|Year : 2020 | Volume
| Issue : 1 | Page : 54-59
Successful pregnancy outcome in a multiparous lady with medical myriad-mixed connective tissue disorder, tuberculosis, chronic hypertension and recurrent pregnancy loss
Anjali Tempe, Tanuja Muthyala, Pushpa Mishra, Niharika Dhiman
Department of Obstetrics and Gynaecology, Maulana Azad Medical College, New Delhi, India
|Date of Submission||16-Jul-2019|
|Date of Decision||10-Dec-2019|
|Date of Acceptance||02-Feb-2020|
|Date of Web Publication||30-Apr-2020|
Assistant Professor Tanuja Muthyala
Department of Obstetrics and Gynecology, All India Institute Of Medical Sciences, Mangalagiri 522504, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Autoimmune diseases/mixed connective tissue disorders are chronic and complex group of disorders with multi-systemic involvement. Untreated cases have significant morbidity and poor quality of life. There is a T helper cell paradigm from T helper1 to T helper 2 in pregnancy and autoimmune diseases may flare or improve in pregnancy depending on the type of autoimmune disease and pre-conception disease activity. There is enough evidence to support that individuals affected with autoimmune diseases are susceptible to tuberculosis (TB) infection and conversely auto-antibodies like antinuclear antibody, and rheumatoid factor are detected in sera of patients with active tuberculosis. If this association applies in pregnancy and if immunosuppressive state of pregnancy would further augment this association is not reported. We report a rare case of a 40 year old multigravida with mixed connective tissue disorder (MCTD) with features of systemic lupus erythematosus, deforming rheumatoid arthritis with gangrenous changes and auto-amputation of toes. She had reactivation of TB in the index pregnancy. She was also a chronic hypertensive, hypothyroid and had recurrent pregnancy losses. Index pregnancy was following invitro fertilisation (IVF) conception with donor oocyte and was managed by a multidisciplinary team in obstetric high dependency unit and delivered a healthy baby; both mother and baby were discharged in stable condition. We report this case as there are no reports of MCTD with active TB in pregnancy and to review if pregnancy affects the course of MCTD, TB or association between these two, and management options in such high risk cases.
Keywords: Autoimmune diseases, mixed connective tissue disorder, preeclampsia, rheumatoid arthritis, tuberculosis
|How to cite this article:|
Tempe A, Muthyala T, Mishra P, Dhiman N. Successful pregnancy outcome in a multiparous lady with medical myriad-mixed connective tissue disorder, tuberculosis, chronic hypertension and recurrent pregnancy loss. MAMC J Med Sci 2020;6:54-9
|How to cite this URL:|
Tempe A, Muthyala T, Mishra P, Dhiman N. Successful pregnancy outcome in a multiparous lady with medical myriad-mixed connective tissue disorder, tuberculosis, chronic hypertension and recurrent pregnancy loss. MAMC J Med Sci [serial online] 2020 [cited 2020 May 28];6:54-9. Available from: http://www.mamcjms.in/text.asp?2020/6/1/54/283507
| Introduction|| |
Mixed connective tissue disease (MCTD) is defined as the occurrence of at least two connective tissue diseases (CTD) like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis, polymyositis/dermatomyositis or Sjogren syndrome at same or at different times in the same patient. MCTD affects women of reproductive age group and features non-inflammatory vasculopathy, Raynauds’ phenomenon, digital ulcerations and pulmonary hypertension which may affect pregnancy outcomes. Pregnancy may also affect the course of the disease, there may be improvement, flares or relapses of symptoms. Shared immune reactivity between autoimmune diseases (ADs) and tuberculosis is reported, but literature in pregnancy is scanty. Immune suppressive state of pregnancy can have a deleterious effect on tuberculosis, as it may promote recrudescence or reactivation of latent tuberculosis. We present a case of a 40-year old multigravida with in-vitro fertilization (IVF) conception, MCTD with deforming and debilitating arthritis, gangrenous toes and unable to walk without support. She had reactivation of tuberculosis in third trimester and was started on Antitubercular therapy. Her pregnancy was further complicated by Antiphospholipid Syndrome, Type 4 placenta previa, chronic hypertension and hypothyroidism.
| Case Report|| |
A 40-year old eleventh gravid with previous nine abortions and one normal delivery (G11P1L0A9) was referred to our centre at 35+3 weeks period of gestation for safe confinement. Index pregnancy was by assisted reproduction: IVF conceived (IVF with donor oocyte at another hospital) and was complicated by hypertension, complete placenta previa, and fetal growth restriction (FGR). She was a known case of rheumatoid arthritis [Positive for Rheumatoid Arthritis factor, C-Reactive Protein, Anti CCP (Anti-cyclic citrullinated peptide)] diagnosed 14 years back, subsequently she was tested positive for Antinuclear antibodies (speckled pattern), Anti-ribonucleoproteins and negative for rest of the autoimmune workup. She developed vasculopathy and had Raynauds’ phenomenon, gangrenous followed by auto-amputation of toes 10 years back and was diagnosed to have MCTD. She was prescribed hydroxychloroquine, prednisolone and aspirin which she did not comply with. These medications and low molecular weight heparin were restarted preconceptionally, when she underwent IVF. She was hypertensive from the past 16 years and was on thyroxine 50 μg replacement for hypothyroidism. She received anti-tubercular treatment (ATT) for pulmonary tuberculosis in 1998. The profile of patient is further complex as she also meets clinical (vasculitis) and obstetric criteria [recurrent pregnancy loss (RPL)-nine abortions prior to this pregnancy with fetal cardiac activity documented in four of nine pregnancy losses] for antiphospholipid syndrome. She was advised against pregnancy considering her advanced age, recurrent abortions, multiple comorbidities, deformities that restrain her to bed, but the couple was keen for pregnancy and sought treatment at various IVF centres. Her first child delivered by normal vaginal delivery, expired at 16 years of age due to cerebral malaria. On admission, patient was symptomatic with productive cough, and dyspnoea. She was confined to bed, afebrile, blood pressure (BP) of 130/80 mm of Hg, reduced air entry in right infra-axillary region. Ulnar drift, subluxation of metacarpophalangeal joint and other deformities of rheumatoid arthritis were seen in bilateral hands. Gross appearance and X-rays of hands and legs are shown in [Figure 1]. Residual stumps of left great toe and right second toe are seen to be healthy. There were no cutaneous findings.
|Figure 1 (A) Characteristic rheumatoid hands in the patient. (B) Legs with amputated toes,residual stumps. (C) Rheumatoid Hands and legs (D) X Ray hand: suggesting marked periarticular osteopenia, ulnar deviation of metacarpo phalangeal joints, subluxation at metacarpo-phalangeal joints (more marked at left hand).Boutenniere deformity of bilateral thumb. (E) X Ray feet: Distal phalanges of 2nd digit of right foot and phalanges of left foot are not visualised|
Click here to view
On obstetric examination, uterine size was corresponding to 30 weeks with single live fetus in transverse lie. Aneuploidy screen at 16 weeks reported increased risk for Down’s syndrome, but couple deferred invasive fetal testing. Anamoly scan and fetal echocardiogram were normal. Ultrasound at 35 weeks detected fetal growth restriction (FGR) and type 4 placenta praevia. MRI pelvis was performed and adherent placenta was ruled out. Her laboratory reports suggested: moderate anaemia, erythrocyte sedimentation rate of 90 mm, normal biochemistry reports, Urine routine microscopic examination was suggestive of nephritis without active disease, 24 hour Urinary protein excretion was 630 mg/dl. Chest x-ray with abdominal shield was suggestive of right sided pleural effusion. Diagnosis of extra-pulmonary tuberculosis was made after pleural fluid analysis [cartridge based nucleic amplification test (CB NAAT)-Negative, adenosine deaminase (ADA)-79.6U/L, Cytology-Slightly yellow, slightly opaque, total leucocyte count (TLC)-900 cells/ul, predominant lymphocytic, RBC-present; two sputum samples for AFB were negative] and started on ATT-HRZE (anti tubercular therapy) category II by withholding streptomycin. Patient symptoms improved one week after starting ATT. On autoimmune workup, she was positive for anti nuclear antibody (ANA), Anti ribonuclear protein (RNP) and negative for Anti ds DNA and other markers, suggesting patient did not have flare. Maternal 2D echocardiography (ECHO) was suggestive of mild concentric left ventricular hypertrophy, grade I Diastolic dysfunction, and no pulmonary arterial hypertension. These changes may be secondary to chronic hypertension or autoimmune myocarditis, for which cardiologist advised supportive management and control of hypertension.
Low molecular weight heparin (LMWH), aspirin and hydroxychloroquine (HCQ) and prednisolone were continued after referral with rheumatologist. She had high BP records for which antihypertensive medication, labetalol 100 mg as thrice daily dosage was started. Biophysical profile and Doppler study was performed biweekly for fetal surveillance. Elective caesarean section was performed at 37+2 weeks for placenta previa and male child of 1559 g was born. Injection streptomycin was started post-delivery. Baby was admitted in neonatal ICU in view of low birth weight. Her post-operative period was uneventful without flare. In post-operative period, USG Doppler of all the four limbs suggested absent flow in left posterior tibial artery and normal flow pattern in others. CT Angiography of aorta and lower limbs suggested poor opacification of distal right anterior tibial artery, rest had normal flow pattern as shown in [Figure 2]. Rheumatologist advised to continue aspirin, LMWH and HCQ and planned for methotrexate therapy after cessation of breast feeding. Mother and baby were discharged on tenth postoperative day.
|Figure 2 Computerised tomography angiography of aorta and lower limb: Poor opacification of distal right anterior tibial artery|
Click here to view
| Discussion|| |
The incidence of MCTD is around 3.1 per 100,000 population and female to male ratio in incidence is 5:1. Pregnancy in women with MCTD can have major medical and obstetric complications, and active disease augments the risk. The relapse rate in pregnancy is comparable to that of other autoimmune diseases, and if relapses, it can have serious complications like Pulmonary arterial hypertension, interstitial lung disease or renal dysfunction. Maternal risks include high probability of abortion, preeclampsia, cesarean section, thromboembolism and death. The offspring has risks like Neonatal Lupus, prematurity, FGR, congenital heart block and death. Proper disease control can reduce some of these risks. Hydroxychloroquine, steroids, Azathioprine can be given in pregnancy. MCTD is a stable disease with milder course than SLE or systemic sclerosis.
In a retrospective study by Lundberg, among 40 pregnancies in 20 women with MCTD, there was only a slight increased risk of fetal loss or exacerbation of maternal disease. In a recent study by Marie-Lou Tardif, around 25% patients relapsed, 20% developed preeclampsia, 2.5% had thromboembolic events and death occurred in 2.5%. Prematurity was seen in around 50%, FGR in 40% and neonatal lupus in 28%. In women with active disease, prematurity and perinatal death rates were high. In a similar study by Massimo Radin et al, live birth rate was 72% and the cohort with MCTD and antiphospholipid antibodies, pulmonary or muscular involvement had poor perinatal outcomes. Review of reports of pregnancies with MCTD and their outcomes, reported after year 2000 are shown in [Table 1].
The association of MCTD and autoimmune diseases with tuberculosis is that, there are several documented reports about the onset or detection of SLE after tuberculosis infection. Auto-antibodies like antinuclear antibody and rheumatoid factor (RF) are detected in patients with active tuberculosis due to molecular mimicry between mycobacterium and self antigens. Other plausible mechanisms for association of tuberculosis and SLE is mediated via heat-shock proteins (HSP) and deficiency of vitamin D. Various reports on shared immune reactivity between human antigens and mycobacterium suggest that ADs course may precede tuberculosis, especially in tuberculosis endemic regions like India. MCTD/ADs require treatment with steroids cytotoxic drugs. Inherent primary defects in the innate immunity also may predispose to infections, thus women with CTD are at increased risk for infections including Mycobacterium tuberculosis. There are multiple reports of tuberculosis infection during lupus flares. Pregnancy is a state of immunodeficiency with significant changes in cellular and humoral immunity, which may augment the risk of activation of latent tubercular bacilli in the potentially predisposed individuals like those with autoimmune diseases. This is only a hypothesis and is to be confirmed from studies in a larger population. Our patient with MCTD had a recurrence of tuberculosis in index pregnancy. She had deforming rheumatoid arthritis with loss of most of the toes, erosive arthritis of multiple joints that she could not walk without support.
Thrombosis of Arterial or venous systems characterizes the thromboembolic antiphospholipid syndrome (APS) [throboebolic (TE)-APS] and recurrent pregnancy loss for obstetric APS (O-APS). Our patient has both features of TE and O-APS, but negative for APS antibodies. APS occurring in association with CTD has a worse pregnancy outcome with an increased risk of preterm births, FGR, perinatal death than patients with CTD alone.
Yamaguchi described preeclampsia in MCTD may be secondary to glomerular vasculopathy, like arteriolosclerosis and thickening of intima. PE incidence is further high (up to 40%) with pre-existing renal involvement. Placentas examined after delivery in these women had multiple infarcts.
For optimal pregnancy outcome: (i) the prophylactic therapy with low dose aspirin preconceptionally if not started for MCTD and LMWH once fetal cardiac activity is detected; (ii) strict clinical, laboratory and ultrasound for fetal surveillance along with multidisciplinary management for early recognition of disease flare, preeclampsia, FGR. LMWH regulates activation of the counter-receptors for P-selectin on circulating white blood corpuscles and modulates complement system activation.
Preconceptional counselling and management offers best perinatal outcomes. Preconceptional counseling should ensure conception during disease remission (>6 months), discontinue cytotoxic medications, review medications by rheumatologist to lowest possible dose without compromising the efficacy. Laboratory evaluation of markers for disease activity in early pregnancy, serial monthly monitoring of Complete blood cell count, ESR, Biochemistry profile, urinalysis with microscopic examination and antibody assays if features of flare are present.
Contraindications to pregnancy in MCTD include: Severe primary pulmonary hypertension /severe restrictive lung disease, severe Renal disease (Serum creatinine level >2.8 mg/dL), Heart failure or Eisenmenger syndrome, Stroke or severe disease or flare within the last 6 months. Mode of delivery has to be individualized as per obstetric indications. Postpartum relapses are common both for MCTD and tuberculosis, therefore continuous surveillance on monthly or every 2 months is required. Avoid bbreastfeeding if mother requires cytotoxic drugs. For birth spacing, barrier contraception or intrauterine contraceptive devices can be given.
| Conclusion|| |
Pregnancy outcome in patients with MCTD is usually favourable provided patient is in remission, on regular treatment, with no organ involvement and is managed by a multidisciplinary team of Obstetrician, Rheumatologist and perinatologist at a tertiary care centre.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
We are indebted to Dr Anjali Tempe is the first author for excellent care of this patient and for critical review of the manuscript.
Financial support and sponsorship
There are no funding agents.
Conflicts of interest
The authors declare that there is no conflict of interest.
| References|| |
Sharp GC, Irvin WS, Tan EM, Gould RG, Holman HR. Mixed connective tissue disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable Nuclear antigen (ENA). Am J Med 1972;52:148-59.
Ribeiro FM, Szyper-Kravitz M, Klumb EM, Lannes G, Ribeiro FRE, Albuquerque EMM et al.
Can lupus flares be associated with tuberculosis infection? Clinic Rev Allerg Immunol 2010;38:163-8.
Loto OM, Awowole I. Tuberculosis in pregnancy: a review. Journal of Pregnancy 2012;2090-727.
Ungprasert P, Crowson CS, Chowdhary VR, Ernste FC, Moder KG, Matteson EL. Epidemiology of mixed connective tissue disease, 1985-2014: a population-based study. Arthritis Care Res (Hoboken) 2016;68:1843-8.
Reiseter S, Gunnarsson R, Corander J, Haydon J, Lund MB, Aaløkken TM et al.
Disease evolution in mixed connective tissue disease: results from a long-term nationwide prospective cohort study. Arthritis Res Ther 2017;19:284.
Lundberg I, Hedfors E. Pregnancy outcome in patients with high titer anti-RNP antibodies. A retrospective study of 40 pregnancies. J Rheumatol 1991;18:359-62.
Tardif ML, Mahone M. Mixed connective tissue disease in pregnancy: a case series and systematic literature review. Obstetric Medicine 2018;0:1-7.
Radin R, Schreiber K, Cuadrado MJ, Cecchi1 I, Andreoli L, Franceschini F et al.
Pregnancy outcomes in mixed connective tissue disease: a multicentre study. 2019; doi:10.1093/rheumatology/kez141.2019
Antovic A, Sennström M, Bremme K, Svenungsson E. Obstetric antiphospholipid syndrome. Lupus Sci Med 2018;5:e000197.
Yamaguchi T, Ohshima S, Tanaka T, Tsukada S, Matsushita M, Kohmo S et al.
Renal crisis due to intimal hyperplasia in a patient with mixed connective tissue disease (MCTD) accompanied by pulmonary hypertension. Intern Med 2001;40:1250-3.
Kitridou RC. Pregnancy in mixed connective tissue disease. Rheum Dis Clin North Am 2005;31:497-508.
Sliwa K, van Hagen IM, Budts W, Swan L, Sinagra G, Caruana M et al.
Pulmonary hypertension and pregnancy outcomes: data from the Registry Of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology. Eur J Heart Fail 2016;18:1119-28.
Aoki S, Tada Y, Ohta A, Koarada S, Ushiyama O, Suzuki N et al.
Autoimmune hepatitis associated with mixed connective tissue disease: report of a case and a review of the literature. Nihon Rinsho Meneki Gakkai Kaishi 2001;24:75.
Horita Y, Tsunoda S, Inenaga T, Kawano Y, Ishibashi-Ueda H, Chiba Y et al.
Pregnancy outcome in nephrotic syndrome with mixed connective tissue disease. Nephron 2001;89:354-6.
Cimaz R, Spence DL, Hornberger L, Silverman ED. Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies. J Pediatr 2003;142:678-83.
Fujiwaki T, Urashima R, Urushidani Y, Takahashi T, Ishioka C. Neonatal lupus erythematosus associated with maternal mixed connective tissue disease. Pediatr Int 2003;45:210-3.
Chung L, Flyckt R, Colon I, Shah AA, Druzin M, Chakravarty EF. Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease. Lupus 2006;15:595-9.
Chitayat D, Keating S, Zand DJ, Costa T, Zackai EH, Silverman E et al.
Chondrodysplasia punctata associated with maternal autoimmune diseases: Expanding the spectrum from systemic lupus erythematosus (SLE) to mixed connective tissue disease (MCTD) and scleroderma report of eight cases. Am J Med Genet 2008;146:3038-53.
Hoshino T, Kita M, Takahashi T, Nishimura T, Yamakawa M. Management of two pregnancies ina woman with mixed connective tissue disease, pulmonary fibrosis, frequent pneumothorax and oxygen inhalation therapy along with a published work review. J Obstet Gynaecol Res 2008;34:613-8.
Hasmuller S, Ehrhardt H, Kahlert S, Möller R, Friese K, Hasbargen U et al.
Peripartum bilateral uterine rupture in a patient with mixed connective tissue disease with favorable outcome for the severely asphyctic newborn after hypothermia. Arch Gynecol Obstet 2010;281:617621.
[Figure 1], [Figure 2]