Is Canakinumab Safe During Pregnancy? New Insights from Three Cases in Slovakia

Abstract

Background and Objectives: Canakinumab, a human recombinant monoclonal antibody against interleukin-1ß (IL-1ß), is indicated for the treatment of selected autoinflammatory periodic fever syndromes and rheumatic diseases. Data on its use during pregnancy remain limited and all are primarily derived from case reports. Although animal studies indicate no evidence of reproductive toxicity, the risk to the fetus or mother remains unknown. This study aims to provide more findings about this important topic. Methods: A retrospective analysis was conducted on three patients followed and treated in the National Center for Periodic Fever Syndromes. Although due to the small sample size, no general conclusions regarding the safety of canakinumab during pregnancy can be drawn. Results: Three maternal-exposed pregnancies were assessed, with no paternal exposure. Diagnoses included mevalonate kinase deficiency, familiar Mediterranean fever and TNF-receptor-associated periodic syndrome. All mothers were treated with canakinumab, and two of those continued the canakinumab treatment during the whole course of pregnancy. The diseases remained under full control during pregnancy, enabling conception in two cases where attempts prior to treatment were unsuccessful. The therapy led to disease control, a reduction in inflammation and subsequently successful conception. One patient underwent IVF repeatedly. All pregnancies resulted in three healthy infants, with no reported miscarriages during the canakinumab-exposed pregnancies, no complications during pregnancies and no serious infections in the newborns. The children had normal development, without any developmental delays or chronic illnesses. Conclusions: The current data, including our findings, indicate no harmful effects of canakinumab during pregnancy. However, because of the scarcity of data, the use of canakinumab during pregnancy should be carefully managed, and women who want to become pregnant should continue treatment only after a thorough benefit–risk evaluation.

1. Introduction

Autoinflammatory diseases (AIDs) are defined as diseases with clinical and biological inflammatory components and are linked to abnormalities of innate immunity [1]. The understanding of AIDs has evolved over time, and these conditions are now seen as resulting from innate immune system dysregulation in individuals that are genetically predisposed. This imbalance can culminate in inappropriate and uncontrolled inflammation, sometimes also with secondary activation of adaptive immunity [2]. Advances in genomic technologies, particularly next-generation sequencing, have uncovered that many AIDs are caused by single gene variants in components affecting the innate immune system. Nevertheless, there are also more complex polygenic forms of AIDs, such as adult-onset Still’s disease and periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome [2].

Autoimmune and autoinflammatory conditions are frequently mistaken for one another, as both stem from the abnormal activation of the immune system. Autoimmune diseases are mainly driven by T- and B-lymphocytes that recognize and react to self-antigens due to a failure of immune tolerance. In contrast, AIDs are driven by innate immune cells of the myeloid lineage, particularly macrophages, monocytes, neutrophils and dendritic cells [2]. A hallmark of AIDs is recurrent inflammatory flare-up in the absence of autoantibodies or antigen-specific T-lymphocytes. Monogenic forms of these disorders can result from pathogenic variants present in all (germline) or in only a portion of (somatic) cells, the latter resulting from variants that occur shortly after the earliest zygotic division during embryogenesis [2].

The best described subgroup of AIDs, previously known as ‘hereditary recurrent fevers’, include four interleukin-1-driven diseases: familial Mediterranean fever (FMF), cryopyrinopathies related to NLRP3 mutations (CAPS), mevalonate kinase deficiency (MKD) and tumor necrosis factor-type 1A receptor associated periodic syndrome (TRAPS). Some autoinflammatory diseases result from heightened sensitivity to extracellular and intracellular danger signals. The best examples are inflammasomopathies, which trigger the excessive production of pro-inflammatory cytokines such as interleukin-1 (IL-1) and interleukin-18 (IL-18). These disorders are linked to genetic mutations affecting inflammasome components, such as pyrin (in FMF), NLRP3 (in cryopyrinopathies), NLRC4 and NLRP12 inflammasomes [1,2]. Additional types of AIDs stem from the insufficient removal of excess immune proteins, proteasome-related diseases, or from the buildup of misfolded proteins in the endoplasmic reticulum, which can lead to the increased secretion of pro-inflammatory cytokines. TRAPS is an example linked to this pathophysiological mechanism [1].

The dysregulation of the ubiquitin pathway represents another mechanism in AIDs, involving abnormalities associated with defects in the linear ubiquitin chain assembly complex (LUBAC) and abnormalities associated with defects in protein deubiquitination, as seen in A20 deficiency and otulipenia (ORAS). Finally, some AIDs are linked to the inability to regulate cytokine signaling, leading to the formation of abnormal cytokine loops that amplify and perpetuate the inflammatory response. This mechanism can be seen by the deficiency of the interleukin-1 receptor antagonist (DIRA) and the deficiency of the interleukin-36 receptor antagonist (DITRA), where the lack of antagonistic signaling for IL-1 and IL-36 leads to uncontrolled inflammation. In adenosine deaminase 2 (ADA2) deficiency, an imbalance of pro- and anti-inflammatory macrophages, in favor of pro-inflammatory ones, results in vasculitis and increased pro-inflammatory cytokine release [1,2].

Autoinflammatory disease should be considered in patients with recurrent documented fevers or attacks of inflammation where more common causes, such as infections, malignancies and autoimmune conditions, have been ruled out. Importantly, the absence of fever does not exclude the possibility of autoinflammation [2]. The flare-ups of autoinflammation often follow stereotypical patterns, including manifestations such as rash, arthritis, pleuritis, peritonitis, lymphadenopathy, pharyngitis or ocular inflammation. When suspecting an autoinflammatory disease, the initial step is to exclude non-inflammatory conditions, including infections and/or malignancies [1].

Interleukin-1β is a pro-inflammatory cytokine that mediates peripheral immune responses during infection and inflammation. It plays an important role in the pathogenesis of both acute and chronic autoimmune diseases, diabetes, pain and neurological disorders [3]. Compared to IL-1α, IL-1β is a more potent inflammatory mediator. IL-1 can be released by a wide range of cell types, including macrophages, keratinocytes, fibroblasts, microglia and astrocytes, as well as mast, endothelial, neuronal and Schwann cells [3]. Dysregulated IL-1β activity is characteristic of many autoimmune diseases and can result either from abnormally increased levels of the cytokine or from a qualitative or quantitative deficiency of its endogenous inhibitor, the IL-1receptor antagonist (IL-1Ra) [3]. Therefore, targeting IL-1 signaling is a valuable therapeutic strategy for the management of IL-1-mediated disorders [2].

Canakinumab is a fully human IgG kappa monoclonal antibody that specifically targets IL-1β, that was developed to treat various immune-mediated disorders [3]. To date, most clinical studies on canakinumab have focused on its effectiveness in treating CAPS and three types of arthritis: rheumatoid arthritis; systemic-onset juvenile idiopathic arthritis; and gout arthritis. Beyond these indications, ongoing research is exploring its potential use in other diseases, including chronic obstructive pulmonary disease (COPD), diabetes and age-related macular degeneration [3]. Currently, together with anakinra (IL-1 receptor antagonist), canakinumab presents the cornerstone for the management of selected AIDs, predominantly from the group of inflammasomopathies [3,4].

Despite their proven utility, data on the safety of IL-1 blockers during pregnancy are sparse. Women of reproductive age with AIDs face difficult decisions regarding the continuation of treatment during conception and gestation. The current recommendations emphasize an individual benefit–risk evaluation, but a lack of controlled studies limits guidance. In our retrospective case series, we document three more pregnancies, where canakinumab was used through pregnancy including one pregnancy from IVF, where anti-IL1 agent seemed to be a safe and useful option for both mother and baby, aiming to expand the limited clinical data on this topic.

2. Materials and Methods

We conducted a retrospective analysis of three patients diagnosed with AIDs and treated with canakinumab during pregnancy. The patients are followed by the National Center for Periodic Fever Syndromes in the University Hospital in Martin and in Bratislava (Slovakia). All the patients underwent a consultation with the clinical pharmacologist straight after the confirmation of the pregnancy. They signed the informed consent regarding the following of the therapeutic strategy during the pregnancy in relation to the continuation of canakinumab treatment after the evaluation of the benefit–risk ratio. Of those, we contacted the parents and asked about the perinatal history of their children, the course of the pregnancy and the later adaptation and development. We asked two parents to undergo a laboratory check-up. In one case, the parent did not approve of the testing, while in the other case we have been able to conduct laboratory test control. All parents received and signed informed consent about being included in the study. The study was approved by the Ethics Committee of the Jessenius Faculty of Medicine, Comenius University in Bratislava (decision no. EK UNM 77/2022, dated 7 December 2022).

Our main objective was to document the pregnancy outcomes related to treatment with canakinumab (IL-1ß antagonist) during pregnancy. Currently, there are not enough data regarding the safety of using this treatment during pregnancy. This retrospective case series includes only three patients, limiting the ability to draw definitive conclusions about the safety of canakinumab during pregnancy. Data on pregnancy course and neonatal outcomes were obtained through parental interviews, which may be subject to recall bias. Nonetheless, presenting these findings remains important.

3. Results

3.1. Patient No. 1—Familial Mediterranean Fever

Maternal history. The first patient was born in January 2024. The mother of this patient is being treated in the National Center for Hereditary Periodic Fever Syndromes in the University Hospital in Martin. The mother, born in 1999, was diagnosed with familial Mediterranean fever; she is a carrier of the homozygous Met694Val variant in the MEFV gene. This variant is considered pathogenic according to the Infevers database [5]. The family history for AIDs or any other severe diseases is negative. The patient is the first proband with FMF in her family. She is currently treated with canakinumab (150 mg every 4 weeks subcutaneously) and colchicine (1.5 mg per day). As for the course of the disease, recurrent attacks with fever, abdominalgias, arthralgias and myalgias were described in the medical records accompanied by elevated inflammatory markers before the treatment.

Treatment. Treatment with colchicine was commenced at first, but clinical symptoms and persistently elevated values of serum amyloid A (SAA) were present despite the maximal tolerated dose of colchicine. Episodic treatment with anakinra was started during the flare-ups, but was not sufficient. Then, the therapy was stepped up, and in December 2017, biologic therapy with canakinumab was commenced. The response to the treatment was very quick, with relief from all the symptoms, no acute attacks of inflammation and normalized laboratory parameters. Adherence to the treatment was very good and the therapy was very well tolerated, with no severe side effects.

Pregnancy course. Pregnancy was verified in the 8th gestational week. After discussion and evaluating the risks/benefits of the biologic treatment, we continued with canakinumab in the same dosing regimen during the whole course of the pregnancy. No acute attacks were present during the pregnancy, and as for symptoms during pregnancy, the patient mentioned increased tiredness, but this symptom was more likely associated with the pregnancy itself. During the 19th week of pregnancy, the patient was hospitalized because of stomach cramps; magnesium was added to her treatment by the gynecologist, and the symptoms resolved. No other complications appeared. Treatment was also continued during lactation with no side effects.

Delivery and neonatal outcome. A healthy child (girl) was born in the 40th gestational week in January 2024. Delivery was physiological and spontaneous. Birth weight was 3090 g and birth height was 49 cm. The APGAR score was 9/10/10. Perinatal adaptation was without any issues, and all results of the neonatal screening were normal. The child was breastfed for 2 weeks, then continued with formula in adequate doses with good tolerance. The child was vaccinated according to the National Immunization Program of Slovakia. The child did not receive BCG or the rotavirus vaccine. Subfebrilities were present after vaccination with spontaneous termination; no other adverse effects were observed. The child had varicella zoster infection at 3 months of age, one upper respiratory tract infection and one influenza infection (the child was not vaccinated against influenza). The course of the diseases was not complicated, with antibiotics being prescribed in only one case. The child currently has no chronic medication. As for the symptoms of familial Mediterranean fever, none are present so far, and genetic testing has not been performed to date.

3.2. Patient No. 2—TRAPS Syndrome

Maternal history. The second patient was born in February 2025. The mother was born in 1989 and diagnosed with TRAPS in December 2020. As for the course of the disease, a late-onset form of TRAPS was observed in this particular case. Symptoms started in March 2019, at the age of 30 years. As for the clinical presentation—recurrent fevers, tiredness, lethargy, severe myalgias and arthralgias, chest pain (without pleuritis) and elevated inflammatory markers were present. All hematological, rheumatological and infectious etiologies were ruled out. After commencing genetic testing, a variant of uncertain significance c.434A>G, p.(Asn145Ser) in the TNFRSF1A gene was found [5]. The patient’s father is a carrier of the same variant, although we have no available information about his medical state.

Treatment. The patient responded well to episodic treatment with non-steroid anti-inflammatory drugs (NSAIDs) during acute attacks, although because of persistent inflammatory activity, biologic treatment with canakinumab was commenced in June 2021. After the first dose, the patient felt very well, with quick relief of symptoms, normalization of inflammatory markers, and no acute attacks being documented at the time. However, in May 2023, interferon-gamma release assays for mycobacterium tuberculosis were positive, and prophylaxis with isoniazid was then started. The patient was diagnosed with primary ovarian insufficiency at the age of 24 years, and hormonal replacement therapy was recommended. Whether the ovarian insufficiency is associated with AIDs is still not clear.

Pregnancy course and in vitro fertilization (IVF). Nevertheless, in December 2023, the patient started hormonal treatment as part of the in vitro fertilization process. The first embryonal transfer was realized in January 2024. This one was, however, unsuccessful, resulting in abortus imminens in the 6th gestational week due to a massive organized hematoma on the lower part of the gestational sac. Treatment with canakinumab was continued during this course of IVF. After that, three more unsuccessful embryonal transfers were realized. The patient was then referred to the Center for Reproductive Immunology.

In May 2024, the fifth embryonal transfer was realized. During this course, infusions of essential fatty acids were supplemented every 2 weeks, as suggested in the immunological support protocol by the Center for Reproductive Immunology, starting one week before the embryonal transfer and continuing until the 18th gestational week. Immunosuppressive treatment with low doses of methylprednisolone (8 mg/day) was given daily, starting 2 weeks before embryonal transfer, then continued and slowly weaned off until the 19th gestational week. At the 25th gestational week, the clinical pharmacologist was consulted and the biologic treatment with canakinumab was suspended. During the pregnancy, no acute attacks of TRAPS were present in the patient.

Delivery and neonatal outcome. There were no significant complications during the pregnancy, and a healthy boy was born in February 2025. The course of the pregnancy was physiological, childbirth was spontaneous, and the child was born in the 40th gestational week. Birth weight was 3020 g, birth height was 50 cm, and the APGAR score was 9/10/10. No severe issues with perinatal adaptations were described. The child has not yet been ill, and the results of neonatal screening for a broad spectrum of diseases (congenital heart defects, metabolic disorders, hip dysplasia, congenital cataract, otoacoustic emissions) are so far negative. The child and mother are currently in good condition. The child has not yet been genetically tested and did not receive any vaccines due to its very young age.

3.3. Patient No. 3—Mevalonate Kinase Deficiency

Maternal history. The third patient from our group was born in 2023. The mother, born in 1990, is being followed and treated in the Center for Hereditary Periodic Fever Syndromes in Martin. She was diagnosed with mevalonate kinase deficiency in 2016. The disease started at around 8 months of age. She was suffering from attacks of recurrent fevers, occurring mostly every 2–3 months; the duration of flare-ups was usually 5–7 days. The fevers were not responding to antipyretic medications and were accompanied by aphthous stomatitis, reactive cervical lymphadenopathy, urticaria, arthralgias, abdominal pain and cefalea. All attacks were also associated with elevated inflammatory markers and elevated immunoglobulin D and A concentrations. Family history for rheumatological or AIDs was negative. Genetic testing found two variants—c.604G>A and c.1129G>A—in the MVK gene (compound heterozygosity). Both are considered pathogenic according to the Infevers database [5].

Treatment. At first, treatment with episodic dosing of corticosteroids (prednisone) started with good effect, then treatment with anti-interleukin-1 inhibitor anakinra in an on-demand regiment was commenced. The treatment was at first well tolerated; however, we recorded persistent elevated levels of SAA, and acute attacks became more severe—twice during an attack the patient suffered from loss of consciousness. Because of the severe course of the disease and the risk of organ amyloidosis development, we started the treatment with canakinumab in 2022. Dosing was 150 mg every 4 weeks. The effect of canakinumab was very good, with no acute attacks and normalization of SAA levels. In terms of adverse effects, the patient described flu-like symptoms shortly after administering the medication.

Pregnancy course. With regard to the pregnancy, the patient had a spontaneous miscarriage in the 9th week in 2016. A second pregnancy was documented in August 2022. The patient continued the treatment with canakinumab in an unchanged regimen during the whole course of the pregnancy. The course of the pregnancy was physiological, and no acute attacks of MKD were present.

Delivery and neonatal outcome. A healthy child (girl) was born in March 2023. The birth took place by the elected Caesarean section because of orthopedic indications. The child was born in the 39th gestational week, birthweight was 3190 g, and birth height was 50 cm; the APGAR score was 8/10/10. Perinatal adaptation was without any significant issues. The child was breastfed at first, but because of hypogalactia was then also fed milk formula. All results of the neonatal screening were negative; the child has been vaccinated according to the National Immunization Program without any adverse reactions after vaccinations. The child did not receive BCG or the rotavirus vaccine. At almost 2 years of age, the child was ill on two occasions—both illnesses were short, with no severe complications, and she did not have varicella zoster or influenza infections. Genetic testing has not been performed on the child to date. We were able to perform a laboratory check-up. As for the assessment of the results, no severe pathologic deviations were found. All inflammatory markers were negative, aside from a mild TNF-alpha elevation, mild hypogammaglobulinemia G, which could be a sign of transient hypogammaglobulinemia of infancy and mild vitamin D deficiency. The results can be seen summarized in

Table 1. Laboratory results of patient No. 3.

Parameter	Values	Normal Values
	Blood count
Leukocytes	8.20 × 109/L	(4.00–13.00)
Erythrocytes	4.49 × 109/L	(3.60–5.20)
Haemoglobin	122 g/L	(100–140)
Thrombocytes	399 × 109/L	(150–500)
Neutrophiles	2.33 × 109/L	(1.30–9.50)
Lymphocytes	5.18 × 109/L	(2.20–11.70)
Monocytes	0.46 × 109/L	(0.60–1.50)
Eosinophiles	0.15 × 109/L	(0.00–1.10)
Basophiles	0.05 × 109/L	(0.00–0.30)
	Inflammatory markers
Alpha-1 acid glycoprotein	0.41 g/L	(0.40–1.20)
C-reactive protein	0.1 mg/L	(0.00–5.00)
Interleukin-6	0.62 ng/L	(0.00–6.40)
Procalcitonin	0.04 μg/L	(0.00–0.50)
Serum amyloid A	0.52 μg/L	(0.00–10.00)
Serum calprotectin	1.11 g/L	(0.57–2.25)
TNF-alpha	30.90 pg/mL	(0.00–8.00)
	Immunoglobulins and complement
Immunoglobulin G	4.230 g/L	(4.750–12.100)
Immunoglobulin A	0.283 g/L	(0.210–2.910)
Immunoglobulin M	0.520 g/L	(0.470–2.400)
Immunoglobulin E	<15.7 kU/L	(0.0–60.0)
C3-complement	0.89 g/L	(0.90–1.80)
C4-complement	0.15 g/L	(0.10–0.40)
Vitamin D	22.4 ug/L	(30–100)
Phagocytosis—respiratory burst	99%	(80–100)
	Flow cytometry
CD3+ T-lymphocytes	4248 cells/μL	(2542–4933)
CD19 B-lymphocytes	622 cells/μL	(733–1338)
CD3+CD4+ T-lymphocytes	2331 cells/μL	(1573–2949)
CD3+CD8+ T-lymphocytes	1606 cells/μL	(656–1432)
CD16+CD56+ NK cells	207 cells/μL	(186–724)
CD4:CD8 Ratio	1.40	(1.34–3.04)
CD8+CD38+	2642 cells/μL	(13–124)
CD3+HLADR+	104 cells/μL	(18–186)
Marginal zone cells	13.5%	(4.1–13.9)
Naive B-lymphocytes	73.3%	(68.1–89.3)
Switched memory B-lymphocytes	10.9%	(3.9–13.6)
Transient B-lymphocytes	27.8%	(3.3–16.5)
CD21 low CD38 low	3.9%	(1.0–5.7)
CD21 low	16.0	(5.1–21.3)
Plasmablasts	6.8%	(0.5–3.0)
Nonswitched memory B-lymphocytes	13.5%
TCR/alpha/beta/CD4-CD8	1.8%	(0.0–2.0)
CD8CD38HLA	0.7%	(0.1–2.7)
RTE CD4+	1420	(800–2400)
Naive CD4+	1951	(1000–3200)
CM CD4+	219
EM CD4+ RO+	61
EM CD4+ RO-	9
AM CD4+	14	(0–5)
Naive CD8+	1431	(200–1300)
CM CD8+	66
EM CD8+ RO+	37
EM CD8+ RO-	48
AM CD8+	8	(2–80)
TCR gamma/delta	234	(20–340)

Abnormal values are in bold.

.

A few days after our examination the patient was hospitalized in the pediatric intensive care unit. She was infected by COVID-19 infection (verified by a nasal antigen test). The infection was complicated by recurring seizures during febrile episodes. At first, complicated febrile seizures were thought to be the cause of the issues, however, because of the recurrence of the seizures, the patient underwent a lumbar puncture to rule out central nervous system (CNS) infection. Examination of the cerebrospinal fluid (CSF) yielded completely negative results. Cytobiochemical results were normal, PCR tests for neurotropic agents and COVID-19 came out negative. Furthermore, cultivation of CSF and microscopic analysis did not find anything pathological. After that, the family history was updated and we found out that the mother experienced similar febrile seizures at the age of 2–3 years and was temporarily treated with antiepileptic medications. EEG and video-EEG were performed with no epileptic activity detected. The patient was prescribed levetiracetam due to a neurologic indication. During the hospitalization, no more seizures were detected. After that, the patient was discharged in a stable state from the hospital.

All data regarding pregnancies, patients, their mothers and pregnancy outcomes are summarized in

Table 2. Canakinumab-exposed pregnancies and outcomes; maternal exposure.

IL-1 Inhibitor	Canakinumab	Canakinumab	Canakinumab
Maternal age at pregnancy (years)	23	34 a	32 b
Diagnosis	FMF	TRAPS	MKD
Dose and interval	150 mg every 4 weeks	150 mg every 4 weeks	150 mg every 4 weeks
During pregnancy	Continued canakinumab	Stopped canakinumab at 25th week	Continued canakinumab
Week of delivery	40 + 5	40 + 2	39
Mode of delivery	vaginal birth	vaginal birth	elected C-section c
Birth weight (grams)	3090	3020	3190
Birth height (centimeters)	49	50	50
APGAR	9/10/10	9/10/10	8/10/10
Gender	F	M	F
Development	normal	normal	normal
Mode of feeding	breastfed for 2 weeks, then bottle	breastfed	breastfed + bottle
Neonatal outcome	healthy	healthy	healthy, mild immunological variations, suspected febrile seizures
Age at last contact	14 months	2 weeks	22 months

^a IVF pregnancy, four unsuccessful attempts. ^b One miscarriage in 2019, before commencing anti-IL-1 treatment. ^c Due to orthopedic indication. FMF—familial Mediterranean fever; TRAPS—TNF-receptor associated periodic syndrome; MKD—mevalonate kinase deficiency; F—female; M—male.

.

4. Discussion

Canakinumab is a fully human IgG kappa monoclonal antibody targeting IL-1β that was developed for the treatment of immune-mediated disorders: monogenic periodic fever syndromes (TRAPS, CAPS, FMF and MKD); Still’s disease and adult-onset Still’s disease (in patients older than 2 years); as well as for the treatment of gout arthritis with frequent attacks in adults [4]. Data supporting its use in pregnancy and during breastfeeding remain insufficient, and most data come from case report series. Up to now, formal clinical recommendations have been lacking. In general, its use is recommended only in situations where the benefit of the treatment outweighs the risk for the patient. Information about the use of canakinumab in pregnancy from the European Medicine Agency (EMA) in the official summary of product characteristics can be summarized as follows [4]: “(a) Data on canakinumab use in pregnant women are limited; (b) Animal studies did not indicate direct or indirect harmful effects with respect to reproductive toxicity; (c) The potential risk to the fetus or mother remains unknown; (d) Women should use effective contraceptives during treatment with canakinumab and for up to 3 months after the last dose; (e) Women who are pregnant or who desire to become pregnant should therefore only be treated after a thorough benefit–risk evaluation”. It remains unclear whether canakinumab is secreted into human breast milk; therefore, the decision to breastfeed while undergoing the treatment should only be based on a thorough assessment of potential risks and benefits [4]. Animal studies using a murine anti-murine IL-1β antibody showed no undesirable effects on the development of nursing mouse pups, although transfer of the antibody was observed. While formal studies of the potential effect on human fertility are lacking, canakinumab has not been shown to affect male fertility parameters in marmosets (C. jacchus), and similar murine anti-murine IL-1β antibodies showed no undesirable effects on fertility in male or female mice [4].

If we looked at the safety data on canakinumab from human studies, we would not find a lot of appropriate results. In 2017, Youngstein et al. [6] published an international multicenter analysis from seven countries on the usage of anti-IL1 treatment during pregnancy. A total of 31 maternal-exposed pregnancies and also the first data on paternal exposure—six to anakinra and five to canakinumab—have been reported, with no negative outcomes. Among the maternal exposures to canakinumab, seven pregnancies were described, four with CAPS, two with FMF and one with syndrome of undifferentiated recurrent fever (SURF). They reported eight pregnancies altogether that resulted in the delivery of seven healthy infants at normal gestational age and with appropriate birthweight. One of the patients had Cogan syndrome, and this pregnancy ended with the miscarriage of the baby [6]. In the same study, 23 anakinra-exposed pregnancies were reported, resulting in the birth of 21 healthy infants. One infant was born with unilateral renal agenesis and ectopic neurohypophysis. There were two first-trimester miscarriages occurring in mother with active and uncontrolled disease. No serious neonatal infections were noted in either treatment group [6]. Within the canakinumab cohort, the duration of the treatment and its relation to pregnancy varied in each case. Two pregnancies were conceived while the mothers were on canakinumab, which was discontinued as soon as the pregnancy was confirmed in the first trimester, at 8 and 12 weeks, respectively. Two mothers switched to anakinra at 8 and 36 weeks of gestation. One patient received canakinumab continuously from preconception to term with 300 mg canakinumab administered every 8 weeks, with the last dose in the 36th gestational week [6].

An additional case series from 2022 reported seven pregnancies exposed to canakinumab, all resulting in live births [7]. Canakinumab was given at a median dose of 150 mg monthly; indications included CAPS (n = 3), systemic juvenile idiopathic arthritis (SJIA, n = 2), FMF (n = 1) and MKD (n = 1). Of these patients, all except one reached full-term pregnancy (there was one patient with a premature rupture of membranes in the 35th gestational week) with normal birthweight. Canakinumab was given to six mothers during the conception period. The length of the treatment varied: one of the patients continued the therapy from preconception until the 40th gestational week; in another patient, treatment with canakinumab started during the third trimester (in the 27th gestational week) due to a disease flare. This patient was treated with canakinumab with a final dose 6 months before conception. In another patient, canakinumab was not stopped until the 16th gestational week, and in the remaining three patients, the treatment was given 7–10 days before conception. Two babies were breastfed, with no serious infections or developmental delay issues in follow-up (mean time, 9 months). One of the mothers, who was treated with canakinumab during the whole pregnancy, developed anal and vulvar condylomas, which resolved spontaneously. This patient was also infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy, presenting with only mild symptoms [7]. In addition, three other case reports were reported by three authors (two patients with CAPS and one with SJIA complicated by macrophage activation syndrome [MAS]) [8,9,10]. All of these pregnancies ended with the birth of healthy infants; in two cases, canakinumab treatment was started before conception and continued until the 34th and 35th gestational week, respectively [8,9].

An additional concern in patients with AIDs is the impact of chronic pro-inflammatory state on infertility. According to the latest World Health Organization (WHO) recommendations [11]: “Infertility is a disease of male or female reproductive system defined by the failure to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse.” A number of studies have found that pyroptosis plays a common role in many reproductive diseases, such as ovarian aging or premature ovarian insufficiency, polycystic ovary syndrome (PCOS), endometriosis, recurrent spontaneous abortion and male subfertility. However, the precise contribution of inflammasome activation to the development of these conditions remains unclear [12,13]. Multiple recurrent episodes of peritonitis may result in peritoneal adhesions, which can lead to intestinal or fallopian tube obstruction.

On the other hand, if left untreated, chronic autoinflammation may progress to amyloidosis, with the deposition of amyloid fibrils in different organs. This is why patients with non-treated AIDs can be at risk of infertility [10,11,12,13,14,15]. Historical data support this concern. In 1970, Mamou [10] investigated the reproductive system in 20 women with FMF and identified ovarian insufficiency as the leading cause of infertility. Ismajovich et al. [14] found ovulatory disturbances in 13 out of 45 patients with FMF and primary sterility. Similarly, Ehrenfeld et al. [15] investigated the fertility and obstetric history of 36 women with FMF, finding that 13 women experienced infertility, 6 of whom had ovulatory dysfunction and 4 as a result of peritoneal adhesions.

The possible effect of persistent inflammation on pregnancy and missed abortion was also observed in our patient number two with TRAPS. Canakinumab was safely continued in this patient until the 25th gestational week in combination with low-dose methylprednisolone with no side effects. Treatment was stopped according to the consultation with the clinical pharmacologist. Canakinumab may have contributed to controlling the pro-inflammatory state connected with TRAPS and the woman was able to give birth to a healthy boy. Other cases of missed abortion are documented in the literature. Youngstein et al. [6] reported two first-trimester miscarriages affecting a mother with active disease receiving anti-IL-1 treatment. Only one case of miscarriage was reported in association with canakinumab treatment, occurring at 6 weeks of gestation in a 26-year-old mother with refractory Cogan syndrome, with only a partial clinical and biochemical response to canakinumab at a dose of 150 mg every 4 weeks. Notably, this was her second miscarriage; the first occurred during treatment with anakinra in the previous year [6]. Cogan syndrome is by definition a rare multisystem autoimmune disease affecting the ocular and audiovestibular system with unknown pathogenesis, typically presenting with interstitial keratitis and hearing loss in the third decade of life. It connects autoimmunity with some inflammatory features, which can contribute to all of the pro-inflammatory states observed during pregnancy as well as in the uncontrolled course of AIDs [16].

To the best of our knowledge, to date we can find 21 cases of pregnancies exposed to canakinumab documented in the literature (including our three patients). Of these, 20 ended in successful births, and one miscarriage was observed in a patient with Cogan syndrome. Canakinumab showed a good safety profile, with no severe infections or developmental delay in breastfed children. Canakinumab can also help to control the pro-inflammatory state in patients with AIDs and infertility in combination with other agents. We present data that support the safe and personalized use of canakinumab in pregnancy in selected patients, according to the risk versus benefit for each individual patient. The absence of randomized controlled trials (RCTs) in this area remains a significant limitation in assessing the safety profile of canakinumab during pregnancy. However, more data extracted from the registries and clinical trials are needed. Future research should include long-term follow-ups of children exposed to canakinumab in utero and prospective registry data to assess potential developmental or immunological outcomes beyond infancy.