ABSTRACT
Janus kinase inhibitors (JAKIs) are immunomodulatory drugs used for autoimmune and inflammatory conditions. Their potential impact on pregnancy and fetal development remains a concern due to placental transfer and potential disruption of cytokine and growth factor signaling, with limited human data. This study analyzed VigiBase, the World Health Organization global pharmacovigilance database of individual case safety reports (ICSRs), to assess signals of disproportionate reporting (SDRs) for pregnancy‐related adverse drug reactions (ADRs) reported with systemic JAKIs, including abrocitinib, baricitinib, deucravacitinib, fedratinib, filgotinib, itacitinib, momelotinib, pacritinib, peficitinib, ritlecitinib, ruxolitinib, tofacitinib, and upadacitinib. As of May 26, 2024, 163 ICSRs met inclusion criteria, mainly from North America (41.7%) and Europe (39.3%). The most frequently reported JAKIs were tofacitinib (44.8%) and upadacitinib (34.4%), primarily indicated for rheumatoid arthritis (29.4%). Among 213 pregnancy‐related ADRs, spontaneous abortion was the most frequently reported event (47.9%) without representing an SDR compared with other drugs in the database (reporting odds ratio [ROR] 0.37, 95% confidence interval [CI] 0.30–0.46). Congenital anomalies were reported in 16.0% of ICSRs (43 events), but no specific organ‐related patterns were identified. Prematurity occurred in 9.2% of ICSRs, without SDR compared to the full database (ROR 0.07, 95% CI 0.04–0.11). Current pharmacovigilance data from VigiBase do not indicate SDRs for spontaneous abortion or prematurity following JAKI exposure during pregnancy. Findings should be interpreted cautiously given the limitations of spontaneous reporting systems and the exploratory nature of the analysis. Further studies are needed to better characterize the JAKI safety in pregnancy.
Keywords: disproportionality, JAK inhibitors, pharmacovigilance, pregnancy, VigiBase
Study Highlights
What is the current knowledge on the topic?
JAK inhibitors are used to treat various immune‐mediated diseases but their safety profile during pregnancy is not established due to limited clinical data.
What question did this study address?
The study explored whether the use of systemic JAK inhibitors was associated with disproportionate reporting of pregnancy‐related adverse reactions in VigiBase, a global pharmacovigilance database.
What does this study add to our knowledge?
No signals of disproportionate reporting were found for spontaneous abortion or prematurity among cases reported with JAK inhibitors. Cases of congenital anomalies were observed; however without consistent patterns associated with specific malformations.
How might this change clinical pharmacology or translational science?
Whilst no clear safety signal emerged from this analysis, the findings highlight the need for further research to better understand the safety profile of JAK inhibitors during pregnancy and support informed clinical decisions.
1. Introduction
Janus kinases (JAKs) are protein tyrosine kinases that associate with type I and type II cytokine receptors, mediating cellular responses to a wide range of growth factors and inflammatory reactions, via the JAK signal transducer and activator of transcription (intracellular JAK–STAT signaling pathway) [1]. These processes constitute a central mechanism underlying vital functions, such as immune defense, cellular growth, organogenesis, and contribute to the pathogenesis of immune‐mediated inflammatory diseases [2]. In recent years, JAK inhibitors (JAKIs), a class of immunosuppressive drugs, have emerged as important treatments for a wide range of inflammatory and oncological conditions—particularly autoimmune diseases, such as rheumatoid arthritis, giant cell arteritis, lupus, atopic dermatitis, and inflammatory bowel disease—that often manifest in women of childbearing age [3].
Managing immune‐mediated diseases during pregnancy presents unique challenges [4], as it necessitates a careful risk–benefit assessment, balancing the maternal need for effective disease control with the potential fetal exposure to pharmacological agents, which may pose adverse effects. As small molecules, JAKIs passively cross the placental barrier [5] and most reported adverse effects appeared dependent on JAKIs' exposure and dosage [6]. Still, current evidence on JAKIs' safety profile in human pregnancy is limited, with clinical trial data remaining scarce and real‐world findings primarily derived from isolated case reports and small case series [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20]. Given this assumption, post‐marketing reports of adverse drug reactions (ADRs) collected in pharmacovigilance databases constitute a valuable source of real‐world evidence that can aid in the further characterization of the safety profile of medications in pregnancy [21, 22, 23].
This study aims to use VigiBase, the World Health Organization (WHO) global pharmacovigilance database, to describe individual case safety reports (ICSRs) related to systemic JAKI exposure during pregnancy. It also seeks to assess the presence of signals of disproportionate reporting (SDRs) for specific pregnancy‐related ADRs associated with this drug class, compared to the other drugs recorded in the database.
2. Methods
2.1. Study Design and Data Source
We conducted a pharmacovigilance study with disproportionality analysis of de‐duplicated ICSRs collected in VigiBase between January 01, 2012 (when the first ICSR with JAKIs was recorded in VigiBase) and May 26, 2024.
VigiBase is the global pharmacovigilance database created and maintained by the WHO‐Uppsala Monitoring Centre (WHO‐UMC). It collects ICSRs of ADRs and vaccine‐related adverse events from member countries of the WHO International Drug Monitoring Programme (currently over 180 countries). In VigiBase, drugs are coded based on the “WHO Drug Global” drug reference dictionary, while ADRs are coded using the MedDRA dictionary (Medical Dictionary for Regulatory Events). The latter has a hierarchical organization, with the terms “System Organ Classes” (SOCs) identifying groups of ICSRs related to specific organ toxicities.
2.2. Study Population
The study population included ICSRs reporting pregnancy‐related ADRs with systemically administered JAKIs as suspected drugs during pregnancy. The drugs of interest included the following active ingredients: abrocitinib, baricitinib, deucravacitinib, fedratinib, filgotinib, itacitinib, momelotinib, pacritinib, peficitinib, ritlecitinib, ruxolitinib, tofacitinib, upadacitinib. Events of interest were identified using the standardized MedDRA query (SMQ) “pregnancy and neonatal topics—broad” (MedDRA version 27.0). The extracted dataset was refined using the algorithm developed and validated by Zaccaria et al. [24] to identify pregnancy‐related ICSRs in the European pharmacovigilance database, EudraVigilance. In VigiBase, the algorithm was adapted and simplified to align with the available information (which, for example, excludes narrative text sections), and the intrinsic characteristics of VigiBase (e.g., substantial proportions of missing data for the variable “route of administration”). First, ICSRs concerning patients aged 50 years or older were excluded. Subsequently, the reported events were assessed by comparison with the MedDRA term lists described by Zaccaria et al., classified as “is equal to” or “is not equal to” and detailed in Table S1. This automated selection process was complemented by a case‐by‐case assessment considering the sex and age of the patients involved (carried out independently by two persons, NA and RN, with the intervention of a third person to discuss and resolve any disagreements, UW). ICSRs describing drug exposure in relation to pregnancy without any maternal or infant/neonatal ADRs or referring solely to paternal drug exposure were excluded. For disproportionality analyses, the comparator group consisted of ICSRs associated with all other drugs recorded in VigiBase, excluding JAKIs.
2.3. Covariates
For the ICSRs included in the study population, the following variables were analyzed: the country of origin and year of reporting; the reporter's qualification; the patient's sex and age; the suspected JAKIs and their indications. The timing of drug exposure in relation to pregnancy was also defined based on the presence among the reported reactions of the following terms: “maternal exposure before pregnancy,” “maternal exposure during pregnancy,” “foetal exposure during pregnancy,” “exposure during pregnancy,” “maternal exposure timing unspecified.” For each ICSR, the seriousness was described whereby serious ICSRs caused or prolonged hospitalization, were life threatening, led to death, caused congenital anomalies or birth defects, were disabling/incapacitating, or determined other medically important conditions (not further specified). Congenital anomalies were further classified into organ‐specific subcategories according to the classification system used by EUROCAT (European Surveillance of Congenital Anomalies) [25]. In VigiBase, reporters assign a causal role to each drug in relation to ADR onset, categorized as suspected, interacting, or concomitant. ICSRs included in the study population reported ≥ 1 JAKI as suspected drug(s), independent of any additional drugs (designated as suspected, interacting or concomitant, and collectively referred to as co‐reported drugs).
2.4. Statistical Methods
Categorical variables were summarized as absolute frequencies and percentages. For continuous quantitative variables (identified as normally distributed), the mean and standard deviation were calculated. Disproportionality analysis compares the reporting frequency of a specific drug‐ADR combination to that of all other drugs and ADRs in the reference database [26]. Using a 2 × 2 contingency table, the reporting odds ratio (ROR) and its 95% confidence interval (CI) were calculated to identify signals of disproportionate reporting (SDRs) for pregnancy‐related ADRs reported in at least 10 ICSRs involving JAKIs [27]. The full database served as the primary comparison group and consisted of ICSRs associated with all other drugs recorded in VigiBase, excluding JAKIs. The same inclusion/exclusion criterion based on patient age applied to the study population (i.e., excluding ICSRs where age was 50 years or older) was employed when defining the reference group. The ROR estimates were considered statistically significant when the lower bound of the 95% CI exceeded one. To minimize false‐positive findings and mitigate the risk of signal leakage (i.e., confounding due to ADRs linked to coadministered drugs) [28], sensitivity disproportionality analyses were conducted. These analyses focused on pregnancy‐related ADRs reported in ≥ 10 ICSRs where JAKIs were the only drugs reported. Data management and analysis were performed using the Statistical Analysis System Software (version 9.4; SA Institute, Cary, NC, USA). The study was conducted following the REporting of A Disproportionality analysis for drUg Safety signal detection using ICSRs in PharmacoVigilance guidelines (READUS‐PV) [29, 30]. In accordance with the Swiss Human Research Act (810.30, of 30 September 2011—status as of 1 September 2023, Art.2), from the Federal Assembly of the Swiss Confederation, ethical approval and written informed consent were not required.
3. Results
3.1. Demographic and Clinical Characteristics of the Study Population
As of May 26, 2024, 892 ICSRs reported ADRs classified under the SMQ “pregnancy and neonatal topics” in association with JAKIs. Figure 1 illustrates the selection process of the study population; 163 ICSRs met the inclusion criteria.
FIGURE 1.
Selection process of the study population. ICSR, individual case safety report.
The majority of ICSRs originated from North America (68, 41.7%) and Europe (64, 39.3%). Physicians reported 93 ICSRs (57.1%); 83 (50.9%) ICSRs involved adult females with a median age of 33.5 years (standard deviation 6.9 years), while 17 ICSRs concerned ADRs affecting infants or neonates. Tofacitinib (73, 44.8%) and upadacitinib (56, 34.4%) were the most frequently reported JAKIs suspected of pregnancy‐related ADRs. Rheumatoid arthritis was the primary indication for JAKI use (48, 29.4%). A high proportion (147, 90.2%) of ICSRs were categorized by reporters as serious primarily due to unspecified medically important events. JAKIs were the sole drugs reported in 78 ICSRs of pregnancy‐related ADRs (47.9%). Table 1 provides detailed information on the demographic and clinical characteristics of the study population.
TABLE 1.
Demographics and clinical characteristics of the individual case safety reports included in the study population.
| Characteristic | n (%), N = 163 |
|---|---|
| Country | |
| North America | 68 (41.7) |
| Europe | 64 (39.3) |
| South America | 19 (11.7) |
| Asia | 6 (3.7) |
| Australia | 5 (3.1) |
| Africa | 1 (0.6) |
| Year | |
| 2012 | 1 (0.6) |
| 2014 | 1 (0.6) |
| 2015 | 2 (1.2) |
| 2016 | 6 (3.7) |
| 2017 | 7 (4.3) |
| 2018 | 10 (6.1) |
| 2019 | 8 (4.9) |
| 2020 | 9 (5.5) |
| 2021 | 25 (15.3) |
| 2022 | 30 (18.4) |
| 2023 | 40 (24.5) |
| 2024 | 24 (14.7) |
| Reporter qualification | |
| Physician | 93 (57.1) |
| Patient/consumer | 34 (20.9) |
| Other health professional | 31 (19.0) |
| Pharmacist | 4 (2.4) |
| Not reported | 1 (0.6) |
| Sex and age | |
| Female | 130 (79.8) |
| Age group | |
| Adult (mean ± SD, range, in years) | 83 (33.5 ± 6.9, 18–49) |
| Infant (≥ 28 days) | 1 |
| Neonate (0–27 days) | 6 |
| Not reported | 40 |
| Male | 7 (4.3) |
| Age group | |
| Adult | — |
| Infant (≥ 28 days) | 2 |
| Neonate (0–27 days) | 3 |
| Not reported | 2 |
| Not reported | 26 (16.0) |
| Age group | |
| Adult | 1 |
| Infant (≥ 28 days) | 1 |
| Neonate (0–27 days) | 4 |
| Not reported | 20 |
| Suspect JAK inhibitors | |
| Tofacitinib | 73 (44.8) |
| Upadacitinib | 56 (34.4) |
| Baricitinib | 19 (11.7) |
| Ruxolitinib | 12 (7.4) |
| Filgotinib | 2 (2.0) |
| Abrocitinib | 1 (0.6) |
| Indication of JAK inhibitors | |
| Arthritis rheumatoid | 48 (29.4) |
| Ulcerative colitis | 16 (9.8) |
| Atopic dermatitis | 9 (5.5) |
| Crohn's disease | 4 (2.5) |
| Juvenile arthritis | 3 (1.8) |
| Psoriatic arthritis | 3 (1.8) |
| Other a | 16 (9.8) |
| Not reported | 64 (39.3) |
| Timing of drug exposure in relation to pregnancy | |
| Before pregnancy | 3 (1.8) |
| During pregnancy | 108 (66.3) |
| Unspecified | 52 (31.9) |
| Seriousness | |
| Yes | 147 (90.2) |
| Other medically important condition | 101 |
| Congenital anomaly/birth defect | 17 |
| Caused/prolonged hospitalization | 17 |
| Death | 4 |
| Life threatening | 3 |
| Disabling/incapacitating | 1 |
| Not reported | 4 |
| No | 10 (6.1) |
| Not reported | 6 (3.7) |
| Number of ICSRs reporting additional drugs beside JAK inhibitors | 78 (47.9) |
| Reported in ≥ 5% of ICSRs | |
| Methotrexate | 22 |
| Prednisone | 15 |
| Sulfasalazine | 12 |
| Ibuprofen | 11 |
| Folic acid | 10 |
Abbreviations: ICSR, individual case safety report; SD, standard deviation.
Other: atopic eczema, chronic polyarthritis, myelofibrosis (all n = 2); alopecia areata, autologous graft versus host disease, inflammatory bowel disease, multicentric reticulohistiocytosis, polycythemia vera, polyneuropathy, psoriasis, seronegative arthritis, seropositive rheumatoid arthritis, spondylarthritis (all n = 1).
3.2. Reported Pregnancy‐Related ADRs With JAKIs
The 163 ICSRs from the study population collectively documented 213 pregnancy‐related ADRs, categorized as shown in Table 2. Spontaneous abortion was the most frequently reported event (78 ICSRs, 47.9%). Among the 35 ICSRs of spontaneous abortion with co‐reported medications, methotrexate (n = 17) and mycophenolate (n = 1) were the only known teratogens. Other frequently co‐reported drugs belonged to diverse pharmacological classes, including corticosteroids, immunosuppressants, and antirheumatic agents. Congenital anomalies were described in 26 ICSRs (16.0%) with 43 events, with no specific organ‐related patterns identifiable. Table 3 summarizes the reported ICSRs of congenital anomalies following JAKI exposure during pregnancy, including the type of anomaly, co‐reported adverse events, and co‐reported medications. Reported pregnancy complications were also heterogeneous, with gestational diabetes being the most frequent (9 out of 21 ICSRs of pregnancy complications). Prematurity was reported in 15 ICSRs (9.2%), 10 ICSRs reported adverse neonatal outcomes, and eight ICSRs reported adverse fetal outcomes, with plagiocephaly and hydrocele being the most frequently reported specific events in the two categories (i.e., 5 ICSRs each).
TABLE 2.
Reported pregnancy‐related adverse drug reactions with JAK inhibitors.
| Categories of pregnancy‐related ADRs | Number of ICSRs, n (%), N = 163 |
|---|---|
| Spontaneous abortion | 78 (47.9) |
| Spontaneous abortion | 66 |
| Abortion | 7 |
| Missed abortion | 5 |
| Congenital anomaly a | 26 (16.0) |
| Nervous system anomalies | 4 |
| Anencephaly | 3 |
| Spina bifida | 1 |
| Ear, face, and neck anomalies | 5 |
| Micrognathia | 5 |
| Anomaly of external ear congenital | 3 |
| Ear malformation | 1 |
| Prominent epicanthal folds | 4 |
| Congenital heart defects | 4 |
| Ventricular septal defect | 2 |
| Pulmonary valve stenosis congenital | 1 |
| Univentricular heart | 1 |
| Oro‐facial clefts | 1 |
| Cleft palate | 1 |
| Laryngeal cleft | 1 |
| Abdominal wall defects | 1 |
| Abdominal wall anomaly | 1 |
| Congenital anomalies of kidney and urinary tract | 1 |
| Congenital hydronephrosis | 1 |
| Congenital vesicoureteric reflux | 1 |
| Genital anomalies | 1 |
| Hypospadias | 1 |
| Chordee | 1 |
| Limb anomalies | 2 |
| Polydactyly | 1 |
| Developmental hip dysplasia | 1 |
| Other anomalies | 7 |
| Fibula agenesis | 2 |
| Skeletal dysplasia | 1 |
| Congenital knee deformity | 1 |
| Hemangioma congenital | 3 |
| Genetic | 2 |
| Trisomy 21 | 1 |
| Muscular dystrophy | 1 |
| Unspecified | 3 |
| Pregnancy complication a | 21 (12.9) |
| Gestational diabetes | 9 |
| Pre‐eclampsia | 2 |
| Gestational hypertension | 2 |
| Oligohydramnios | 2 |
| High risk pregnancy | 2 |
| Amniorrhea | 1 |
| Hemorrhage in pregnancy | 1 |
| HELLP syndrome | 1 |
| Herpes gestationis | 1 |
| Premature separation of placenta | 1 |
| Uterine contractions abnormal | 1 |
| Complication of pregnancy | 1 |
| Prematurity | 15 (9.2) |
| Premature baby | 11 |
| Premature delivery | 2 |
| Premature labor | 2 |
| Abortion induced | 11 (6.7) |
| Adverse neonatal outcome a | 10 (6.1) |
| Plagiocephaly | 5 |
| Coagulation disorder neonatal | 1 |
| Granulocytopenia neonatal | 1 |
| Neonatal pneumothorax | 1 |
| Poor weight gain neonatal | 1 |
| Tremor neonatal | 1 |
| Umbilical cord short | 1 |
| Adverse fetal outcome | 8 (4.9) |
| Hydrocele | 5 |
| Bradycardia fetal | 1 |
| Fetal arrhythmia | 1 |
| Fetal heart rate decreased | 1 |
| Ectopic pregnancy | 5 (3.1) |
| Fetal death | 5 (3.1) |
| Cesarean section | 4 (2.5) |
| Fetal growth restriction | 4 (2.5) |
| Low birth weight baby | 2 (1.2) |
| Small for dates baby | 2 (1.2) |
| Large for dates baby | 1 (0.6) |
Abbreviations: ADR, adverse drug reaction; ICSR, individual case safety report.
ADRs outnumbering ICSRs due to some ICSRs reporting multiple pregnancy‐related ADRs of the same category.
TABLE 3.
Individual case safety reports of congenital anomalies reported with JAK inhibitors.
| Progressive number of ICSR | Country | Reporting year | JAKI | Indication of JAKI | Congenital anomaly | Other ADRs | Co‐reported medications |
|---|---|---|---|---|---|---|---|
| 1 | Switzerland | 2015 | Tofacitinib | Rheumatoid arthritis | Ventricular septal defect | Poor weight gain neonatal | Paracetamol; citalopram; clorazepate dipotassium |
| 2 | US | 2017 | Tofacitinib | Not reported | Pulmonary valve stenosis congenital | — | Losartan |
| 3 | US | 2017 | Tofacitinib | Juvenile idiopathic arthritis | Congenital hydronephrosis; congenital vesicoureteric reflux | — | Folic acid; anti‐d immunoglobulin; diphtheria vaccine toxoid; pertussis vaccine acellular; polio vaccine inact; tetanus vaccine toxoid; ondansetron; pyridoxine; calcium carbonate; influenza vaccine; docosahexaenoic acid; cefalexin |
| 4 | Germany | 2019 | Baricitinib | Rheumatoid arthritis | Anencephaly | — | Hydroxychloroquine; golimumab; ibuprofen; prednisolone; methotrexate a |
| 5 | US | 2019 | Tofacitinib | Juvenile idiopathic arthritis | Cleft palate; laryngeal cleft | — | Diphtheria vaccine; pertussis vaccine; tetanus vaccine; calcium carbonate; paracetamol; influenza vaccine; anti‐d immunoglobulin; cetirizine hydrochloride |
| 6 | Germany | 2020 | Baricitinib | Not reported | Developmental hip dysplasia | — | Leflunomide a ; sulfasalazine |
| 7 | Netherlands | 2020 | Tofacitinib | Psoriatic arthritis | Spina bifida | — | Omeprazole; prednisone |
| 8 | US | 2021 | Tofacitinib | Not reported | Abdominal wall anomaly; prominent epicanthal folds; plagiocephaly; micrognathia; hemangioma congenital; anomaly of external ear congenital; hydrocele | — | Sulfasalazine; hydroxychloroquine; prednisone |
| 9 | US | 2021 | Tofacitinib | Not reported | Anomaly of external ear congenital; plagiocephaly; hydrocele; prominent epicanthal folds; hemangioma congenital; micrognathia | — | Hydroxychloroquine; sulfasalazine; prednisone |
| 10 | US | 2021 | Tofacitinib | Not reported | Micrognathia; hydrocele; plagiocephaly | — | Sulfasalazine; hydroxychloroquine; prednisone |
| 11 | US | 2021 | Tofacitinib | Not reported | Hydrocele; prominent epicanthal folds; hemangioma congenital; micrognathia; anomaly of external ear congenital; plagiocephaly | — | Hydroxychloroquine; sulfasalazine; prednisone |
| 12 | US | 2021 | Tofacitinib | Not reported | Neonatal pneumothorax; prominent epicanthal folds; ear malformation; micrognathia; plagiocephaly; hydrocele | — | Hydroxychloroquine; prednisone; sulfasalazine; rituximab |
| 13 | Spain | 2022 | Tofacitinib | Inflammatory bowel disease | Polydactyly | Premature baby, Bradycardia fetal | Tozinameran; mesalazine |
| 14 | US | 2023 | Tofacitinib | Colitis ulcerative | Univentricular heart | — | Adalimumab; tilactase; infliximab; sertraline; calcium carbonate; elasomeran; diphtheria vaccine toxoid; pertussis vaccine acellular; tetanus vaccine toxoid |
| 15 | US | 2023 | Tofacitinib | Colitis ulcerative | Chordee; hypospadias | — | Acetylsalicylic acid; balsalazide sodium; cetirizine |
| 16 | Germany | 2023 | Tofacitinib | Rheumatoid arthritis | Ventricular septal defect | — | Certolizumab |
| 17 | Austria | 2023 | Upadacitinib | Not reported | Muscular dystrophy; skeletal dysplasia | Abortion induced | Acetylsalicylic acid |
| 18 | US | 2024 | Baricitinib | Not reported | Anencephaly | Abortion spontaneous | Golimumab; methotrexate a ; hydroxychloroquine |
| 19 | Egypt | 2024 | Baricitinib | Rheumatoid arthritis | Congenital knee deformity | Abortion | Leflunomide a |
| 20 | US | 2024 | Baricitinib | Not reported | Anencephaly | — | Golimumab; methotrexate a ; hydroxychloroquine |
| 21 | US | 2024 | Upadacitinib | Not reported | Fibula agenesis | — | — |
| 22 | US | 2024 | Upadacitinib | Not reported | Fibula agenesis | — | — |
| 23 | Germany | 2024 | Upadacitinib | Not reported | Trisomy 21 | — | — |
Note: ICSRs reporting only unspecified congenital anomalies (n = 3) are not presented.
Abbreviations: ADR, adverse drug reaction; JAKI, janus kinase inhibitor.
Known or suspected teratogens.
3.3. Disproportionality Analyses
Disproportionality analyses were performed for two pregnancy‐related ADRs for which more than 10 ICSRs were reported: spontaneous abortion (reported as “spontaneous abortion,” “abortion,” or “missed abortion”) and prematurity (reported as “premature baby,” “premature delivery,” or “premature labour”).
During the study period and considering (as for the study population) ICSRs involving patients aged < 50 years or of unknown age, VigiBase contained 13,777,812 ICSRs, of which 128,784 were associated with JAKIs.
Under the same conditions, by applying the case‐non‐case approach of disproportionality analysis, ICSRs reporting the ADR of interest (cases) were compared with ICSRs reporting all other ADRs (non‐cases) for both JAKIs and all other drugs in VigiBase. Spontaneous abortion and prematurity reported with JAKIs did not represent SDRs compared with the entire database (ROR 0.37, 95% CI 0.30–0.46 and ROR 0.07, 95% CI 0.04–0.11, respectively). Considering the subgroup of ICSRs where JAKIs were the only drugs reported (73,245 in total), sensitivity disproportionality analyses confirmed the absence of SDRs for both spontaneous abortion (n = 43, ROR 0.36, 95% CI 0.27–0.49) and prematurity (n = 10, ROR 0.08, 95% CI 0.04–0.15). Further details on disproportionality measurements for spontaneous abortion and prematurity issued from ROR computations are provided in Table 4.
TABLE 4.
Computation of disproportionality measurements for spontaneous abortion and prematurity (over the time window 2012 to May 26, 2024 and excluding individual case safety reports where age was 50 years or older).
| Spontaneous abortion | |||||
|---|---|---|---|---|---|
| No. of ICSRs of spontaneous abortion with JAKIs | No. of ICSRs of adverse events other than spontaneous abortion with JAKIs | No. of ICSRs from the full database reporting spontaneous abortion | No. of ICSRs from the full database reporting adverse events other than spontaneous abortion | ROR [95% CI] | |
| Primary analysis | 78 | 128,706 | 22,282 | 13,626,746 | 0.37 [0.30–0.46] |
| Sensitivity analysis | 43 | 73,202 | 22,282 | 13,626,746 | 0.36 [0.27–0.49] |
| Prematurity | |||||
|---|---|---|---|---|---|
| No. of ICSRs of prematurity with JAKIs | No. of ICSRs of adverse events other than prematurity with JAKIs | No. of ICSRs from the full database reporting prematurity | No. of ICSRs from the full database reporting adverse events other than prematurity | ROR [95% CI] | |
| Primary analysis | 15 | 128,769 | 23,285 | 13,625,743 | 0.07 [0.04–0.11] |
| Sensitivity analysis | 10 | 73,235 | 23,285 | 13,625,743 | 0.08 [0.04–0.15] |
Abbreviations: CI, confidence interval; JAKI, janus kinase inhibitor; ROR, reporting odds ratio.
4. Discussion
Utilizing data from the WHO global pharmacovigilance database, this study identified a relatively large number of more than a hundred ICSRs of pregnancy‐related ADRs with systemically administered JAKIs. The results indicated that spontaneous abortion and prematurity were among the most frequently reported pregnancy‐related ADRs with JAKIs; however without representing SDRs. The reporting frequencies of spontaneous abortion and prematurity were similar to those of all the other drugs registered in VigiBase, even when only ICSRs with JAKIs as the sole reported drugs were considered (excluding ICSRs with co‐reported drugs as confounding factors).
To our knowledge, this is the first study exploring the safety profile of JAKIs in pregnancy using a worldwide spontaneous reporting system. The data source allowed the selection of ICSRs in which any active ingredient from the class of interest was reported as a suspected drug. JAKIs are small molecules that, despite differences in target selectivity, share the potential to passively cross the placental barrier throughout all stages of pregnancy [31]. Previous studies on JAKIs' safety in pregnancy have typically focused on individual JAKIs, especially those with a longer history of use, such as tofacitinib [7, 8, 9, 10, 11, 12, 13, 14], baricitinib [15], and upadacitinib [17]. Moreover, these studies often considered restrictive conditions of use and primarily relied on data from randomized clinical trials, individual clinical cases, or small case series. A few studies also included post‐marketing data, although these were often small in scale and mostly derived from pharmaceutical company databases [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20].
Previous studies describing the occurrence of spontaneous abortion among patients treated with systemically administered JAKIs during pregnancy found no significant increase in risk compared to the background rate of this adverse pregnancy outcome [15, 16, 17, 18]. A recent systematic review, which included 12 case reports and three reviews of over 30 randomized controlled trials involving four JAKIs (tofacitinib, baricitinib, ruxolitinib, and upadacitinib) and 256 patients, similarly found no evidence of an increased risk [18]. The reported rates of spontaneous abortion were comparable to those observed in the general population [18]. Furthermore, a study on pregnancy outcomes following upadacitinib exposure documented various adverse outcomes, including spontaneous abortions, but the observed rates were comparable to those in the general population or in patients with autoimmune diseases [17]. These observations are consistent with our results, in which no SDR for spontaneous abortion was observed. Notably, in several ICSRs of spontaneous abortion with JAKIs, co‐medications such as methotrexate and mycophenolate, both known teratogens associated with an increased risk of early pregnancy loss, were reported and may have contributed to the outcomes [32, 33, 34, 35].
Our study identified 26 ICSRs of congenital anomalies reported with JAKI exposure during pregnancy. These anomalies were heterogeneous and did not exhibit a specific organ‐related pattern. The reported anomalies ranged from craniofacial malformations such as micrognathia and cleft palate, to cardiac defects including ventricular septal defect and univentricular heart, and musculoskeletal anomalies such as skeletal dysplasia and fibula agenesis. Of note, all three ICSRs reporting anencephaly involved co‐exposure to methotrexate, a known teratogen and folate antagonist that inhibits DNA and RNA synthesis. Teratogenic effects, such as craniofacial, central nervous system, and limb anomalies, have been observed in animal studies. Although a causal link to central nervous system anomalies in humans remains unclear [36], the presence of methotrexate in these cases may have contributed to the outcomes and should be considered when interpreting the potential role of JAKIs. One additional ICSR describing a congenital knee deformity involved co‐exposure to leflunomide, a drug suspected to be teratogenic. Although its teratogenicity in humans has not been clearly established, animal studies have reported anomalies such as skeletal malformations, anophthalmia or microphthalmia, and hydrocephalus [37]. Preclinical studies have shown that tofacitinib was teratogenic in animals, with anomalies including membranous ventricular septal defects and skeletal deformities [38]. Baricitinib and upadacitinib were also associated with reduced fetal viability and a range of malformations in rats and rabbits when used at dosages equal to or greater than 10 times the treatment dose in humans [39, 40, 41]. While some anomalies observed in animals, such as skeletal and cardiac defects, were also reported in our dataset, including two cases of ventricular septal defect, this type of heart defect is common and may occur independently of drug exposure [42]. Overall, the overlap between animal and human findings remains limited, and no consistent pattern of anomalies was identified. Our observations add to previous literature, which focused on a narrower range of JAKIs and described a more limited spectrum of congenital anomalies, such as congenital heart defects described with baricitinib and limb anomalies reported with upadacitinib [15, 16]. However, given the heterogeneity of the reported congenital anomalies and the co‐exposure to other drugs, including known teratogens, we did not perform a disproportionality analysis for congenital anomalies as a group, as this could have led to misleading spurious associations. This heterogeneity further underscores the complexity of assessing teratogenic risks and highlights the importance of continuous monitoring and data collection to identify potential patterns of malformation more accurately.
Additionally, our study documented 15 cases (9.2%) of prematurity reported with JAKI exposure. Prior literature has described an association between JAKIs and preterm birth, particularly in patients with autoimmune diseases where disease activity itself may contribute to the risk of prematurity [16]. However, our findings suggest that the reporting frequency of prematurity with JAKIs was similar to that with all the other drugs registered in VigiBase. This highlights the need for further research to distinguish between drug‐related effects and underlying disease contributions to adverse pregnancy outcomes.
By exploiting VigiBase and selecting all pregnancy‐related ADR ICSRs associated with any of the currently licensed systemic JAKIs at once, this study expanded the currently available literature on the safety profile of JAKIs in pregnancy, which is lacking data on the more recently approved molecules, such as filgotinib, ritlecitinib, momelotinib, and abrocitinib. This broader scope provides a more comprehensive understanding of the potential risks associated with JAKIs as a drug class when used in pregnancy and highlights the necessity of continued pharmacovigilance efforts.
This study has several limitations. First, it relies on spontaneous reports from VigiBase, which are inherently subject to reporting bias, underreporting, and lack of verification. ICSRs are not systematically validated, and the clinical accuracy of reported outcomes or drug exposures cannot be confirmed. This limitation restricts the ability to draw causal inferences and may affect the generalizability of the findings. Additionally, the disproportionality analysis was conducted using all other ICSRs collected in VigiBase during the same time period as the comparator group, restricted to patients aged < 50 years or age unknown. This approach cannot entirely exclude a dilution bias, as the comparator group may include ICSRs with demographic characteristics (sex, age) different from those of pregnancy‐related ICSRs with JAKIs, which involved mostly adult females. Despite these limitations, such pharmacovigilance data remain a valuable tool for early signal detection and hypothesis generation—particularly for understudied drug classes such as JAKIs in pregnancy. We restricted disproportionality analyses to events reported in at least 10 ICSRs to balance the risk of false‐positive associations from very small sample sizes against missing true statistical associations. By analyzing global data across multiple JAKIs, our study provides a broader safety overview while acknowledging that further pharmacoepidemiological studies are necessary to confirm these signals.
In conclusion, the current pharmacovigilance data available in VigiBase indicate no SDRs for spontaneous abortion or prematurity following JAKI exposure during pregnancy. Whilst several congenital anomalies were reported, no specific organ‐related patterns emerged. Continued post‐marketing surveillance, along with dedicated registries collecting comprehensive data on pregnancy outcomes following JAKI exposure and further observational studies are needed to fully characterize the safety profile of JAKIs during pregnancy and provide evidence‐based recommendations for clinicians, health authorities, and patients.
Author Contributions
R.N., N.A., K.D., F.R.G., F.B., A.C., A.P., and U.W. wrote the manuscript; R.N., N.A., A.P., and U.W. designed the research; R.N., N.A., and U.W. performed the research; R.N., N.A., and U.W. analyzed the data.
Funding
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: MedDRA term lists used to evaluate reported reactions (set out in the algorithm of Zaccaria et al. [25]).
Acknowledgments
The authors would like to thank the Uppsala Monitoring Centre (UMC), which manages VigiBase. The data presented in this study do not reflect the views of the UMC or the World Health Organization. VigiBase includes reports from various sources, and the likelihood that a reported adverse effect is related to a drug varies between cases. Open access publishing facilitated by Universite de Lausanne, as part of the Wiley ‐ Universite de Lausanne agreement via the Consortium Of Swiss Academic Libraries.
Abolhassani N., Noseda R., Dao K., et al., “Janus Kinase Inhibitors During Pregnancy and Adverse Drug Reactions: A Pharmacovigilance Disproportionality Analysis in VigiBase,” Clinical and Translational Science 18, no. 12 (2025): e70429, 10.1111/cts.70429.
Nazanin Abolhassani, Roberta Noseda, Alice Panchaud, and Ursula Winterfeld contributed equally to this article.
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Associated Data
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Supplementary Materials
Table S1: MedDRA term lists used to evaluate reported reactions (set out in the algorithm of Zaccaria et al. [25]).