Analysis of potential risks between acetaminophen and ibuprofen use during pregnancy via the FAERS database

doi:10.21203/rs.3.rs-3977270/v1

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Analysis of potential risks between acetaminophen and ibuprofen use during pregnancy via the FAERS database

https://doi.org/10.21203/rs.3.rs-3977270/v1

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Purpose: The aim of this study was to compare the potential risks of acetaminophen and ibuprofen use during pregnancy in relation to adverse events (AEs) from real-world practice via the FAERS database.

Methods: We detected signals of the AEs of acetaminophen and ibuprofen use during pregnancy by data mining using FAERS database. Disproportionality analysis was used to the FAERS for the suspected pregnancy data from January 2017 to December 2022.

Results: On the basis of 51,936 acetaminophen reports, the reports of 331 (0.64% of total adverse drug reactions, ADRs) were associated with pregnancy; On the basis of 84,810 ibuprofen reports, the reports of 530 (0.62%) were associated with pregnancy. Among acetaminophen reports, the most AE was exposure during pregnancy (59.52%) that belongs to injury, poisoning and procedural complications. The associated pregnancy outcome of those reports was missing may suggest no cause serious consequences. Among ibuprofen reports, the major AE was abortion spontaneous (26.79%), and oligohydramnios (17.74%).

Conclusion: This is the first study of comprehensively compare and analyze the potential risks between acetaminophen and ibuprofen for drug-associated adverse fetal and pregnancy outcomes by assessing the reported AEs from the real-world database. The results suggested acetaminophen may be the better choice during pregnancy.

Health sciences/Health care

Biological sciences/Drug discovery/Drug delivery

Biological sciences/Drug discovery/Drug safety

acetaminophen

ibuprofen

adverse drug events

FAERS

pregnancy

disproportionality analysis

The potential risks between acetaminophen and ibuprofen use during pregnancy

Background: Understanding both acetaminophen and ibuprofen during pregnancy-associated potential risks is very important, which is essential for avoiding or improving drug-associated adverse outcomes for fetal and pregnancy. Our study was to compare the potential risks of acetaminophen and ibuprofen use during pregnancy, and then to provide applicable clinical evidence.

Methods: Via a real-world database, we compare the potential risks of acetaminophen and ibuprofen use during pregnancy. The data was from January 2017 to December 2022.

1) The characteristics of acetaminophen and ibuprofen reports were similar. However, ibuprofen exhibited more adverse events than acetaminophen within the same duration of use.

2) The main potential risks of ibuprofen and acetaminophen are congenital disorders.

3) The potential risks of ibuprofen were more significant than those of acetaminophen.

4) Ibuprofen was more significant than acetaminophen for pharmacotherapy in pregnant women with the same potential risks.

Conclusion: The results suggested acetaminophen may be the better choice than ibuprofen during pregnancy only when needed.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for their analgesic and antipyretic properties during pregnancy worldwide. Analgesics are the class of medication most frequently used during pregnancy. Approximately 56% of pregnant women report using the analgesic drugs. Because of ethical concerns, safety data for analgesic use in pregnancy is largely limited to animal studies or observational studies in humans.¹ Drug absorption increases during pregnancy through the mother’s slowed gastrointestinal motility, increased cardiac output and blood flow.² Data from observational studies regarding other potential embryo-fetal risks of NSAIDs use in women in the first or second trimesters of pregnancy are inconclusive. Prostaglandins play an essential role in maintenance of early pregnancy, whereby suppression of prostaglandin biosynthesis by NSAIDs may disrupt this process and lead to miscarriage. Maternal NSAIDs use at about 20 week’s gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and neonatal renal impairment. However, there are still no adequate, well-controlled studies in pregnant women about analgesics and antipyretics use during pregnancy.³

Acetaminophen is one of the most commonly used medications during pregnancy and considered maybe the preferred safe for maternal health and fetal development. The prevalence of acetaminophen use during pregnancy is nearly 65%, half of them in the first trimester.⁴ However, epidemiological studies have associated with prenatal acetaminophen use with several developmental disorders in offspring at least first and second trimesters with males being more susceptible, such as neurodevelopmental, reproductive (cryptorchidism), urogenital disorders.^5–8 Although limited data on the risk of congenital malformations with prenatal acetaminophen use has not demonstrated convincing associations. Growing evidence indicates that acetaminophen in uterus exposure may be associated with a higher risk of male genital tract abnormalities.^{9, 10}

Up to 30% of pregnant women reported ibuprofen used at some stages during pregnancy, ranking ibuprofen as the second most used Over the Counter (OTC) analgesic after acetaminophen. The label of ibuprofen definitely indicated: Ibuprofen could increase the risk of ductus arteriosus premature closure in pregnant women after about 30 week’s gestation. Ibuprofen may cause fetal renal dysfunction leading to oligohydramnios and neonatal renal impairment after about 20 week’s gestation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may be limb contractures and delayed lung maturation. In human fetuses, ibuprofen exposure is deleterious for ovarian germ cells in vitro.¹¹ Inhibition of prostaglandins leads to an unopposed vasoconstriction of the kidneys in newborns, and it is likely this same mechanism underlies renal impairment in the fetus.¹ Their application may be associated with drug-induced adverse fetal and pregnancy outcomes. Available data about acetaminophen or ibuprofen for adverse outcomes of pregnancy are sporadic and mainly from clinical retrospective studies, which may not well reflect the overall drug-induced adverse outcomes.

Data mining techniques are increasingly being used to explore medical databases and analyze the accumulated data to identify potential associations between drugs AEs. The FDA’s Adverse Event Reporting System (FAERS) is one of the largest databases of AEs designed to support the FDA post-marketing safety surveillance program for approved drugs and therapeutic biological products.¹² It relies mainly on health professionals, consumers, and pharmaceutical manufacturers to report AEs and medication error reports to the FDA all over the world.¹³ The purpose of this system is to support the FDA’s safety monitoring for post-marketing drugs and biologics. This study collected, screened, and statistically analyzed the data in the FAERS, conducted a signal mining analysis of suspicious adverse reactions (ADRs) generated by acetaminophen and ibuprofen use, and focused on the pregnancy. In this article, we compared the potential risk of acetaminophen and ibuprofen use during pregnancy in relation to AEs from real-world practice via the FAERS database, and then to show a possible rank-order of the drugs in terms of susceptibility.

Pharmacovigilance is involved in the entire life cycle of drug clinical application. Real-world research has emerged after the drug post-marketing. In this article, we compared the potential risk of acetaminophen and ibuprofen use during pregnancy in relation to AEs from real-world practice via the FAERS database, and then to suggest a possible rank-order of the drugs in terms of susceptibility.

2.1 Data source

We conducted a retrospective pharmacovigilance study that included all reports among gestational patients treated with acetaminophen or ibuprofen from the first quarter of 2017 to the fourth quarter of 2022 using data from the FAERS database. The database is designed to support the FDA’s post-marketing safety surveillance program for drug and therapeutic biologic products. It is a useful tool for activities such as looking for potential safety concerns that might be related to a marketed product.¹⁴ FAERS data files describe demographic and administrative information, drug information, preferred terms coded for the adverse events, report sources and so on.¹⁵ A total of 136,746 reports (acetaminophen: 51, 936; ibuprofen: 84, 810) were retrieved from FAERS database. A deduplication process was performed according to the FDA recommendations. If the CASEIDs (a number for identifying a FAERS case) were the same, the latest FDA_DT (date FDA received the case) was selected. If the CASEID and FDA_DT were the same, the higher PRIMARYID (a unique number for identifying a FAERS report) was selected.¹⁶ Ultimately, a total of 861 reports (acetaminophen: 331; ibuprofen: 530) were used for further analysis.

2.2 Drug and adverse event identification

The drug names are registered multifarious in FAERS database, such as generic names, brand names, synonymous names, or abbreviations. Both generic name and brand name were used as keywords for FAERS database retrieval. Most retrieved reports of acetaminophen and ibuprofen are fixed-dose combination. In the REAC files, preferred terms (PTs) are recommended medical terminology describing the event provided by the Medical Dictionary for Regulatory Activities (MedDRA). PT can be assigned to one or more High-level Term, and System Organ Class (SOC) level in MedDRA. In addition, different PT can be combined to define a specific clinical syndrome through an algorithmic approach known as Standardized MedDRA Queries. The primary outcome was overall pregnancy-related AEs. The secondary outcome was the inherited disease.

2.3 Data mining

For detection methods of ADRs, disproportionality analysis is acknowledged used to analyze the post-marketing surveillance databases. Disproportionality analysis includes the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). Disproportionality analysis is a validated concept that compares the proportion of selected AEs reported for a single drug with the proportion of the same AEs for a control group of drugs.¹⁷ All the measures of disproportionality are based on the same principles of calculation.

2.4 Statistical analysis

Descriptive analyses were used to summarize the clinical data characteristics of gestational patients treated with acetaminophen or ibuprofen from the FAERS database. The algorithms’ computation and statistical criteria are shown as follows.¹⁸ ROR = ad/bc, 95% CI is e^{ln(ROR)±1.96}(1/a + 1/b + 1/c + 1/d)^0.5 (criteria: 95% CI > 1 and N ≥ 3); PRR = a(c + d)/c/(a + b), χ² = [(ad - bc)²](a + b + c + d)/[(a + b)(c + d)(a + c)(b + d)] (criteria: PRR ≥ 2, χ² ≥ 4 and N ≥ 3). Notes: a is the number of reports with suspect ADRs of the suspect drug; b is the number of reports with the suspect ADRs of all other drugs; c is the number of reports with all other ADRs of the suspect drug; d is the number of reports with all other ADRs of all other drugs; CI is the confidence interval; N is the number of AEs of acetaminophen or ibuprofen use during pregnancy; χ² is chi squared. The χ² contingency test was used to measure the statistical significance of an observed disproportionality.

The total number of ADRs reported during the first quarter of 2017 to the fourth quarter of 2022 was 136,746 (acetaminophen: 51, 936; ibuprofen: 84, 810). Of these, 861 reports (acetaminophen: 331; ibuprofen: 530) were used to further analysis, for which there was a very possible relationship between drug use and adverse fetal and pregnancy outcomes.

3.1 General characteristics of AE reports for acetaminophen and ibuprofen

General characteristic of patients as follows: 1) the age of one-third patient was 18–64 years old. 2) More than 50% patients were female. 3) The administration route of more than 98% was oral. 4) The majority of acetaminophen and ibuprofen reports were submitted by consumers and healthcare professionals. 5) For the reporter countries, the acetaminophen was mostly from United States and Canada. The ibuprofen was mainly from United States, Germany, United Kingdom, France, and Canada. The above results suggested the general characteristics of acetaminophen and ibuprofen reports were quite similar, but ibuprofen had more AE reports than acetaminophen in the same time interval all over the world (Table 1).

3.2 Signal of disproportionality reporting for the difference of AEs between acetaminophen and ibuprofen use during pregnancy

The signal of disproportionality reporting in the FAERS database identified 17 PTs for acetaminophen and 36 PTs for ibuprofen respectively (just listed top 20) (Fig. 1). The disproportionality analysis highlighted five same PTs of potential risk with statistically significant for ROR:1) Ductus arteriosus premature closure [acetaminophen (6.34%): ROR 36.54; ibuprofen (7.17%): ROR57.81]. 2) Fetal heart rate disorder [acetaminophen (3.63%): ROR 11.90; ibuprofen (1.32%): ROR 33.44].3) Premature labor [acetaminophen (3.63%): ROR 2.33; ibuprofen (6.42%): ROR 5.27].4) Oligohydramnios [acetaminophen (3.02%): ROR = 2.62; ibuprofen (17.74%): ROR 21.03].5) Tachycardia fetal [acetaminophen (1.81%): ROR 10.31; ibuprofen (2.08%): ROR 15.33]. The above results indicated the same potential risks and AEs incidence rateof ibuprofen were more significant than acetaminophen, especially for oligohydramnios. In addition, the potential risk for placental cyst of ibuprofen was more significant than others extremely.

Table 1

General characteristics of AE reports for acetaminophen and ibuprofen
Characteristics	Reports, N (%)
Characteristics	Acetaminophen	Ibuprofen
Patient age, (years)
0–17	3,478 (6.70%)	11,262 (13.28%)
18–64	17,336 (33.38%)	35,074 (41.36%)
65–84	8,094 (15.58%)	11,831 (13.95%)
≥ 85	2,031 (3.91%)	1,781 (2.10%)
Unknown or missing	20,997 (40.43%)	24,862 (29.31%)
Patient gender
Female	31,619 (60.88%)	44,893 (52.93%)
Male	13,385 (25.77%)	27,590 (32.53%)
Unknown or missing	6,932 (13.35%)	12,327 (14.53%)
Administration route
Oral	51,168 (98.52%)	84,666 (99.83%)
Intravenous	578 (1.11%)	46 (0.05%)
Rectal	150 (0.29%)	0 (–)
Unknown or missing	40 (0.08%)	98 (0.12%)
Reporters
Consumer	30,408 (58.55%)	30,043 (35.42%)
Medical staff	15,252 (29.37%)	39,992 (47.15%)
Non-medical staff	5,946 (11.45%)	12,382 (14.60%)
Unknown or missing	330 (0.64%)	2,393 (2.82%)
Reporter country
Canada	6,347 (12.22%)	4,589 (5.41%)
China	335 (0.65%)	1,298 (1.53%)
France	667 (1.28%)	6,366 (7.51%)
Germany	249 (0.48%)	12,015 (14.17%)
Netherlands	497 (0.96%)	2,327 (2.74%)
United States	40,758 (78.48%)	33,002 (38.91%)
United Kingdom	595 (1.15%)	9,532 (11.24%)
Other Countries	2,488 (4.79%)	15,681 (18.49%)
Total number	51,936	84,810

A is the AE reports of acetaminophen; B is the AE reports of ibuprofen.

A is the SOCs of the ADE reports for acetaminophen; B is the SOCs of the ADE reports for ibuprofen.

Table 2

The signal strength of acetaminophen uses during pregnancy at the PTs level
SOCs	Preferred Terms	Acetaminophen
SOCs	Preferred Terms	Number	ROR (95%CI)	PRR (χ²)
Cardiac disorders	Baseline fetal heart rate variability disorder	3	38.78 (11.64, 129.18)	38.78 (97.67)
	Bradycardia fetal	3	3.26 (1.04, 10.16)	3.26 (4.64)
	Fetal heart rate deceleration abnormality	12	11.90 (6.68, 21.19)	11.89 (115.11)
	Tachycardia fetal	6	10.31 (4.57, 23.28)	10.31 (48.76)
Congenital, familial and genetic disorders	Ductus arteriosus premature closure	21	36.54 (23.22, 57.50)	36.51 (645.98)
	Patent ductus arteriosus	15	4.00 (2.41, 6.67)	4.00 (33.35)
Hepatobiliary disorders	Acute fatty liver of pregnancy	3	59.47 (17.21, 205.43)	59.46 (143.69)
Injury, poisoning and procedural complications	Exposure during pregnancy	197	2.41 (2.09, 2.77)	2.39 (159.32)
Pregnancy, puerperium and perinatal conditions	Eclampsia	5	12.93 (5.28, 31.66)	12.93 (52.72)
	Fetal distress syndrome	7	3.44 (1.63, 7.25)	3.44 (11.98)
	Hydrops fetalis	3	3.91 (1.25, 12.22)	3.91 (6.42)
	Low birth weight baby	23	2.03 (1.35, 3.06)	2.03 (11.90)
	Oligohydramnios	10	2.62 (1.41, 4.89)	2.62 (9.96)
	Placental insufficiency	3	4.98 (1.59, 15.60)	4.98 (9.39)
	Premature labor	12	2.33 (1.32, 4.11)	2.33 (9.03)
	Premature separation of placenta	5	3.18 (1.32, 7.67)	3.18 (7.38)
	Uterine hypertonus	3	13.12 (4.13, 41.69)	13.12 (32.16)
Notes: ^*: The adverse events are mentioned in the acetaminophen label.

Table 3

The signal strength of ibuprofen uses during pregnancy at the PTs level
SOCs	Preferred Terms	Ibuprofen
SOCs	Preferred Terms	Number	ROR (95%CI)	PRR (χ²)
Cardiac disorders	Fetal heart rate deceleration abnormality	7	33.44 (15.14, 73.82)	33.43 (192.69)
	Tachycardia fetal	11	15.33 (8.33, 28.21)	15.32 (138.21)
Congenital, familial and genetic disorders	Anencephaly	7	10.18 (4.77, 21.69)	10.17 (55.50)
	Atrioventricular septal defect	3	4.98 (1.59, 15.63)	4.98 (9.34)
	Cerebral atrophy congenital	4	78.01 (25.16, 241.90)	78.00 (228.04)
	Congenital genital malformation female	3	87.76 (23.28, 330.82)	87.75 (187.12)
	Congenital knee dislocation	3	46.81 (13.55, 161.69)	46.80 (112.06)
	Congenital musculoskeletal anomaly	3	4.68 (1.49, 14.68)	4.68 (8.51)
	Congenital umbilical hernia	4	3.56 (1.33, 9.552)	3.56 (7.25)
	Congenital uterine anomaly	3	24.21 (7.37, 79.48)	24.21 (60.49)
	Distichiasis	3	100.30 (25.93, 387.89)	100.29 (206.43)
	Ductus arteriosus premature closure^#	38	57.81 (40.53, 82.47)	57.74 (1699.53)
	Ductus arteriosus stenosis Fetal	12	35.56 (19.37, 65.27)	35.55 (349.76)
	Haemangioma congenital	3	5.44 (1.73, 17.10)	5.44 (10.63)
	Limb malformation	11	10.26 (5.61, 18.76)	10.26(88.03)
	Macrocephaly	6	10.97 (4.84, 24.88)	10.97 (51.93)
	Oculoauriculovertebral dysplasia	3	41.30 (12.10, 140.93)	41.30 (100.26)
	Persistent fetal circulation	9	27.36 (13.72, 54.58)	27.35 (204.58)
	Pyloric stenosis	12	13.19 (7.37, 23.59)	13.18 (127.91)
	Renal aplasia	4	4.52 (1.68, 12.16)	4.52 (10.76)
	Renal fusion anomaly	6	31.92 (13.60, 74.90)	31.91 (158.09)
	Tracheo-oesophageal fistula	9	9.08 (4.67, 17.67)	9.08 (62.28)
	Transposition of the great vessels	3	3.27 (1.04, 10.21)	3.27 (4.65)
	Urinary tract malformation	5	36.57 (14.25, 93.86)	36.56 (149.58)
	Vaginal atresia	3	702.08 (73.03, 6749.97)	702.02 (525.01)
	Ventricular septal defect	17	2.32 (1.44, 3.74)	2.32 (12.64)
	Vertebral artery hypoplasia	6	87.77 (34.34, 224.32)	87.75 (374.24)
Pregnancy, puerperium and perinatal conditions	Abortion spontaneous	142	2.52 (2.14, 2.97)	2.51 (128.28)
	Fetal death	27	2.99 (2.04, 4.37)	2.99 (35.22)
	Fetal hypokinesia	7	5.83 (2.75, 12.34)	5.83 (27.33)
	Fetal placental thrombosis	4	39.01 (13.53, 112.43)	39.00 (126.95)
	Oligohydramnios^#	94	21.03 (17.02, 25.98)	20.97 (1640.82)
	Placental cyst	5	1170.22 (136.71, 10017.06)	1170.03 (973.36)
	Placental insufficiency	5	18.57 (7.47, 46.18)	18.57 (77.02)
	Premature labor	34	5.27 (3.75, 7.41)	5.27 (115.03)
Renal and urinary disorders	Fetal renal impairment^#	14	63.03 (34.93, 113.73)	63.00 (673.04)
Notes: ^#: The adverse events are mentioned in the ibuprofen label.

3.3 The difference of SOCs of the ADE reports between acetaminophen and ibuprofen during pregnancy

According to MedDRA, the total of 861 related ADE reports were belonged to 6 SOCs (Fig. 2). The major SOCs of the ADE related to acetaminophen were injury, poisoning and procedural complications (59.52%), pregnancy, puerperium and perinatal conditions (21.45%), and congenital, familial and genetic disorders (10.88%). The major SOC of the ibuprofen were pregnancy, puerperium and perinatal conditions (60.00%), and congenital, familial and genetic disorders (33.96%). Because the High-level Term of injury, poisoning and procedural complications is exposure associated with pregnancy, childbirth, and lactation. For pregnant women, acetaminophen was believed to have the lowest risk and greatest benefit. ⁵ We thought that there indeed had some ADRs for acetaminophen use during pregnancy but didn’t result in the unbeneficial gestational outcome for the mother and the fetus. Therefore, the above results indicated the mainly potential risks of acetaminophen and ibuprofen were the same, which were congenital disorders, and pregnancy and perinatal conditions.

3.4 The difference of signal strength of between acetaminophen and ibuprofen use during pregnancy at the PTs level

In this study, 861 reports involved 47 PTs were belonged to 6 SOCs, but only 6 PTs were the same. On the basis of Figs. 1 and 2, we further comprehensively analyzed the differences of potential risks between acetaminophen and ibuprofen on SOC sand PTs (Table 2 and Table 3). We compared the potential risks between acetaminophen and ibuprofen use during pregnancy at the same PTs level on the same SOCs. 1) The potential risks for cardiac disorders of ibuprofen were more significant than acetaminophen: Fetal heart rate deceleration abnormality [acetaminophen: ROR 11.90; ibuprofen: ROR 33.44]. Tachycardia fetal [acetaminophen: ROR 10.31; ibuprofen: ROR 15.33]. 2) The potential risk for congenital disorders of ibuprofen was more significant than acetaminophen: Ductus arteriosus premature closure [acetaminophen: ROR 36.54; ibuprofen: ROR 57.81]. 3) The potential risks for pregnancy and perinatal conditions of ibuprofen were more significant than acetaminophen: Oligohydramnios [acetaminophen: ROR 2.62; ibuprofen: ROR 21.03]. Placental insufficiency [acetaminophen: ROR 4.98; ibuprofen: ROR 18.57]. The above results suggested the potential risks of ibuprofen were more statistically significant than acetaminophen at the same PTs level on the same SOCs.

To the best of our knowledge, this is the first pharmacovigilance study of comprehensively compare and analyze the potential risks between acetaminophen and ibuprofen for drug-associated adverse fetal and pregnancy outcomes by assessing the reported AEs from a real-world database.

The association between acetaminophen and ibuprofen use during pregnancy and potential risks was investigated by performing a disproportionality analysis (Fig. 1). More than half of the AEs which occurred with acetaminophen use occurred during pregnancy (59.52%). However, we believe that this maybe just one medical term for AE. This suggests that some ADRs were present during pregnancy but didn’t result in an unbeneficial gestational outcome. The seven main potential risks of acetaminophen usage during pregnancy are premature closure of the ductus arteriosus, fetal heart rate disorder, fetal tachycardia, eclampsia, acute fatty liver of pregnancy, baseline fetal heart rate variability disorder, and uterine hypertonus. A systematic review suggested that exposure to acetaminophen during pregnancy is associated with a significant reduction in the risk of low birth weight and small for gestational age, but not preterm labor. In particular, the third trimester of pregnancy was not significantly associated with preterm labor, low birth weight, and small for gestational age.¹⁹ The pharmacovigilance, clinical pharmacology of acetaminophen in pre-term and term neonates, and premature ductus arteriosus closure case-level clinical review with data mining analysis data concluded that it is reasonable that acetaminophen may be at least a contributory cause of premature ductus arteriosus closure.^{20, 21} Of the top 20 AEs associated with ibuprofen, spontaneous abortion (26.79%) and oligohydramnios (17.74%) were the most frequent. The nine main potential risks of ibuprofen during pregnancy use include oligohydramnios, premature ductus arteriosus closure, fetal renal impairment, fetal ductus arteriosus stenosis, persistent fetal circulation, fetal heart rate disorder, renal fusion anomaly, vertebral artery hypoplasia, and placental cyst. Our results indicated that the main potential effects of acetaminophen on the fetus were more significant than those on the mother, such as the incidence rate of premature ductus arteriosus closure and low birth weight. The main potential effects of ibuprofen on the mother were more significant than those on the fetus, such as the spontaneous abortion. Maternal use of mild analgesics (acetaminophen and ibuprofen) during pregnancy was associated with a shorter anogenital distance in boys whereas no effect was found in girls.²² The potential risks of acetaminophen and ibuprofen use during pregnancy were compared and analyzed; ibuprofen was found to exhibit more significant potential risk for pregnancy outcomes, especially with regards to congenital malformations and genetic disorders in the fetus and infant.

Epidemiological studies on acetaminophen use during pregnancy have not reported a clear association between this medication and birth defects, miscarriages, and adverse maternal or fetal outcomes. Exposure to acetaminophen and ibuprofen at therapeutically relevant levels in humans caused significant reductions in fetal germ cell numbers in both human fetal testes and ovaries.²³ Prenatal exposure to acetaminophen is associated with an increased risk of neurodevelopmental, preeclampsia, atopic, and reproductive adverse outcomes.^{24, 25} In addition to cryptorchidism, acetaminophen and ibuprofen use during pregnancy has also been associated with hypospadias and cerebral palsy in children.²⁶ A cohort study suggested that ibuprofen may consider an analgesic and antipyretic of choice in the first trimester.²⁷ It is difficult to conclude whether acetaminophen significantly increases the risk of congenital malformations.²⁸ On the contrary, ibuprofen maybe had much more potential risks of congenital malformations, which are consistent with the data shown in our study. The available literatures suggest that ibuprofen has greater potential risk for congenital malformations in fetuses and infants, which is consistent with the data shown in our study.

Pharmacovigilance is defined as the scientific activity of discovering, evaluating, understanding, and preventing adverse drug effects and drug-related problems.²⁹ Pharmacovigilance systems have been established in countries or organizations, such as the World Health Organization (WHO) and the FDA, for ADR monitoring.³⁰ Real-world FAERS data corroborate the usefulness of pharmacovigilance research.¹⁷ In the post-marketing surveillance phase, the challenge of pharmacovigilance is how to provide a more scientific and persuasive report by analyzing observational data. It was concluded that ADR signals were generated and tested. Therefore, choosing an effective signal detection method is crucial for providing valuable signals for drug applications and clinical evaluation. Analysis of FAERS ADR signal data mining could promote the rational use of drugs and avoid unnecessary adverse drug events (ADEs).

This study has several strengths. First, FAERS contains all AEs submitted to the FDA and the sample size is sufficient to identify rare ADRs that cannot be found in conventional studies. Second, signals for 47 PTs belonging to 6 SOCs were detected, which could reflect all AEs of acetaminophen and ibuprofen use during pregnancy. Third, as the potential risks of AEs related to pregnancy mainly reflect pregnancy, puerperium, and perinatal conditions, and congenital, familial, and genetic disorders, we further analyzed both SOCs and all related PTs in our study. Therefore, this study reflects the difference in potential risks between acetaminophen and ibuprofen for drug-associated adverse fetal and pregnancy outcomes.

This study has some inherent limitations. FAERS is a database of AEs that is based on a self-reporting system. The data lack a meaningful denominator and cannot exclude prevalent reports; therefore, it is difficult to estimate the true risk or assess the incidence rate of AEs.³¹ It is also difficult to investigate the underlying reason for use during pregnancy, pregnancy outcome for the mother, long-term effects on the fetus, and effects during early childhood using only the FAERS database. In this study, the United States had the highest number of reports for acetaminophen and ibuprofen use (78.48% and 38.91%, respectively). The cheapest and simplest method for detecting rare and serious ADRs is spontaneous ADEs reports. Mild adverse effects are occasionally reported, with severe cases reported more often in self-reported databases. The most common adverse effect of acetaminophen is liver injury for overdose.³² It is well known that the longer the duration of medication use, the higher is the risk of drug associated ADEs.³³ However, many of the retrieved reports lacked a detailed duration of medication use. Data mining using large-scale databases has attracted attention as an exploratory method for the prevention of ADRs. Monitoring ADEs could contribute to the discovery of rare but potentially serious ADRs and provide an important basis for their prevention. For ethical reasons, the relevance of the findings in this study could mainly be discovered after the administration of acetaminophen or ibuprofen for pharmacotherapy in pregnant women by retrospective observation. In particular, it is very difficult to achieve this purpose through animal research or other clinical studies with limited sample sizes.

In recent years, data mining using large-scale databases has been attracting attention as an exploratory study method for the prevention of ADRs.¹² Monitoring ADEs could contribute to discover rare but potentially serious ADRs, and then provide an important basis for prevention. Reliable monitoring results can be used to avoid the results of possible serious adverse reactions. The relevance may only be discovered after acetaminophen or ibuprofen is used in pregnancy via the retrospective observation. Especially, it is very difficult to achieve the purpose only through animal research or other clinical research with limited sample sizes. Therefore, our study provided a reference for confirming the occurrence associated with between acetaminophen and ibuprofen use in pregnancy via the FAERS database.

Overall, this study showed four main findings: 1) The characteristics of acetaminophen and ibuprofen reports were similar; however, ibuprofen exhibited more AEs than acetaminophen within the same duration of use. 2) The main potential risks of ibuprofen and acetaminophen are congenital disorders, and pregnancy and perinatal conditions. 3) The potential risks of ibuprofen were more significant than those of acetaminophen, especially the risks of oligohydramnios, premature ductus arteriosus closure, and premature labor. 4) Ibuprofen was more significant than acetaminophen for pharmacotherapy in pregnant women with the same potential risks.

Despite the limitations of this study, our findings firstly showed the real-world trends of reported acetaminophen and ibuprofen use during pregnancy signals and potential rank-order in terms of susceptibility. In summary, our findings showed the real-world trends of reported acetaminophen and ibuprofen use during pregnancy signals and potential rank-order in terms of susceptibility. It was suggested acetaminophen may be the better choice than ibuprofen for pharmacotherapy in pregnant women. Health professionals should pay more attention to the potential risks when acetaminophen or ibuprofen use during pregnancy only when needed, especially for considering the lowest therapeutic dose for the shortest possible duration.

Author contributions

XD: Conceptualization; Funding acquisition; Investigation; Methodology; Writing-original draft.

YW: Conceptualization; Investigation; Writing-original draft.

SL: Methodology; Resources; Writing-review & editing.

CH: Methodology; Investigation; Writing-review & editing.

QW: Conceptualization; Methodology; Resources; Writing-review & editing.

LC: Methodology; Investigation.

YR: Conceptualization; Investigation; Writing-review & editing.

Acknowledgements

We would like to thank the FAERS database for providing us with valuable data and acknowledge the support given by Christine Huand Shilei Yang in English proofreading.

Funding

This research was funded by the young pharmacist’s scientific research project of Sichuan Provincial Hospital Association (No. 22020) and the key project of Zigong Health Commission (No. 22zd014).

Ethics approval and consent to participate

Our study did not require an ethical board approval because the FAERS database is based on the self-reporting system and open to the public. In addition, this study does not involve personal privacy.

Consent for publication

All authors have consented to the publication of this article.

Competing interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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No competing interests reported.

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Analysis of potential risks between acetaminophen and ibuprofen use during pregnancy via the FAERS database

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1. Introduction

2. Materials and methods

2.1 Data source

2.2 Drug and adverse event identification

2.3 Data mining

2.4 Statistical analysis

3. Results

3.1 General characteristics of AE reports for acetaminophen and ibuprofen

3.3 The difference of SOCs of the ADE reports between acetaminophen and ibuprofen during pregnancy

4. Discussion

5. Conclusion

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