Abstract
This cohort study examines whether the risk of low birth weight is associated with prenatal exposure to proton pump inhibitors.
Introduction
Pregnant women are at increased risk of gastroesophageal reflux disease due to hormonal changes and elevated pressure on the stomach.1 Although lifestyle modifications are the recommended first-line therapy to treat gastroesophageal reflux disease, proton pump inhibitors (PPIs) are frequently used in unresolved symptoms.1 Evidence on the fetal safety of PPI use during pregnancy is limited, particularly for nonteratogenic outcomes, such as low birth weight, an important factor associated with neonatal mortality and morbidity. Preclinical studies have reported a dose-dependent risk of reduced fetal weight associated with PPI use and increased placental penetration of PPI with gestational age.2 However, most observational studies have focused on the teratogenic outcomes associated with PPI exposure in early pregnancy, and the association of PPI exposure during the entire pregnancy with fetal outcomes other than malformation has not been thoroughly demonstrated.3 To date, only 3 studies4,5,6 have investigated the risk of low birth weight associated with maternal PPI use, which found no association; however, with insufficient power and the sole evaluation on a specific period (eg, first trimester) and PPI (eg, omeprazole), these results are inadequate to guide clinicians and patients. We conducted a nationwide cohort study to examine the risk of low birth weight associated with prenatal PPI exposure.
Methods
We used Korea’s National Health Insurance Service database to identify all pregnancies resulting in live births between April 1, 2008, and December 31, 2019. Pregnancies in women older than 44 years at delivery and those with missing information on perinatal birth weight were excluded. Women were considered exposed if they filled a prescription for PPIs between the start of pregnancy and the 245th day of gestation. This period was set to avoid the differential opportunity of PPI exposure between preterm and term deliveries. The reference group consisted of women without exposure to PPIs from 90 days before pregnancy to the delivery date. The outcome was low birth weight (perinatal weight <2.5 kg). To control for confounders (Table 1), we used a propensity score fine stratification–based logistic regression model to estimate the odds ratios (95% CIs). Additional details on the methods, including secondary analyses and sensitivity analyses, are in the eMethods in Supplement 1. Data were analyzed from September 1, 2022, to February 17, 2023. The study was approved by the institutional review board of Sungkyunkwan University. The requirement for obtaining informed consent was waived because this study used deidentified administrative data. This study followed the STROBE reporting guideline reporting guideline.
Table 1. Baseline Characteristics of the Study Cohort.
| Characteristica | Unadjusted | Adjusted | ||||
|---|---|---|---|---|---|---|
| Pregnancies, No. (%) | Standardized difference | Pregnancies, No. (%) | Standardized difference | |||
| PPI exposed (n = 41 664) | Unexposed (n = 2 121 323) | PPI exposed (n = 41 649) | Unexposed (n = 2 118 941) | |||
| Age at delivery, mean (SD), y | 32.0 (4.5) | 31.7 (4.1) | 0.09 | 32.0 (4.5) | 32.1 (4.4) | 0.00 |
| Age group, y | ||||||
| ≤20 | 134 (0.3) | 4284 (0.2) | 0.02 | 134 (0.3) | 6457 (0.3) | 0.00 |
| 21-25 | 2023 (4.9) | 87 978 (4.1) | 0.03 | 2021 (4.9) | 100 980 (4.8) | 0.00 |
| 26-30 | 9330 (22.4) | 516 994 (24.4) | −0.05 | 9328 (22.4) | 472 718 (22.3) | 0.00 |
| 31-35 | 17 963 (43.1) | 1 013 590 (47.8) | −0.05 | 17 960 (43.1) | 918 975 (43.4) | −0.01 |
| 36-40 | 10 254 (24.6) | 437 651 (20.6) | 0.10 | 10 249 (24.6) | 521 844 (24.6) | 0.00 |
| 41-44 | 1960 (4.7) | 60 826 (2.9) | 0.10 | 1957 (4.7) | 97 967 (4.6) | 0.00 |
| Medical aid recipients | 444 (1.1) | 9810 (0.5) | 0.07 | 440 (1.1) | 21 060 (1.0) | 0.01 |
| Income level, quartile | ||||||
| First | 8762 (21.0) | 413 335 (19.5) | 0.04 | 8755 (21.0) | 443 343 (20.9) | 0.00 |
| Second | 10 266 (24.6) | 524 985 (24.7) | 0.00 | 10 264 (24.6) | 519 891 (24.5) | 0.00 |
| Third | 14 084 (33.8) | 747 763 (35.2) | −0.03 | 14 080 (33.8) | 717 750 (33.9) | 0.00 |
| Fourth | 8552 (20.5) | 435 240 (20.5) | 0.00 | 8550 (20.5) | 437 958 (20.7) | 0.00 |
| Nulliparity | 22 881 (54.9) | 1 203 572 (56.7) | −0.04 | 22 874 (54.9) | 1 167 333 (55.1) | 0.00 |
| Multiple gestation | 1168 (2.8) | 46 733 (2.2) | 0.04 | 1166 (2.8) | 60 473 (2.9) | 0.00 |
| Year of delivery | ||||||
| 2008-2011 | 6234 (15.0) | 723 334 (34.1) | −0.46 | 6233 (15.0) | 295 411 (13.9) | 0.03 |
| 2012-2015 | 13 381 (32.1) | 745 470 (35.1) | −0.06 | 13 380 (32.1) | 684 813 (32.3) | 0.00 |
| 2016-2019 | 22 049 (52.9) | 652 519 (30.8) | 0.46 | 22 036 (52.9) | 1 138 717 (53.7) | −0.02 |
| Indications | ||||||
| GERD | 21 326 (51.2) | 107 056 (5.0) | 1.20 | 21 312 (51.2) | 1 075 514 (50.8) | 0.01 |
| Barrett esophagus | 12 (0.0) | 23 (0.0) | 0.02 | 12 (0.0) | 329 (0.0) | 0.01 |
| Ulcer | 6342 (15.2) | 73 228 (3.5) | 0.41 | 6329 (15.2) | 310 248 (14.6) | 0.02 |
| Gastritis and duodenitis | 25 044 (60.1) | 596 480 (28.1) | 0.68 | 25 030 (60.1) | 1 288 219 (60.8) | −0.01 |
| Dyspepsia | 6169 (14.8) | 159 738 (7.5) | 0.23 | 6159 (14.8) | 308 285 (14.5) | 0.01 |
| Heartburn | 1624 (3.9) | 44 579 (2.1) | 0.11 | 1621 (3.9) | 81 977 (3.9) | 0.00 |
| Zollinger-Ellison syndrome | 3 (0.0) | 13 (0.0) | 0.01 | 3 (0.0) | 155 (0.0) | 0.00 |
| Helicobacter pylori infection | 80 (0.2) | 223 (0.0) | 0.06 | 74 (0.2) | 2816 (0.1) | 0.01 |
| Medical conditions | ||||||
| Anxiety | 1235 (3.0) | 18 089 (0.9) | 0.16 | 1229 (3.0) | 59 220 (2.8) | 0.01 |
| Diabetes | 562 (1.3) | 13 377 (0.6) | 0.07 | 561 (1.3) | 28 271 (1.3) | 0.00 |
| Epilepsy | 123 (0.3) | 3484 (0.2) | 0.03 | 123 (0.3) | 5947 (0.3) | 0.00 |
| Headache or migraine | 3900 (9.4) | 101 285 (4.8) | 0.18 | 3896 (9.4) | 196 793 (9.3) | 0.00 |
| Hypertension | 532 (1.3) | 11 575 (0.5) | 0.08 | 529 (1.3) | 26 049 (1.2) | 0.00 |
| Renal disease | 231 (0.6) | 6341 (0.3) | 0.04 | 230 (0.6) | 11 679 (0.6) | 0.00 |
| Alcohol or drug dependence | 66 (0.2) | 1278 (0.1) | 0.03 | 66 (0.2) | 3340 (0.2) | 0.00 |
| Prescription drug use | ||||||
| Antiepileptic agents | 712 (1.7) | 13 163 (0.6) | 0.10 | 708 (1.7) | 34 706 (1.6) | 0.01 |
| Antidepressants | 2232 (5.4) | 29 312 (1.4) | 0.22 | 2225 (5.3) | 105 283 (5.0) | 0.02 |
| Antidiabetic drugs | 440 (1.1) | 11 140 (0.5) | 0.06 | 439 (1.1) | 22 600 (1.1) | 0.00 |
| Antihypertensives | 1733 (4.2) | 32 869 (1.5) | 0.16 | 1727 (4.1) | 84 730 (4.0) | 0.01 |
| Benzodiazepines | 10 609 (25.5) | 182 629 (8.6) | 0.46 | 10 597 (25.4) | 525 564 (24.9) | 0.01 |
| Corticosteroids | 20 294 (48.7) | 674 244 (31.8) | 0.35 | 20 282 (48.7) | 1 042 858 (49.2) | −0.01 |
| Fertility drugs | 3143 (7.5) | 162 947 (7.7) | −0.01 | 3142 (7.5) | 162 126 (7.7) | 0.00 |
| Opioid analgesics | 23 567 (56.6) | 809 917 (38.2) | 0.38 | 23 554 (56.6) | 1 210 878 (57.1) | −0.01 |
| Nonsteroidal anti-inflammatory drugs | 31 048 (74.5) | 1 224 058 (57.7) | 0.36 | 31 034 (74.5) | 1 598 186 (75.4) | −0.02 |
| Thyroid hormones | 2621 (6.3) | 81 731 (3.9) | 0.11 | 2620 (6.3) | 135 691 (6.4) | −0.01 |
| Obstetric comorbidity index score, mean (SD) | 0.7 (1.0) | 0.5 (0.8) | 0.23 | 0.7 (1.0) | 0.7 (1.0) | 0.00 |
| No. of outpatient visits, mean (SD) | 8.3 (7.9) | 5.3 (5.5) | 0.45 | 8.3 (7.9) | 8.3 (7.2) | 0.00 |
| No. of emergency department visits, mean (SD) | 0.1 (0.5) | 0.1 (0.3) | 0.17 | 0.1 (0.5) | 0.1 (0.5) | 0.00 |
| No. of hospitalizations, mean (SD) | 0.1 (0.4) | 0.1 (0.3) | 0.12 | 0.1 (0.4) | 0.1 (0.4) | 0.00 |
Abbreviations: GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.
Demographic and socioeconomic characteristics, such as age, health insurance type, and income level, were assessed at delivery. Maternal medical conditions and medications used were assessed between the 6 months before pregnancy and the first trimester, and the measures of health care use were assessed during the period 6 months before pregnancy.
Results
In the cohort of 2 162 987 pregnancies (mean [SD] maternal age, 31.7 [4.1] years), 41 664 were exposed to PPIs. After propensity score fine stratification, all baseline characteristics were well-balanced between the 2 groups (Table 1). The mean (SD) birth weights were 3.12 (0.49) kg in PPI-exposed pregnancies and 3.18 (0.46) kg in PPI-unexposed pregnancies. Compared with PPI-unexposed pregnancies, there was no increased risk of low birth weight (adjusted odds ratio, 0.95; 95% CI, 0.91-1.00) associated with PPI use during pregnancy (Table 2). The secondary analyses also revealed no increased risk of low birth weight associated with prenatal PPI use. Findings from the various sensitivity analyses remained consistent (Table 2).
Table 2. Association Between the Use of PPIs During Pregnancy and the Risk of Low Birth Weight.
| Variable | PPI-exposed group | Reference group | Odds ratio (95% CI)a | ||
|---|---|---|---|---|---|
| No. of pregnancies | Low birth weight, No. (%) | No. of pregnancies | Low birth weight, No. (%) | ||
| Main analysis (vs unexposed) | 41 664 | 2357 (5.7) | 2 121 323 | 104 056 (4.9) | 0.95 (0.91-1.00) |
| Subgroups according to individual PPIs | |||||
| Rabeprazole | 11 934 | 676 (5.7) | 2 121 323 | 104 056 (4.9) | 1.00 (0.92-1.08) |
| Esomeprazole | 12 868 | 726 (5.6) | 2 121 323 | 104 056 (4.9) | 0.93 (0.86-1.01) |
| Lansoprazole | 8678 | 482 (5.6) | 2 121 323 | 104 056 (4.9) | 0.91 (0.83-1.00) |
| Pantoprazole | 6180 | 398 (6.4) | 2 121 323 | 104 056 (4.9) | 1.05 (0.95-1.16) |
| Omeprazole | 3372 | 204 (6.0) | 2 121 323 | 104 056 (4.9) | 1.02 (0.88-1.17) |
| Subgroups according to exposure window, trimester | |||||
| First | 27 575 | 1504 (5.5) | 2 121 323 | 104 056 (4.9) | 0.97 (0.91-1.02) |
| Second | 8034 | 486 (6.0) | 2 121 323 | 104 056 (4.9) | 0.97 (0.88-1.06) |
| Third | 8702 | 529 (6.1) | 2 121 323 | 104 056 (4.9) | 0.94 (0.86-1.02) |
| Subgroups according to cumulative dose, DDD | |||||
| <7 | 21 676 | 1180 (5.4) | 2 121 323 | 104 056 (4.9) | 0.95 (0.90-1.01) |
| 7 to <14 | 9771 | 526 (5.4) | 2 121 323 | 104 056 (4.9) | 0.92 (0.85-1.01) |
| ≥14 | 10 217 | 651 (6.4) | 2 121 323 | 104 056 (4.9) | 1.02 (0.94-1.11) |
| Sensitivity analysis | |||||
| ≥2 PPI prescriptions | 9446 | 591 (6.3) | 2 121 323 | 104 056 (4.9) | 1.01 (0.93-1.10) |
| Compared with H2RA | 35 418 | 1823 (5.1) | 94 578 | 5023 (5.3) | 0.99 (0.94-1.05) |
| Restrict to first-time pregnancy | 22 881 | 1448 (6.3) | 1203 572 | 67 629 (5.6) | 0.95 (0.90-1.01) |
| Restrict to singleton pregnancy | 40 496 | 1722 (4.3) | 2074 590 | 74 982 (3.6) | 1.03 (0.98-1.08) |
| Adjust for BMI and smoking status | 23 827 | 1324 (5.6) | 1085 333 | 54 142 (5.0) | 0.95 (0.88-1.01) |
| Restrict to maternal age <35 y | 29 450 | 1495 (5.1) | 1622 846 | 72 513 (4.5) | 0.97 (0.92-1.03) |
| Sibling design | 13 678 | 522 (3.8) | 754 382 | 27 854 (3.7) | 0.87 (0.76-1.00) |
Abbreviations: BMI, body mass index; DDD, defined daily dose; H2RA, histamine2 receptor antagonists; PPI, proton pump inhibitor.
Propensity score–weighted odds ratio.
Discussion
This cohort study indicated that the use of PPIs any time during pregnancy was not associated with an increased risk of low birth weight. These results are in line with previous studies4,5,6 that found no associations between prenatal PPI exposure and low birth weight. The large cohort in this study allowed us to evaluate risk by individual PPIs, trimester, and cumulative dose, which all showed no associations.
Study limitations include residual confounding and the possibility of misclassification of the pregnancy period. In addition, ascertainment of PPI exposure was based on prescription data, which may have led to misclassification. However, redefining the exposure as 2 or more prescriptions in sensitivity analyses did not change our results. Overall, our findings provide reassurance on the fetal safety of PPI use while enlarging the available epidemiological body of evidence.
eMethods. Supplemental Methods
Data Sharing Statement
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Associated Data
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Supplementary Materials
eMethods. Supplemental Methods
Data Sharing Statement
