gastrointestinal symptoms. From 2010 to 2018, the use of proton pump inhibitors doubled. The benefits and risks associated with increased exposure to proton pump inhibitors during pregnancy need to be further investigated.

Supporting information

S1 Fig. Flow-chart.

(TIF)

Click here for additional data file.^{(275KB, tif)}

S2 Fig. Number of pregnancies over time.

(TIF)

Click here for additional data file.^{(192.2KB, tif)}

S3 Fig. Drug exposure before, during and after pregnancy by the mother's age at the beginning of pregnancy.

A: 15–24 years; B: 25–34 years; C: 35-49years. Trim: trimester.

(TIF)

Click here for additional data file.^{(429.3KB, tif)}

S4 Fig. Drug exposure before, during and after pregnancy by deprivation index.

A: quintile 1 (less deprived); B: quintile 2–4; C: quintile 5 (more deprived). The deprivation index expressed in quintiles was developed in France as the first component of a principal component analysis of 4 socioeconomic variables. Trim: trimester.

(TIF)

Click here for additional data file.^{(455.4KB, tif)}

S5 Fig. Ant nauseant exposure during pregnancy over time.

(TIF)

Click here for additional data file.^{(359.7KB, tif)}

S6 Fig. Antispasmodic exposure during pregnancy over time.

(TIF)

Click here for additional data file.^{(335.7KB, tif)}

S7 Fig. Laxative exposure during pregnancy over time.

(TIF)

Click here for additional data file.^{(325.3KB, tif)}

S8 Fig. Antidiarrheal exposure during pregnancy over time.

(TIF)

Click here for additional data file.^{(309KB, tif)}

S1 Table. Pregnancy identification algorithms.

(DOCX)

Click here for additional data file.^{(14.3KB, docx)}

S2 Table. Drugs.

(DOCX)

Click here for additional data file.^{(15.6KB, docx)}

S3 Table. Hospitalization for gastrointestinal diseases.

(DOCX)

Click here for additional data file.^{(12.8KB, docx)}

S4 Table. Drug exposure (thousands): Sensitivity analysis excluding pregnancies lasting less than 37 weeks.

(DOCX)

Click here for additional data file.^{(19KB, docx)}

Acknowledgments

The authors would like to thank Anthony Saul, MD, for assistance with English grammar and spelling.

Data Availability

The authors had access to the SNDS database in application of the provisions of Articles R. 1461-12 et seq. of the French Public Health Code and the French data protection authority decision CNIL-2016-316. Future researchers can request access via the Health data hub: (https://documentation-snds.health-data-hub.fr/introduction/03-acces-snds.html#les-acces-sur-projet).

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0245854.r001

Decision Letter 0

Angela Lupattelli

1 Dec 2020

PONE-D-20-33435

Drug use for gastrointestinal symptoms during pregnancy: a French nationwide study 2010–2018

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5. Review Comments to the Author

Reviewer #1: This is a well-written and interesting paper mapping the dispensation of gastrointestinal drugs during pregnancy in France. It provides useful data as to the prevalence of the use of such drugs and it appears that some of the drugs in particular proton pump inhibitors have increased substantially in recent years. What is missing for me is more justification of why this is important, i.e. what are the potential risks/benefits of understanding patterns in gastrointestinal drug use? It is covered a little bit at the end and it may not be the focus of the paper but the paper needs to justify why understanding patterns of use are important in order to justify why this paper is important.

Specifically:

1. The introduction is very brief and this is where a couple of paragraphs explaining why understanding gastrointestinal drug use is important (ie potential risks/benefits/unknowns) could be added. It would just set up the value of the paper from the start as while a prevalence paper is useful, it is not clear why the issue needs examination at the moment.

Methods, graphs, data all clearly presented and easy to understand. Discussion briefly covers the impact of gastrointestinal drug use in pregnancy. Could also do with some more analysis on why rates are seemingly higher in France and what that could mean in terms of potential risks to mother/child.

Reviewer #2: This study aimed to assess the drug utilization pattern of drugs used to treat gastrointestinal symptoms during pregnancy in France in the period from April 1, 2010 to 2018. As pregnant women are not included in randomized controlled trials for ethical reasons, observational studies are important for assessing drug use and safety of drugs during pregnancy. The data were retrieved from the French national health database, SNDS, that covers more than 99% of the French population. The study population included all pregnancies ending in a live birth or stillbirth after 22 weeks of amenorrhea in the whole study period and thus represents an unselected pregnant population. The study shows that a large proportion of pregnant women in France redeemed prescriptions of drugs used to treat gastrointestinal symptoms in the study period. This is important and clinically relevant information.

Data are not available because access is restricted to French public institutions.

The manuscript is well-written and the methods are sound. However, some revisions and clarifications are required.

Major revisions

1. Hospitalizations for gastrointestinal symptoms or diseases during pregnancy is presented as one of the main results in the manuscript (Table 3), but not mentioned in the abstract. Suggest adding this result to the abstract.

2. In the Materials and Methods section (p3), please add some more information about what information is available regarding pregnancy and birth in the SNDS data source.

3. In the Materials and Methods section (p4), please specify how the trimesters were defined, e.g. in number of days/weeks/months from start of pregnancy. Since trimesters could be defined differently in different studies this is important information to be able to compare studies. Some examples are -90 days to +97 days, 0-90 days, or 0-97 days for the first trimester etc. In the figures and the tables you present additional exposure periods such as Trim-2, Trim-1, Trim 1-3, Trim+1 and Trim+2. Please also clarify the definition of these periods in the Materials and Methods section.

4. In the Materials and Methods section (p6), please clarify how prevalence of use was calculated. What was the denominator? Total number of pregnancies? Add a definition to the statistical analysis paragraph. See also next comment.

5. On page 6, line 139 it is stated that “The unit of analysis was a pregnancy, i.e. all of a patient’s pregnancies were included in the analysis”. Hence, the denominator should be the total number of pregnancies. If this is the denominator, how come the prevalence of use of at least one gastrointestinal drug is reported to be 74% among all pregnancies in the abstract and result section? Shouldn’t it rather be 70% (4,452,779/6,365,471), i.e. the number of pregnancies filling at least one prescription of a gastrointestinal drug divided by the total number of pregnancies included in the study? This goes for the rest of the percentages reported for the specific drug classes as well. Did you use another denominator than the total number of pregnancies for the calculations?

6. Page 6, line 140: What is meant by “inclusion”? All pregnancies in the study period are included and the unit of analysis is a pregnancy. It is my understanding that Table 1 shows baseline characteristics per pregnancy, i.e. a woman could be “included” twice if giving birth twice during the study period. Please clarify.

7. Regarding antinauseants, what is the rational for not including first generation antihistamines such as meclozine (R06AE05) and promethazine (R06AD02)? These drugs are among the most frequently used drugs to treat nausea in pregnancy and they are also considered first line treatment for nausea in pregnancy, at least in some European countries. Not including them will give the wrong picture of antinauseants use in pregnancy (unless these drugs are not used for that purpose in France). Please consider including first generation antihistamines in your study or, if not relevant to the study setting, please add a statement in the manuscript explaining why these drugs were not included.

8. The manuscript could benefit from first presenting a figure showing the overall drug utilization pattern, i.e. the prevalence of use per year for the total use of “all gastrointestinal drugs” and all the drug classes. This figure would be similar to Figure S4, but with the inclusion of the category “all gastrointestinal drugs” as defined in Table S2. Hence, Figure S4 could rather be presented as Figure 1 with the inclusion of “all gastrointestinal drugs”. Then the reader would be presented with the overall picture right away. Figure 1 (flow chart) could rather be moved to supplementary (see minor revisions).

9. Table S2 (and throughout the manuscript): Suggest changing “topical” to “locally-acting” for antacids (A02A, A02BX). Although these antacids are not absorbed systemically, it is not correct to use the term “topical” as they are administered orally and not topically.

10. p12, lines 240-242: In addition to differences in recording drug use and reimbursement of drugs, there could also be differences due to different availability of drugs and treatment traditions. In the Nordic countries for example antispasmodics are rarely used to treat nausea and vomiting in pregnant women, whereas this is the most frequent drug class in France.

11. p14, lines 279-280: What is the scientific evidence for stating that a patient will not use the drug particularly after having read the package leaflet? Do you mean that pregnant women might be more reluctant about taking medications during pregnancy? If so, please rephrase and add a reference after this statement.

12. p14, Suggest to add to the strengths that studying dispensed prescriptions has an advantage compared with studying issued prescriptions as you avoid primary non-compliance, i.e. that the patient does not redeem the prescription.

13. In the Introduction/Discussion section, please add some more information about French recommendations for pharmacological treatment of gastrointestinal symptoms in pregnancy to provide rational for the included drug classes and to discuss whether your results are in accordance with treatment guidelines or recommendations.

14. In general, more explanatory text is needed for figure legends, i.e. more detailed descriptions of what is shown in the figures and explanation of abbreviations etc. Also add labels to x-axis and y-axis, e.g. “Year of birth” for the x-axis in Figure 2.

Minor revisions

1. p3, line 81: Since SNDS contains information on dispensed drugs to outpatients it would be good to add “dispensed” since that would be helpful for the reader to know.

2. p4, line 93: Explain the abbreviation WA.

3. p5, line 121-122 and Table 1: It is a bit confusing that the total number of pregnancies during the study period (“Gravidity”) is presented as 1st, 2nd and 3rd and more pregnancies. This should be 1, 2, 3 or more pregnancies as a woman can only enter one of the categories during the study period, i.e. you refer to the total number of pregnancies and not whether it is the 1st or 2nd pregnancy.

4. p7, line 162: Suggest moving the flow chart (Figure 1) to supplementary. Also, please include “pregnancies” to the textbox at the bottom of the flow chart, i.e. “6,365,471 pregnancies ending with live birth or stillbirth included in the analysis”.

5. p8, line 177: Suggest adding “The antispasmodic phloroglucinol was…” to enhance readability.

6. p9, line 192: What is meant by setron? Does it refer to A04AA? Please use the term from the WHO ATC/DDD index, i.e. “serotonin (5-HT3) antagonists” in the text, tables (Table 2, Table S2, Table S4), and figures (Figure S5) for this drug class.

7. Table 1: suggest changing “Total” (leftmost column) to “Number of pregnancies” so that the reader understands that the unit of measurement is pregnancies and not women. A table should be self-explanatory.

Reviewer #3: This paper describes the consumption of gastrointestinal medication during pregnancy between 2010-2018 in France. Given the high prevalence of medication use during pregnancy and concerns about medication safety, this topic area is very important. Here are a few comments and suggestion to consider

1) The mention of time period is not consistent throughout the paper, during pregnancy, 6 months before to 6 months after pregnancy, trimester -2 to trimester +2. Please clarify

2) Why have the authors chosen to investigate 6 months prior to pregnancy and 6 months postpartum if the objective is medication use during pregnancy. I understand that 3 months prior to pregnancy could be reflective of behavior during the first trimester of pregnancy but there is no justification on to why the authors decided on this particular time period

3) Related to comment 2, how did the authors distinguish between taking the GI medications due to pregnancy-related complications vs. non-pregnancy complications 6 months prior to pregnancy or 6 months postpartum?

4) In line 86 on page 4 please clarify term termination as stated in Table S1

5) In line 109 on page 5 the authors mention the study of the most common reasons for hospitalization for a GI symptom or disease between 6 months before and 6 months after pregnancy. At the bottom of the page in line 133, they mention pregnancy-related hospitalization included hospitalizations during pregnancy for a pregnancy complication. It seems to me that these two variables may have overlaps (for instance, a pregnant woman may get hospitalized due to extreme nausea and vomiting. Please clarify.

6) The statistical analysis section needs to be expanded to explain how medication dispending and hospitalizations during each trimester of pregnancy were described. What method was used? Were the models adjusted for any competing risk factors?

7) Please explain why you decided to excluded pregnancies that did not end in birth. Is there any data to suggest that adverse pregnancy outcomes such as spontaneous abortions, ectopic pregnancy etc occurred as a result of taking GI medications? It would be interesting (as a sensitivity analysis) to determine the % of use of GI medications in pregnancies that were terminated before birth

8) In Line 167, is no income the same as missing? Please clarify in the text and the Table.

9) It is not clear whether “drug exposure” results (lines 174- 178) are presented as a Table or not. If not, it would be more helpful to include a table with these results

10) What methods were used to determine “drug exposure over time”? and are the % in 2010 and 2018 significantly different from each other? Please clarify in the methods section and the results

11) Are the results related to dug exposure before, during, and after pregnancy calculated separately or longitudinally? And are they adjusted or unadjusted %s? Please clarify in methods and the results sections

12) For Table 2, please Add in the footnote of the table how the % were calculated and whether they were adjusted for any of the maternal factors.

13) Table 3, what is N?

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Reviewer #2: Yes: Ingvild Odsbu

Reviewer #3: No

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PLoS One. 2021 Jan 22;16(1):e0245854. doi: 10.1371/journal.pone.0245854.r002

Author response to Decision Letter 0

6 Jan 2021

Comments for Manuscript "Drug use for gastrointestinal symptoms during pregnancy: a French nationwide study 2010–2018"

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We thank the academic editor for her comments. We provide hereafter a point-by-point response to these comments, which we hope will clarify and improve the manuscript.

We have adapted our manuscript to meet PLOS ONE's style requirements.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

We added the following data availability statement in the cover letter and the manuscript: The authors had access to the SNDS database in application of the provisions of Articles R. 1461-12 et seq. of the French Public Health Code and the French data protection authority decision CNIL-2016-316. Future researchers can request access via the Health data hub: (https://documentation-snds.health-data-hub.fr/introduction/03-acces-snds.html#les-acces-sur-projet).

3. Thank you for stating the following in the Competing Interests section:

'Conflict of Interest:

- Antoine Meyer: no conflict of interest.

- Marion Fermaut: no conflict of interest.

- Jérôme Drouin: no conflict of interest.

- Alain Weill: no conflict of interest.'

Please note that we cannot proceed with consideration of your article until this information has been declared.

We added the following statement in the cover letter and the manuscript: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.”

b. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

We added the updated Competing Interests statement in our cover letter.

Reviewers' comments:

Reviewer #1:

This is a well-written and interesting paper mapping the dispensation of gastrointestinal drugs during pregnancy in France. It provides useful data as to the prevalence of the use of such drugs and it appears that some of the drugs in particular proton pump inhibitors have increased substantially in recent years. What is missing for me is more justification of why this is important, i.e. what are the potential risks/benefits of understanding patterns in gastrointestinal drug use? It is covered a little bit at the end and it may not be the focus of the paper but the paper needs to justify why understanding patterns of use are important in order to justify why this paper is important.

We thank the reviewer for his/her comments. We provide hereafter a point-by-point response to these comments, which we hope will clarify and improve the manuscript.

Specifically:

Thank you for this important comment. We added a paragraph at the beginning of the introduction to better reflect why understanding gastrointestinal drug use is important:

“Thalidomide was used as an antinauseant medication during pregnancy until its teratogenic effect was demonstrated in the 1960s. This scandal led to an increased awareness of the safe use of drugs during pregnancy. Yet, data on the safety of drugs used during pregnancy (for both women and offspring) is often lacking as pre-marketing clinical trials exclude pregnant women. Observational studies are therefore essential to study the efficacy and safety drugs in pregnant women and their offspring. For instance, a French nationwide study on recent data confirmed that valproic acid, a treatment for epilepsy, cause birth defects and delayed cognitive development.”

We also added this sentence before the aim of the study:

“Drug use studies in pregnancy are useful to identify the most frequently used drugs and thereby decide which drug safety studies should be prioritized.”

That’s a very good point and it is addressed in the discussion: “We found that approximately three-quarters of women used drugs for gastrointestinal symptoms during pregnancy. This rate is higher than those reported elsewhere: 4 to 13% in Italy, 6% in Ireland, 7% in British Columbia, 9% in Sweden, 8 to 34% in the United States of America and 44% in a worldwide web-based study. Gastrointestinal drug use was already high in 1996 in France, as 69% of women took at least one drug during pregnancy. However, the comparison between countries might be biased by differences in terms of recording of the use, availability and reimbursement of drugs, as well as treatment traditions.”

We have modified a sentence in the discussion to better reflect the potential risks to mother/child:

Previous sentence in the discussion: Altogether, these data suggest that a more detailed risk-benefit assessment of prescription during pregnancy is necessary, particularly for proton pump inhibitors and metopimazine.

New sentence in the discussion: Altogether, these data suggest that a more detailed risk-benefit assessment of prescription during pregnancy is necessary, particularly for proton pump inhibitors and metopimazine which are frequently used during pregnancy.

Reviewer #2:

This study aimed to assess the drug utilization pattern of drugs used to treat gastrointestinal symptoms during pregnancy in France in the period from April 1, 2010 to 2018. As pregnant women are not included in randomized controlled trials for ethical reasons, observational studies are important for assessing drug use and safety of drugs during pregnancy. The data were retrieved from the French national health database, SNDS, that covers more than 99% of the French population. The study population included all pregnancies ending in a live birth or stillbirth after 22 weeks of amenorrhea in the whole study period and thus represents an unselected pregnant population. The study shows that a large proportion of pregnant women in France redeemed prescriptions of drugs used to treat gastrointestinal symptoms in the study period. This is important and clinically relevant information.

Data are not available because access is restricted to French public institutions.

The manuscript is well-written and the methods are sound. However, some revisions and clarifications are required.

We thank the reviewer for her comments. We provide hereafter a point-by-point response to these comments, which we hope will clarify and improve the manuscript.

Major revisions

We added this sentence in the methods section of the abstract: “We also assessed hospitalization for gastrointestinal symptoms during pregnancy.”

We added this sentence in the results section of the abstract: “Nausea/vomiting was the most common cause of hospitalization for gastrointestinal symptoms or diseases during pregnancy, although it accounted for only 1.0% of pregnancies.”

2. In the Materials and Methods section (p3), please add some more information about what information is available regarding pregnancy and birth in the SNDS data source.

The information available in our database and used in this study regarding pregnancy and birth were included in the methods in the sections: data source, study population and maternal and pregnancy characteristics. We have added references to the content of the database that is not used in our study: Blotiere 2018, Blotiere 2019, Blotiere 2020.

We added in the methods how trimesters were defined.

Previous sentence in the methods: We studied each drug dispensed for gastrointestinal symptoms in the 6 months before, during and in the six months after pregnancy, for each trimester, including: antacids, antispasmodics, antinauseants, laxatives, antidiarrheals and other drugs for functional gastrointestinal disorders. Details on International Non-Proprietary name and Anatomical Therapeutic Chemical Classification are given in S2 Table.

New sentence in the methods: We studied each drug dispensed for gastrointestinal symptoms including: antacids, antispasmodics, antinauseants, laxatives, antidiarrheals and other drugs for functional gastrointestinal disorders. Details on International Non-Proprietary name and Anatomical Therapeutic Chemical Classification are given in S2 Table. For each pregnancy, seven trimesters were studied: two trimesters before the beginning of pregnancy (Trim-2: day −182 to day −92; Trim-1: day −91 to day −1), each trimester of pregnancy (Trim1: day 0 i.e. fertilisation to day 90; Trim2: day 91 to day 181; Trim3: day 182 to delivery −1) and two trimesters after the end of pregnancy (Trim+1: delivery to delivery + 91; Trim+2: delivery + 92 to delivery + 182).

We clarified this definition in the statistical analysis section of the methods.

Previous sentence in the methods: Medication dispensing and hospitalizations during each trimester of pregnancy were then described.

New sentence in the methods: Medication dispensing during pregnancy over time was then described for pregnancy ending between April 2010 and December 2018: crude numbers and percentages of exposed pregnancies by year of pregnancy end. Medication dispensing and hospitalizations before, during and after pregnancy was described for pregnancies ending between April 2010 and June 2018: crude numbers and percentages of exposed pregnancies by trimester.

The answer to the previous question also answers this question. Medication dispensing before, during and after pregnancy was described for pregnancies ending between April 2010 and June 2018. Indeed, pregnancies ending between July 2018 and December 2018 were excluded to have the full seven trimesters of exposure for each pregnancy. Therefore, 74.0% (4,452,779 / 6,014,811) received at least one gastrointestinal drug during pregnancy as shown in Table 2.

You understood correctly. We modified a sentence in the methods to further clarify this point:

Previous sentence in the methods: We first described maternal and pregnancy characteristics at inclusion: median and interquartile range (IQR) for continuous variables and proportions for dichotomous and categorical variables.

New sentence in the methods: We first described maternal characteristics at the beginning of pregnancy and pregnancy characteristics for each pregnancy: median and interquartile range (IQR) for continuous variables and proportions for categorical variables.

H1 anti-histamines drugs such as meclozine and promethazine are not used in France for nausea as they are not authorized for use in this indication.

We added a sentence in the discussion to clarify this point: “In addition, the type of drug used during pregnancy is not the same around the world; for example, in some countries, H1 anti-histamines are used as a first line of treatment for nausea while this drug class is not used in France for this indication.”

Again, a very good point. We have followed your recommendations by adding an "all gastrointestinal drugs" category to S4 Fig which is now Fig 1. Flow-chart has been moved to supplementary

We replaced “topical” to “locally-acting” for antacids.

We added availability of drugs and treatment traditions in the difference between countries in the discussion.

Previous sentence in the discussion: However, the comparison between countries might be biased by differences in terms of recording of the use and reimbursement of drugs.

New sentence in the discussion: However, the comparison between countries might be biased by differences in terms of recording of the use, availability and reimbursement of drugs, as well as treatment traditions.

We have removed the end of the sentence in the discussion concerning the package leaflet, in fact, there can be several reasons for not taking a delivered medication.

Previous sentence in the discussion: Third, a dispensed drug does not mean that it has been used, particularly after the patient has read the package leaflet.

New sentence in the discussion: Third, a dispensed drug does not mean that it has been used. However, studying dispensed drugs and not prescriptions avoids primary non-compliance, i.e., that the patient does not redeem the prescription.

We added this strength in the discussion:

Previous sentence in the discussion: Third, a dispensed drug does not mean that it has been used, particularly after the patient has read the package leaflet.

Unfortunately, there is no French recommendation on the use of gastrointestinal medications during pregnancy.

To increase clarity, we added labels to x-axis and y-axis, description and explanation of abbreviations for all figures.

Minor revisions

1. p3, line 81: Since SNDS contains information on dispensed drugs to outpatients it would be good to add “dispensed” since that would be helpful for the reader to know.

We modified this sentence in the methods to increase clarity:

Previous sentence in the methods: The SNDS contains all outpatient information (demographics, drugs, and procedures) and all inpatient information (expensive drugs dispensed, procedures performed during hospital stays, and diagnoses).

New sentence in the methods: The SNDS contains all outpatient information (demographics, drugs dispensed, and procedures) and all inpatient information (expensive drugs dispensed, procedures performed during hospital stays, and diagnoses).

2. p4, line 93: Explain the abbreviation WA.

We replaced all the “WA” by “weeks” throughout the manuscript and specified in the methods that they were weeks of amenorrhea.

Previous sentence in the methods: All pregnancies ending with a birth - either livebirth or stillbirth (delivery of a dead fetus after 22WA) - between April 2010 and December 2018 were included.

New sentence in the methods: All pregnancies ending with a birth - either livebirth or stillbirth - between April 2010 and December 2018 were included. A stillbirth was the delivery of a dead fetus after 22 weeks of amenorrhea (referred to as weeks thereafter).

Gravidity refers here as it is the 1st, 2nd,… pregnancy during the study period. We modified a sentence in the methods to increase clarity:

Previous sentence in the methods: Gravidity (1st pregnancy, 2nd and more pregnancy) was defined as the number pregnancies in a woman during the study period.

New sentence in the methods: Gravidity (1st pregnancy, 2nd pregnancy,…) was defined as the pregnancy number in a woman during the study period.

We moved the flow-chart to supplementary and modified the bottom box as suggested: “6,365,471 pregnancies ending with live birth or stillbirth included in the analysis”.

5. p8, line 177: Suggest adding “The antispasmodic phloroglucinol was…” to enhance readability.

We modified this sentence to enhance readability:

Previous sentence in the results: Phloroglucinol was by far the most commonly prescribed drug (51.0% of all pregnancies).

Previous sentence in the results: The antispasmodic phloroglucinol was by far the most commonly prescribed drug (51.0% of all pregnancies).

We replaced “setron” by “5-HT3 antagonists” throughout the manuscript.

We replaced “Total” by “Number of pregnancies” in Table 1.

Reviewer #3:

This paper describes the consumption of gastrointestinal medication during pregnancy between 2010-2018 in France. Given the high prevalence of medication use during pregnancy and concerns about medication safety, this topic area is very important. Here are a few comments and suggestion to consider

We thank the reviewer for his/her comments. We provide hereafter a point-by-point response to these comments, which we hope will clarify and improve the manuscript.

1) The mention of time period is not consistent throughout the paper, during pregnancy, 6 months before to 6 months after pregnancy, trimester -2 to trimester +2. Please clarify

We replaced “6 months” by “2 trimesters” throughout the manuscript.

We studied three periods: before, during and after pregnancy because we wanted not only to study drug exposure during pregnancy but also to compare it with that outside of pregnancy. The choice of two trimesters before and after pregnancy was arbitrary, but it seemed to us that it could capture drug exposure before and during pregnancy.

In this study we cannot know what was the cause of the gastrointestinal symptom that led to the use of these gastrointestinal drugs, but this was not the aim of our study, we simply studied drug use for gastrointestinal symptoms during pregnancy. Drug use studies in pregnancy are useful to identify the most frequently used drugs and thereby decide which drug safety studies to conduct.

4) In line 86 on page 4 please clarify term termination as stated in Table S1

As there was no pregnancy termination (abortions, ectopic pregnancies,…) included in our study, we simplified this sentence to increase clarity:

Previous sentence in the methods: The pregnancy end date was the date of delivery or termination of pregnancy, or, when missing, the date of admission for pregnancy completion.

New sentence in the methods: The pregnancy end date was the date of delivery, or, when missing, the date of admission for pregnancy completion.

That’s a very good point. As these two variables may overlap and as pregnancy-related hospitalizations are not studied here, we removed pregnancy-related hospitalizations in the methods and in Table 1.

As requested by reviewer 2, we have completed the methods to specify the statistical analyses performed. No adjustments were made because the objective of the study was to study drug use in the entire French population, we added the word “crude” in the statistical analysis section to clarify this point.

We added in the statistical analysis section: “Medication dispensing during pregnancy over time was then described for pregnancy ending between April 2010 and December 2018: crude numbers and percentages of exposed pregnancies by year of pregnancy end. Medication dispensing and hospitalizations before, during and after pregnancy was described for pregnancies ending between April 2010 and June 2018: crude numbers and percentages of exposed pregnancies by trimester.”

Point well taken. Whether gastroenterological medications cause more abortions or more ectopic pregnancies is an important question, but this was not the aim of our study, which was a descriptive analysis of drug use during pregnancy. We excluded these pregnancies because to study drug exposure throughout pregnancy, pregnancies that last three trimesters are needed. We added this precision in the methods:

“We excluded pregnancies with elective or therapeutic abortions, spontaneous abortions, ectopic pregnancies and hydatidiform moles and other abnormal products of conception (blighted ovum and nonhydatidiform moles) because to study drug exposure throughout pregnancy, pregnancies that last three trimesters are needed.”

A sensitivity analysis was also performed excluding pregnancies of less than 37 weeks to have only pregnancies with three full trimesters (S4 Table). We added this precision in the statistical analysis section of the methods: “A sensitivity analysis was performed and excluded pregnancies of less than 37 weeks.”

8) In Line 167, is no income the same as missing? Please clarify in the text and the Table.

No income is not the same as missing. No income means that the woman did not receive a salary before her maternity leave. To increase clarity, we modified a sentence in the methods:

Previous sentence in the methods: … income (none, <€2,000/month, ≥€2,000/month or missing value) calculated from the woman's salary during the three months before maternity leave. Income was only available for pregnancies for which women received maternity benefits, i.e., pregnancies among general health insurance scheme beneficiaries (93.7% of pregnancies).

New sentence in the methods: … income (general health insurance scheme: none, <€2,000/month, ≥€2,000/month; and agricultural/self-employed scheme) calculated from the woman's salary during the three months before maternity leave.

We also modified Table 1 accordingly.

9) It is not clear whether “drug exposure” results (lines 174- 178) are presented as a Table or not. If not, it would be more helpful to include a table with these results

These results are included in Table 2. We added the precision in the results to increase clarity.

Previous sentence in the results: Among all pregnancies with delivery, 4,452,779 (74.0%) received at least one gastrointestinal drug during pregnancy; 2,228,275 (37.0%) pregnancies were exposed to an antacid, 3,096,858 (51.5%) to an antispasmodic, 1,861,731 (31.0%) to an antinauseant, 919,116 (15.3%) to a laxative and 617,808 (10.3%) to an antidiarrheal.

New sentence in the results: Among all pregnancies with delivery, 4,452,779 (74.0%) received at least one gastrointestinal drug during pregnancy; 2,228,275 (37.0%) pregnancies were exposed to an antacid, 3,096,858 (51.5%) to an antispasmodic, 1,861,731 (31.0%) to an antinauseant, 919,116 (15.3%) to a laxative and 617,808 (10.3%) to an antidiarrheal (Table 2).

10) What methods were used to determine “drug exposure over time”? and are the % in 2010 and 2018 significantly different from each other? Please clarify in the methods section and the results

We added a sentence in the statistical analysis section of the methods to define drug exposure over time: “Medication dispensing during pregnancy over time was then described for pregnancy ending between April 2010 and December 2018: crude numbers and percentages of exposed pregnancies by year of pregnancy end.”

However, we did not perform statistical testing since our objective was descriptive. In addition, given the very large sample size of the study (6,365,471), clinically irrelevant differences would be statistically significant.

We added a sentence in the statistical analysis section of the methods to define drug exposure before, during, and after pregnancy: “Medication dispensing and hospitalizations before, during and after pregnancy was described for pregnancies ending between April 2010 and June 2018: crude numbers and percentages of exposed pregnancies by trimester.” No adjustments were made because the objective of the study was to study drug use in the entire French population, we added the word “crude” in the statistical analysis section to clarify this point.

12) For Table 2, please Add in the footnote of the table how the % were calculated and whether they were adjusted for any of the maternal factors.

We added a footnote in Table 2, Table 3 and S4 Table to explain how percentages were calculated: “Medication dispensing before, during and after pregnancy was described for pregnancies ending between April 2010 and June 2018: crude numbers and percentages of exposed pregnancies by trimester.”.

13) Table 3, what is N?

We replaced N by Number of pregnancies to increase clarity in Table 1, Table 2, Table 3 and S4 Table.

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PLoS One. doi: 10.1371/journal.pone.0245854.r003

Decision Letter 1

Angela Lupattelli

11 Jan 2021

Drug use for gastrointestinal symptoms during pregnancy: a French nationwide study 2010–2018

PONE-D-20-33435R1

Dear Dr. Meyer,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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PLoS One. doi: 10.1371/journal.pone.0245854.r004

Acceptance letter

Angela Lupattelli

12 Jan 2021

PONE-D-20-33435R1

Drug use for gastrointestinal symptoms during pregnancy: a French nationwide study 2010–2018

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Flow-chart.

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S2 Fig. Number of pregnancies over time.

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S3 Fig. Drug exposure before, during and after pregnancy by the mother's age at the beginning of pregnancy.

A: 15–24 years; B: 25–34 years; C: 35-49years. Trim: trimester.

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S4 Fig. Drug exposure before, during and after pregnancy by deprivation index.

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S5 Fig. Ant nauseant exposure during pregnancy over time.

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S6 Fig. Antispasmodic exposure during pregnancy over time.

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S7 Fig. Laxative exposure during pregnancy over time.

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S8 Fig. Antidiarrheal exposure during pregnancy over time.

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S1 Table. Pregnancy identification algorithms.

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S2 Table. Drugs.

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S3 Table. Hospitalization for gastrointestinal diseases.

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S4 Table. Drug exposure (thousands): Sensitivity analysis excluding pregnancies lasting less than 37 weeks.

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Attachment

Submitted filename: Response to Reviewers.docx

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Data Availability Statement

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PERMALINK

Drug use for gastrointestinal symptoms during pregnancy: A French nationwide study 2010–2018

Antoine Meyer

Marion Fermaut

Jérôme Drouin

Franck Carbonnel

Alain Weill

Roles

Abstract

Purpose

Methods

Results

Conclusions

Background and aims

Materials and methods

Data source

Study population

Drug exposure and hospitalizations

Maternal and pregnancy characteristics

Statistical analysis

Results

Study population

Maternal and pregnancy characteristics

Table 1. Demographic data and pregnancy characteristics (in thousands).

Drug exposure

Table 2. Drug exposure before, during and after pregnancy (thousands).

Drug exposure over time

Fig 1. Drug exposure during pregnancy over time.

Fig 2. Antacid exposure during pregnancy over time.

Drug exposure before, during and after pregnancy

Fig 3. Drug dispensing before, during and after pregnancy.

Hospitalizations

Table 3. Hospitalizations before, during and after pregnancy (thousands).

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Angela Lupattelli

Roles

Author response to Decision Letter 0

Decision Letter 1

Angela Lupattelli

Roles

Acceptance letter

Angela Lupattelli

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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