The use of H2Ras during pregnancy has been extensively documented [7,8,9,10,11,12]. In a 2009 meta-analysis, data from 2,398 H2Ras-exposed and 119,892 non-exposed subjects found no increase in the risk of teratogenicity (OR: 1.14 [95%CI: 0.45–1.45]) [9]. Based on these data, H2Ras could be used to treat heartburn and gastric acid reflux in pregnant women. However, previous reports provide limited information on H2Ras use, particularly individual agents. In animals, no teratogenic or reproductive changes have been observed at famotidine doses significantly higher than clinical doses, and no contraindications to human administration have been documented [21]. A 1996 prospective cohort study conducted by the Motherisk Program, a teratology information service in Toronto, Canada, compared 178 H2Ras-exposed pregnancies (8% of whom were exposed to famotidine) with 178 unexposed patients and detected major malformation rates of 2.1% and 3.5%, respectively [10]. In 2005, a report by the European Network of Teratology Information Services (ENTIS) examined 553 H2Ras-exposed pregnancies (75 of whom were exposed to famotidine) with controls. The incidence of major malformations was 2.7% in the H2Ras group and 3.5% in the control group (risk ratio [RR], 0.78 [95%CI: 0.42–1.44]) [11]. In 2010, an analysis of babies born to women with early pregnancy exposure to H2Ras was conducted using the database of Israel health maintenance organization registry. The authors identified 878 cases of famotidine exposure, and the incidence of major congenital malformations was 6.6% in the famotidine group and 5.2% in the non-exposed group (aOR: 1.21[95%CI: 0.92–1.58]), which was not significantly increased when compared with that in the non-exposed group [12]. Although this study included a large number of subjects, it involved the analysis of a prescription data and did not confirm its actual use. To the best of our knowledge, our study is the largest prospective study on the safety of famotidine use during pregnancy. Herein, we found that the overall incidence of congenital malformations in the famotidine group was 3.9%, and the incidence of major malformations was 3.3%, which did not exceed the baseline risk (3–5%). Our findings are consistent with the frequency of congenital malformations reported in the latest Japanese branch of the International Clearinghouse for Birth Defects Surveillance and Research [22]. The aORs of the control group were similar to those reported previously for overall congenital malformations (aOR: 1.06 [95%CI: 0.51–2.16]) and major malformations (aOR: 1.26 [95%CI: 0.56–2.86]). No specific trend was observed in the occurrence of malformations in the famotidine group. Although it is impossible to establish a precise conclusion based on the insufficient number of subjects included in the current study, the 1.5% incidence of cardiac malformations is consistent with that reported by the Neonatal Congenital Heart Disease Surveillance Report [23] and the Pediatric Heart Disease Study [24]. Importantly, exposure to famotidine during early pregnancy did not result in an increase in the incidence of specific malformations. To date, there have been no reports of H2Ras exposure during pregnancy indicating an increase in certain malformations such as cardiac malformations, and the results of this study are consistent with these reports [11, 12]. These findings suggest that exposure to famotidine during the first trimester of pregnancy does not increase the risk of developing congenital malformations.
Neonatal data revealed higher rates of preterm delivery and low birth weight in the famotidine group than in the control group. Although these rates are high when compared with the global average [25, 26], they are higher than those reported in recent Japanese studies [27, 28], which reported preterm birth rates of 4.6%, low birth weight rate of 9.4%, and very low birth weight rate of 0.7%. Although ENTIS has reported a higher preterm birth rate (RR: 1.67 [95%CI: 1.18–2.35]) in the H2Ras group, the reason for this remains unclear [11]. Conversely, Ilan et al. in 2010 reported no significant differences in the preterm birth rate or percentage of low and very low birth weight infants between the H2Ras and control groups [12].
Therefore, we focused on the maternal complications of preterm delivery and found that the famotidine group included pregnant women with autoimmune inflammatory disease complications. Autoimmune inflammatory diseases have been associated with preterm delivery [29,30,31,32,33]. The results of the multivariate analysis suggest that the effect of famotidine use during pregnancy may be minimal, and that the presence of an autoimmune inflammatory disease could be an influencing factors. However, no definitive conclusions can be drawn from this analysis alone. The use of steroids to treat autoimmune inflammatory diseases may be a risk factor for preterm delivery [29, 31]. In the famotidine group in the current study, concomitant steroid use during pregnancy was detected in 17% of patients, and the rate of use in the preterm group (47%) was higher than that in the full-term delivery group (16%). This may be partly due to the oral use of famotidine as a prophylactic agent to address steroid-related side effects, which may have impacted our findings.
Given that the current study is based on the clinical databases of two Japanese institutions providing counseling on drug use during pregnancy, the information was obtained during interviews conducted at a single time point by the counselors themselves and not from direct observation throughout the pregnancy period. Therefore, there is a lack of detailed information on patient backgrounds, presence or absence of obstetric complications after consultation, and status of medications taken. Recently, an association between the use of antacids, such as H2Ras, during pregnancy and asthma and allergic symptoms in children was reported [34, 35]. However, after examining confounding factors by indication and familial factors, some reports showed a negative association with the use during pregnancy [36]. The limitations of our analysis of the association between famotidine and preterm delivery include the lack of accounting for confounding factors such as concomitant medications and family factors. We considered the presence of an autoimmune inflammatory disease in the mother as one of the factors, but the presence of this complication may have influenced the presence of steroids and non-steroidal concomitant medications, and the presence of these concomitant medications may have resulted in an interaction with the use of famotidine. Therefore, we believe that further analysis, including stratified analysis in the presence or absence of autoimmune disease, is needed to clarify whether famotidine is involved, and this is a topic for future studies. Furthermore, pregnancy outcomes were determined via interview approximately one month postpartum; hence, the long-term effects of famotidine on the growth and development of children, including its association with asthma and allergic symptoms in children, warrant further investigation in future research.
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