Pregnancy and childbirth in Takayasu arteritis in Japan: A nationwide retrospective study

ABSTRACT

Introduction

Takayasu arteritis (TAK) is a granulomatous large vessel vasculitis mainly involving the aorta and its proximal branches. Patients with TAK are distributed globally, but the prevalence is highest in Asia [1–3]. An estimated 150 new cases occur annually in Japan [4]. TAK has a strong sex ratio, with ∼80–90% of patients being female, and the age of onset is usually between 10 and 40 years [5, 6]. The timing of TAK onset, disease activity, organ damage, and intensive immunosuppressive treatment can affect the establishment of pregnancy and pregnancy course. However, studies of pregnancy in females with TAK are sparse and limited, probably due to disease rarity. A literature review of 505 pregnancies in 373 female patients with TAK [7] reported life-threatening maternal cardiovascular complications in >5% of pregnancies.

In recent years, advances in imaging techniques have made TAK diagnosis possible at an early stage, and the application of biological agents and other treatments has become widespread along with the development of guidelines or recommendations for their use. These changes in the medical environment have made it easier than ever before to control the disease activity of TAK and reduce organ damage and its sequelae. However, data or consensus on medical management in pregnant women with TAK, which is highly sought after in clinical settings, are insufficient. This study aimed to understand the status quo of medical treatments, outcomes of pregnancy, and birth outcomes of the children in pregnant patients with TAK who had a live-born baby in Japan.

Patients and methods

We retrospectively registered patients with TAK who conceived after TAK diagnosis and continued their pregnancies beyond the second trimester from 1967 to 2021 under the management of medical institutions participating in the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis. The following information was collected from patients: age at TAK diagnosis, disease classification, age at delivery, treatments before and during pregnancy, complications during pregnancy, birth outcomes of the children, and changes in disease activity during pregnancy and after delivery.

Data were described as medians with interquartile range (IQR) for continuous variables and numbers with frequencies for categorical variables. Fisher’s exact test was used to compare categorical variables. A P-value of <.05 was considered significant. Analysis was performed using the Statistical Package for the Social Sciences software (Version 28.0.1, Chicago, IL, USA).

Results

This study enrolled 51 cases and 68 pregnancies from 19 ethics committee–approved centres from 2019 to 2021. Registered pregnancies were those who continued their pregnancies beyond the second trimester. Of these, 48 cases and 65 pregnancies (95.6%) resulted in delivery and live-born babies. Three pregnancies that did not result in live births had artificial abortions. In all three cases, the decision to have artificial abortions was based on concerns about the burden and impact of pregnancy on patients with TAK and possible effects of medications on fetus.

Characteristics of the maternal TAK

The median age (IQR) of TAK diagnosis in the 48 cases was 22 (19–29) years, and the year of diagnosis distributed from 1965 to 2017 (Table 1). Numano classification of the 48 cases included Types I, IIa, IIb, III, IV, and V in 10, 15, 12, 1, 1, and 9 cases, respectively, with Type IIa being the most frequent [8]. Pulmonary artery lesions and aortic regurgitation were observed in 3 (6.3%) and 11 (22.9%) patients, respectively. The clinical manifestations indicated that systemic inflammation, such as fever and weight loss, was present in a high proportion (82.6%) of the patients during initial onset, but other clinical symptoms varied depending on the affected arteries (Table 2). Treatment within 1 year after diagnosis included prednisolone (PSL) in 41/46 (89.1%), immunosuppressive drugs in 17/46 (37.0%, including methotrexate in 11, cyclosporine in 5, azathioprine in 4, and tacrolimus in 1), biologics in 5 (10.9%, including infliximab in four and tocilizumab in one), and antihypertensive drugs in 8/46 (17.4%) cases (Table 3).

Obstetric history and medical treatment preconception

The median age (IQR) of the delivery of 65 pregnancies was 31 (28–34) years (year of delivery 1969–2021, year of birth after the 2000s: 72.3%), and the median disease duration at delivery was 9 (5–12) years (Table 4). Menstrual disorders after onset were observed in 11/48 (22.9%) cases, but none had amenorrhea. A total of 26/48 (54.2%) of the patients had been advised by their physicians of contraindications to pregnancy due to disease activity or medications in TAK. Planned pregnancies accounted for 33/65 cases (50.8%, including four pregnancies by artificial insemination/ovulation induction).

Preconception therapy included PSL in 51 pregnancies [78.5%, median dose: 7.5 mg (range: 3–30 mg/day)], immunosuppressive drugs in 18 pregnancies (27.7%, including azathioprine in eight, tacrolimus in seven, methotrexate in four, cyclosporine in one, and colchicine in one), biologics in 12 pregnancies (18.5%, including infliximab in six, tocilizumab in five, and adalimumab in one), and antihypertensive drugs in 5 (7.7%) pregnancies (Table 3). Surgical treatment had been performed before pregnancy in six cases (12.5%, including aortic root replacement in two, subclavian artery dilatation in one, subclavian artery bypass in one, subclavian artery stenting in one, and ascending aorta semicircular artery replacement in one).

Medical treatment and complications during pregnancy

Medications used during pregnancy included PSL in 48 pregnancies [73.8%, median dose: 9 mg (range: 4–30 mg/day), increased in 12 pregnancies and decreased in 1 pregnancy compared to the preconception dose], immunosuppressants in 13 pregnancies (20.0%, including azathioprine in six, tacrolimus in six, and cyclosporine in one), and biologics in 9 pregnancies (13.8%, including infliximab in four, tocilizumab in four, and adalimumab in one). Immunosuppressants and biologics were discontinued in five and four pregnancies after conception, respectively. There were 12 pregnancies during which the PSL dosage was augmented, encompassing three pregnancies aimed at sustaining the therapeutic effect after the discontinuation of immunosuppressive medications or biologic agents. Furthermore, there were four pregnancies where relapses of TAK occurred during the pregnancy, of which three pregnancies witnessed an escalation in PSL dosage. As for relapse, we defined it as a condition that, in the judgement of the attending physician, requires a change in treatment due to worsening of disease activity. Notably, one of these pregnancies introduced tocilizumab during the gestational period. As for the remaining pregnancy with relapses, the PSL dosage of 27.5 mg/day was maintained prior to conception. Despite this, the disease activity deteriorated and persisted until delivery without any alterations in the treatment regimen.

Complications during pregnancy were observed in 20 (30.8%) pregnancies, with hypertension being the most frequent (Table 5). TAK- or its treatment-related complications include severe infections in two pregnancies, and enlargement of an aneurysm was reported in one pregnancy, which might be associated with increased circulating plasma volume. The latter case underwent an aortic arch replacement after delivery. TAK relapse was observed in four (6.2%) and eight (12.3%) pregnancies during pregnancy and after delivery, respectively. The four pregnancies with TAK relapse during gestation were all unplanned pregnancies. Additionally, subclavian artery restenosis developed in one pregnancy, for which a dilatation procedure was performed before the pregnancy.

The outcome of infants born to mothers with TAK

All pregnancies were singleton without congenital malformations. Additionally, 13/62 (20.9%) were preterm infants and 17/59 (28.8%) were low-birth-weight (LBW) infants weighing ≤ 2500 g (5.5 pounds); all but one had a birth weight of >2000 g (4.4 pounds), and none had severe postnatal abnormalities (Table 6). Unplanned pregnancies were not shown to be associated with LBW of the infants. Of the 51 confirmed infants, 42 (82.4%) were breastfed exclusively or mixed with formula.

Discussion

This retrospective study analysed the clinical characteristics and pregnancy and infant outcomes of patients with TAK who continued their pregnancies beyond the second trimester or delivered viable offspring. This study retrospectively examined the clinical characteristics of patients who conceive and deliver although the impact of disease activity and treatment of TAK on fertility cannot be ignored. The disease activity of TAK upon conception was not evaluated, but most of the cases resulted in pregnancy leading to delivery without receiving high-dose PSL, including those with concomitant immunosuppressive agents or biologics as maintenance therapy. In particular, stable disease status of TAK with or without treatment is an acceptable pregnancy condition.

Reports on the fertility of females with TAK are limited [9]. The mechanisms by which systemic vasculitis itself can cause infertility include blood vessel inflammation feeding the reproductive system and autoantibody formation in placental tissue, as demonstrated in polyarteritis nodosa and necrotizing small- and medium-sized vasculitis [10]. The presence of antiendothelial and antiphospholipid antibodies in the serum of patients with TAK has been reported [11], but an association between antiendothelial antibodies and female infertility in TAK is not evidenced. Cyclophosphamide and glucocorticoids (GCs) are the medications affecting ovarian function and infertility. None of the patients in the present study received cyclophosphamide up to conception. GCs can cause hypothalamic–pituitary–gonadal axis dysfunction [12]. This study could not calculate the total dose of GCs up to conception, but the PSL dose as preconception therapy was maintained at a relatively low dose.

Several reports indicate that pregnancy does not significantly affect the inflammatory activity of TAK [13, 14]. The incidence of relapse during pregnancy was relatively low, occurring in only four cases, but one of these cases was characterized by a lack of disease activity control requiring high-dose PSL before pregnancy. Additionally, the 12 cases requiring an increased PSL dose after pregnancy included those who discontinued immunosuppressants or biological agents upon pregnancy, but evidence supporting the necessity of such increases is unclear.

A study by French Takayasu Network revealed a 13-fold increased risk of maternal complications during pregnancy with TAK [15]. A cohort study from India has reported poor pregnancy outcomes in TAK [16]. This is a review of a small number of cases (16 cases, 29 pregnancies), but hypertension was present in all patients, and 11 (64.7%) of them needed >3 antihypertensive drugs. The high proportion of patients with Types IV and V of the Numano classification in India may have caused the high incidence of hypertension as a pregnancy complication [9, 17]. Conversely, several studies from other countries have reported no significant maternal or fetal concerns during pregnancy [18–20].

Our study revealed that 11 of 47 (22.9%) cases were Types III, IV, or V with renal artery involvements. During pregnancy, hypertension, which is the most frequent complication, was observed in 11 cases and 14 (21.5%) pregnancies. Of the six pregnancies with pre-existing hypertension and eight pregnancies with incident hypertension during pregnancy, patients with each of the aforementioned three types accounted for only two and one pregnancy, respectively. These results indicate that renal artery involvement in TAK may not be associated with hypertension during pregnancy. Additionally, of the 14 pregnancies that resulted in hypertension during pregnancy, seven were on GCs, five of which were maintained at 10 mg/day or more as PSL. The disease activity should be stabilized with treatment that does not require moderate to high doses of GCs to prevent complications of gestational hypertension.

The outcomes of infants born to mothers with TAK include intrauterine death, intrauterine growth restriction, preterm infants, LBW, and small for gestational age [9]. The present study reported preterm and LBW infants born in 20.9 and 28.8% of pregnancies, respectively. The Vital Statistics Special Report of the Ministry of Health, Labour and Welfare of Japan reported 3.8 and 4.7% of preterm infants in Fiscal year (FY) 1975 and FY2021, respectively, and 4.6–8.3% frequency of LBW infants from FY1975 to FY2021. Therefore, preterm and LBW are outcomes that should be considered in pregnancies and deliveries of females with TAK.

More than 90% of newborns are breastfed, including mixed nutrition, according to the Infant Nutrition Survey by the Ministry of Health, Labour, and Welfare in Japan since FY1985. Breastfeeding may be limited in cases with unstable disease activity of TAK because breastfeeding consumes maternal energy. This study revealing that >80% of the respondents were able to breastfeed is a gratifying result for females with TAK who wish to breastfeed in the future.

The investigated pregnancy cases beyond the second trimester in this study were largely able to have childbirth without serious complications, and their disease activity was well controlled. The limitation of this study is the inability to assess the causal relationship of LBW to treatment or disease activity and the received medical treatment and the condition of TAK in females who desired pregnancy but were unable to conceive. In this study, planned pregnancies did not affect the LBW of the infants compared to unplanned pregnancies, but they passed without the relapse of TAK during pregnancy. These results indicate that relatively safe pregnancy outcomes are expected if low disease activity is maintained in patients with TAK.

In recent years, guidelines and recommendations for large vasculitis, including TAK, have been developed [21, 22]. Vasculitis is a disease that frequently occurs in females who can give birth, wherein early disappearance of inflammation and maintenance therapy that is not dependent on GCs are believed to contribute to a fulfilling life plan, including childbirth, child-rearing, and work. Advances in TAK treatment are expected to maintain low disease activity and safe delivery in many patients with TAK who wish to conceive.

Acknowledgements

The authors would like to thank Enago (www.enago.jp) for the English language review.

Conflict of interest

T.M., Yu.M., T.S., N.T., Y.A., S.F., H.N., J.I., N.N., T.A., K.K., K.A., Sh.I., R.Y., N.O., S.B., T.N., Sa.I., A.H., S.H., H.A.U., Y.O., Y.K., and Y.N. have no conflicts of interest directly relevant to the content of this article. N.U. has received payments to her institution research grants from Otsuka Pharmaceutical Co., Ltd and consulting fees form Kyowa Kirin Co., Ltd. H.Y. has received grant from GSK. T.K. has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from KISSEI Pharmaceutical CO., LTD and GlaxoSmithKline K.K. Yo.M. has received grants or contracts from any entity from Asahi Kasei Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Kayaku, AbbVie, Eisai Co., Ltd., Astellas Pharma Inc., and Boehringer Ingelheim Japan, Inc. Yo.M. has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AbbVie, Chugai Pharmaceutical, Astellas, Eisai Pharmaceutical, Ayumi Pharmaceutical, UCB Pharmaceutical, Asahi Kasei Pharma, Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Astra Zeneca K. K., GlaxoSmithKline K.K., Mitsubishi Tanabe Pharma Co., Novartis Japan, Pfizer Japan Inc., Nippon Shinyaku Co., Ltd., and Kissei Pharmaceutical Co., Ltd. M.H. has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Novartis Japan, Pfizer Japan Inc. M.H. has received research grants from Chugai Pharmaceutical Co. Ltd, Kissei Pharmaceutical Co. Ltd, and Mitsubishi Tanabe Pharma. M.H. has received consulting fees from Kissei Pharmaceutical Co. Ltd. M.H. has received payment for expert testimony from Chugai Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co. Ltd, and Mitsubishi Tanabe Pharma.

Funding

This work was supported by Ministry of Health, Labour, and Welfare Research on Rare and Intractable Diseases Program Grant Number JPMH23FC1019.

Ethical approval

The ethics committee of Tokyo Women’s Medical University (#4870, #4870R, and #4870-R2) and 18 participating facilities approved this study, and all patients signed written informed consent at the study entry and before the survey.

Author contributions

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. M.H. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Sh.I., N.N., and T.M. contributed to study conception and design. Yu.M., T.S., N.U., H.Y., N.T., Y.A., S.F., H.N., J.I., N.N., T.A., K.K., K.A., T.K., R.Y., N.O., S.B., T.N., Sa.I., A.H., S.H., H.A.U., Y.O., Yo.M., Y.K., and Y.N. contributed to acquisition of data. T.M. and M.H. contributed to analysis and interpretation of data.

References