Pregnancy outcome following in utero exposure to azathioprine: A French comparative observational study

doi:10.1016/j.therap.2017.06.006

Therapies

Volume 73, Issue 3, May–June 2018, Pages 199-207

https://doi.org/10.1016/j.therap.2017.06.006 Get rights and content

Summary

Aim of the study

To evaluate whether azathioprine exposure during pregnancy increases the risk of birth defects and prematurity.

Method

Prospective comparative observational study using the French pregnancy database TERAPPEL. To evaluate birth defects, outcomes of pregnancies exposed to azathioprine during the 1st trimester were prospectively assessed and compared to that of pregnancies exposed to another drug used for the same indications. Secondly, the rate of preterm births was compared between fetuses exposed to azathioprine at least during the third trimester and those exposed during the first trimester only.

Results

From 447 requests for a risk assessment for women receiving azathioprine during pregnancy, 193 pregnancies meet inclusion criteria. One hundred and twenty-four of them were exposed to azathioprine during the 1st trimester and were compared to that of 124 pregnancies exposed to another drug used for the same indication. Azathioprine use during the first trimester was not statistically associated with the risk of all birth defects ([7.3% vs. 5.4%]; [OR = 1.36; 95%CI: 0.44–4.20]) nor with major birth defects (5.2% vs. 1.8% [OR = 2.96; 95%CI: 0.56–15.64]). The rate of preterm births (22.5% vs. 27.3%, P = 0.579) was similar regardless of the exposure period to azathioprine (at least during the third trimester or during the first trimester only).

Conclusions

This study confirms that first trimester exposure to azathioprine is not associated with an elevated rate of birth defects and that the high rate of preterm births among women exposed to azathioprine is probably explained by the underlying maternal disease.

Section snippets

Abbreviations

6-MP6

mercaptopurine

6-MMP

methylmercaptopurine

6-TGN

6-thioguanine

AZA

azathioprine

CNIL

French national commission of informatics and liberties

DNA

deoxyribonucleic acid

gestational weeks

IBD

inflammatory bowel diseases

ICD

International classification of diseases

LBW

low birth weight

LMP

last menstrual period

RNA

ribonucleic acid

Methods

All requests for risk assessment for AZA exposure during pregnancy registered in the French pregnancy database between 1 January 1989 and 15 May 2012 were selected.

Data were obtained from requests made by physicians or patients asking to a French regional pharmacovigilance center to carry out a risk assessment for drug exposure during pregnancy. All these requests are recorded in the French pregnancy database TERAPPEL approved by the French National commission of informatics and liberties

Results

Between 1 January 1989 and 15 May 2012, 447 requests for a risk assessment for women receiving AZA during pregnancy were recorded. The selection of data is described in detail in a flow chart (Fig. 1).

Discussion

In our study, the rate of major birth defects in the AZA group was not statistically different from that in the control group, but the crude rate (percentage) of major birth defects was three times as high as the rate in the control group. However, our sample size was small and a larger study is required to confirm this finding. In French healthy mothers, congenital abnormalities occur in 2% to 3% of pregnancies [30], [31]. In this study, both groups had birth defect rates higher than the

Disclosure of interest

The authors declare that they have no competing interest.

References (43)

L.H. Brent et al.
The effects of antirheumatic drugs on reproductive function
Reprod Toxicol
(1997)
S. Saarikoski et al.
Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus
Am J Obstet Gynecol
(1973)
J.H. Githens et al.
Teratogenic effects of azathioprine (Imuran)
J Pediatr
(1965)
A. Francella et al.
The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study
Gastroenterology
(2003)
L. Shim et al.
The effects of azathioprine on birth oucomes in women with inflammatory bowel disease (IBD)
J Crohns Colitis
(2011)
T. Vial et al.
Terappel: description of a computerised database and examples of studies
Therapie
(2014)
C. Schaefer et al.
Using observational cohort data for studying drug effects on pregnancy outcome – methodological considerations
Reprod Toxicol
(2008)
N. Lelong et al.
Surveillance épidémiologique et diagnostic prénatal des malformations congénitales en population parisienne : évolution sur 27 ans, 1981–2007
Arch Pediatr
(2012)
C. De Vigan et al.
Prévalence et diagnostic prénatal des malformations en population parisienne : vingt ans de surveillance par le registre des malformations congénitales de Paris
J Gynecol Obstet Biol Reprod
(2005)
J.A. Garcia-Donaire et al.
Tacrolimus as basic immunosuppression in pregnancy after renal transplantation. A single-center experience
Transplant Proc
(2005)

E.M. Alstead et al.

Safety of azathioprine in pregnancy in inflammatory bowel disease

Gastroenterology

(1990)

U. Mahadevan et al.

Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from northern California

Gastroenterology

(2007)

J.A. Dominitz et al.

Outcomes of infants born to mothers with inflammatory bowel disease: a population-based cohort study

Am J Gastroenterol

(2002)

L. Coscia et al.

Immunosuppressive drugs and fetal outcome

Best Pract Res Clin Obstet Gynaecol

(2014)

M.J. Carter et al.

Guidelines for the management of inflammatory bowel disease in adults

Gut

(2004)

M.S. Esplein et al.

Immunosuppressive drugs and pregnancy

Obstet Gynecol Clin North Am

(1997)

Ø. Hovde et al.

Crohn's disease: epidemiology and clinical course

World JGarstroenterol

(2012)

J.B. Chevaux et al.

Optimizing thiopurine therapy in inflammatory bowel disease

Inflamm Bowel Dis

(2011)

N.K. De Boer et al.

Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites

Am J Gastroenterol

(2006)

J.E. Polifka et al.

Teratogen update: azathioprine and 6-mercaptopurine

Teratology

(2002)

J.G. Rosekrantz et al.

Azathioprine (Imuran) pregnancy

Am J Obstet

(1967)

Cited by (26)

Diagnosis and management of ANCA-associated vasculitis
2024, The Lancet
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.
Neuroimmunological Disorders: The Gender Effect
2023, Neurologic Clinics
Intrahepatic cholestasis of pregnancy associated with azathioprine: A case series
2021, Journal of Gynecology Obstetrics and Human Reproduction
Citation Excerpt :
Besides, azathioprine is recommended as first-line immmunosuppressant in patients with steroid-dependent inflammatory bowel disease (IBD). Medical data about azathioprine exposure during pregnancy for IBD are reassuring because it is not associated with congenital defects. [5–7] However azathioprine may induce transient elevation in liver enzyme levels and biological cholestasis [6,8].
Intrahepatic cholestasis of pregnancy (ICP) is characterised by otherwise unexplained maternal pruritus, increased serum bile acid concentration over 10 μmol/L and spontaneous relief of symptoms and liver abnormalities after delivery. It occurs most frequently during the third trimester and is usually not induced by medication. Besides, azathioprine is recommended as first-line immunosuppressant in patients with steroid-dependent inflammatory bowel disease and is allowed during pregnancy, in order to stabilize maternal disease.
We reviewed all cases of ICP between 2010 and 2018 in two French perinatal centers.
We encountered eight pregnancies complicated by atypical ICP among patients treated with azathioprine. ICP associated with azathioprine appears to be biologically more severe and to occur earlier than "standard" ICP. Furthermore, clinical and biochemical abnormalities related to ICP disappear when azathioprine is discontinued. Azathioprine safety should be reconsidered and practitioners advised to discuss discontinuing this drug as soon as ICP diagnosis is established.
In utero exposure to Azathioprine in autoimmune disease. Where do we stand?
2020, Autoimmunity Reviews
Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms.
The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors.
In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field.
- •
  There is no study on a significant number of subjects concerning the medium and long-term outcome of children born by mothers with autoimmune disease treated with AZA.
- •
  As AZA use is related to underlying disease and disease activity and many confounders interfere with AZA treatment, there is a major difficulty to distinguish between the influence of the disease itself on the risk of adverse birth outcome and potential AZA effects in offspring at medium and long term.
- •
  Data need to be implemented with large, multicenter studies.
Non-Infectious Uveitis and Pregnancy, is There an Optimal Treatment? Uveitis Course and Safety of Uveitis Treatment in Pregnancy
2024, Ocular Immunology and Inflammation
Immunosuppression in Uterus Transplantation: Experience from the Dallas Uterus Transplant Study
2023, Transplantation

View all citing articles on Scopus

View full text

Pregnancy and drugPregnancy outcome following in utero exposure to azathioprine: A French comparative observational study

Summary

Aim of the study

Method

Results

Conclusions

Section snippets

Abbreviations

Methods

Results

Discussion

Disclosure of interest

Reprod Toxicol

Am J Obstet Gynecol

J Pediatr

Gastroenterology

J Crohns Colitis

Therapie

Reprod Toxicol

Arch Pediatr

J Gynecol Obstet Biol Reprod

Transplant Proc

Gastroenterology

Gastroenterology

Am J Gastroenterol

Best Pract Res Clin Obstet Gynaecol

Guidelines for the management of inflammatory bowel disease in adults

Gut

Immunosuppressive drugs and pregnancy

Obstet Gynecol Clin North Am

Crohn's disease: epidemiology and clinical course

World JGarstroenterol

Optimizing thiopurine therapy in inflammatory bowel disease

Inflamm Bowel Dis

Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites

Am J Gastroenterol

Teratogen update: azathioprine and 6-mercaptopurine

Teratology

Azathioprine (Imuran) pregnancy

Am J Obstet

Pregnancy and drug
Pregnancy outcome following in utero exposure to azathioprine: A French comparative observational study