To discuss how pregnancy affects SLE in increasing lupus flare rates To discuss the effects of SLE on maternal and

d fetal outcome in pregnancy To discuss management of Lupus flare in pregnancy To discuss ethical issues on the case

K. G. 18/F Makati City CC: bipedal edema DOA: 3/18/08

Diagnosed case of Systemic Lupus Erythematosus since Aug. 2007

1997 Revised Classification Criteria for Systemic Lupus Erythematosus [1] Target Organ Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Target Organ Neurologic disorder Hematologic disorder Immunologic disorder Antinuclear antibody

Kliegman, Robert, M.D., et al. Nelsons Textbook of Pediatrics. 18th ed. USA: Sanders, 2007, pp. 1015-191

1 yr PTA 9 mo PTA

(+) alopecia, (+) malar rash (+) fever, (+) discoid rash, (+) oral ulcers (+) R eyelid swelling (+) joint pain and swelling of hands RHEUMA CLINIC A> SLE Labs: ANA (+4) homogenous 1:80 leukopenia (3,800), anemia (10), lymphopenia (ALC 0.934) BUN 2.3 mol/L (N), Crea (N), Proteinuria(++), RBC 0-1

9 mo PTA

(+) fever (+) discoid rash (+) oral ulcers (+) R eyelid swelling (+) joint pain and swelling of hands Consult at PGH OPD Rheuma

2 mo PTA

1 wk PTA

4 d PTA

Pregnant discontinued Prednisone No consult done (+) persistence of cough (+) bipedal and periorbital edema (+) persistence of edema (+) 2 pillow orthopnea (-) PND, palpitations, chest pain

A> SLE Labs: ANA (+4) homogenous 1:80 leukopenia (3,800) , anemia (10), lymphopenia (ALC 0.934) BUN 2.3 mol/L (N), Crea (N) Proteinuria (++), RBC 0-1

7 mo PTA

5 mo PTA

Prednisone (1 mkd) (-) alopecia, oral ulcers, eyelid swelling, malar rash arthritis (-) proteinuria Prednisone tapered Lost to follow-up but asymptomatic

2 mo PTA

2 wks PTA

Pregnant discontinued Prednisone No consult done (+) fever (+) cough (-) dyspnea Meds: Paracetamol Bromhexine syrup

1 wk PTA

(+) persistence of cough (+) bipedal and periorbital edema (+) persistence of edema (+) 2 pillow orthopnea (-) PND, palpitations, chest pain

4 d PTA

2 d PTA

(+) easy fatigability (+) difficulty of breathing (+) vomiting (+) epigastric pain (+) diarrhea (+) tea-colored urine (+) oliguria Rheuma clinic consult PAY

General: (-) generalized weakness, (-) weight loss, (-) anorexia Neurologic: (-) seizure, (-) headache, (-) change in sensorium, (-) change in behavior HEENT: (-) eye pain, blurring of vision, (-) sore throat Hematologic: (-) epistaxis, (-) hematemesis, (-) hematochezia, (-) hemoptysis, (-) easy bruisability, (-) increased bleeding, Dermatologic: (-) active skin lesions

No intake of other Meds except Prednisone (+) similar illness grandmother, paternal side noncontributory Completed at Local health center Unremarkable

Family History

Birth/Maternal History

Immunization History

Nutritional History

(-) other illness (-) hospitalization (-) allergy (-) accidents Medications: no intake of Sulfonamide, Minocycline, anti-TNF biologics, Thiazides, Ca channel blockers, ACEI, MV, FeSO4 and Folic acid

(+) HPN, CA grandmother, paternal side (+) kidney disease maternal side (+) similar illness grandmother, paternal side (-) DM, BA, PTB, CA, liver disease

Full term via spontaneous vaginal delivery to a then 25 y/o G2P1 (1001) mother at a lying in clinic c/o midwife. Regular prenatal check-up, (-) fetomaternal illness, (-) birth complications good cry and good activity

(+) BCG (+) OPV 3 doses (+) DPT 3 doses (+) Hepa B 3 doses (+) measles

Developmental History

At par with age

Obstetrics/Menstrual History
G1P0, (+) pregnancy test in February, (+) spotting in February, (-) vaginal discharge LMP: Dec 3, 2007, 30 days interval, 4 days duration, 3 pads/day, (+) dysmenorrhea

Personal/Social History

2nd child from a brood of 9 Mother is a 39 y/o,housewife. Father is 45 y/o, nurse at PGH PICU.

breastfed for 6 months shifted to formula milk eats regular table food

at par with age 1st year college student, taking up BS Psychology.

2nd child from a brood of 9 Mother is a 39 y/o,housewife. Father is 45 y/o, nurse at PGH PICU.

Home
living with parents and siblings good relationship with them (closest to her

older sister)

Education
incoming 1st year college student, taking up

BS Psychology She didnt finished first year due to her illness plans to finish her study and work to help her parents

Education
incoming 1st year college student, taking up

BS Psychology She didnt finished first year due to her illness plans to finish her study and work to help her parents.

Activity
hangs out with friends in the mall or in their

house, go out preferably at night love to talk about gossips

Drugs
Denies illicit drug use occasional beverage drinker doesnt smoke

Drugs
Denies illicit drug use occasional beverage drinker doesnt smoke

Sex
one relationship and sexually active, with a 15 y/o guy, who is also the father of her present pregnancy Her boyfriend impregnated another woman prior to her no plans of getting married now

Suicidal ideations
when scolded by parents felt very sad when she was diagnosed with SLE

Suicidal ideations
when scolded by parents felt very sad when she was diagnosed with

SLE

G1P0, (+) pregnancy test in February, (+) spotting in February, (-) vaginal discharge LMP: Dec 3, 2007, 30 days interval, 4 days duration, 3 pads/day, (+) dysmenorrhea

General exam: conscious, coherent, not in cardiorespiratory distress Vital signs: BP 140/80, PR 110, RR 24, T 38C, wt 47 kg, ht 151 cm HEENT: slightly pale conjunctivae, anicteric sclera, (+) periorbital edema, bilateral (-) cervical lymphadenopathy, (-) anterior neck mass, (-)neck vein engorgement, (-) tonsillopharyngeal congestion

Chest and Lungs: Equal chest expansion, no retractions, (+) clear breath sounds, (-) crackles/wheeze Cardiovascular: adynamic precordium, distinct HS, tachycardic, normal regular rhythm, AB at 5th LICS MCL, (-) murmur Abdomen: globular abdomen, (+) NABS, soft, (+) epigastric tenderness, (-) organomegaly, abdominal girth = 76 cm, fundic height = 20 cm, fetal heart tone not appreciated by stethoscope

Internal examination: (+) vulvar edema, nulliparous vagina, corpus enlarged to AOG, cervix soft closed, (-) abnormal discharge or masses Extremities: Pink nailbeds, FEP, (-) cyanosis, (+) bipedal edema, pitting, grade 1 External genitalia: grossly female, SMR 4 Skin: (-) active dermatoses Neurologic exam: essentially normal

Conscious, coherent Oriented to time, place and person (-) anosmia, visual acuity 20/20 OU, pupils 2-3 mm EBRTL, EOMS full and equal, (+) corneal, (-) facial asymmetry, (-) gross hearing loss, (+) gag reflex, (+) good shoulder shrug, (+) tongue midline Motor: 5/5 on all extremities Sensory: (-) sensory deficit DTR: (++) on all extremities (-) Babinski Cerebellar: (-) nystagmus (-) nuchal rigidity

RHEUMA CLINIC
periorbital and bipedal edema easy fatigability difficulty of breathing vomiting epigastric pain diarrhea tea-colored urine oliguria

PAYWARD
Serositis (pericarditis)

Renal involvement (lupus nephritis, hypertension, renal failure, nephrotic syndrome) Anemia (normochromic, normocytic)

SLE in activity Pregnancy Uterine 17 2/7 weeks by early UTZ, NIL UTI

1. 2.

3. 4.

Pregnancy SLE Nephritis, Hypertension Pericarditis Anemia Pulmonary edema, noncardiogenic Pleural Effusion, B Infection

S Amenorrhea LMP: Dec 3, 2007 Sexual intercourse

O Pregnancy Test (+) UTZ: Pregnancy Uterine 17 2/7 weeks, good cardiiac and somatic acrtivities

A Pregnancy Uterine 17 2/7 weeks by early UTZ, NIL t/c APAS

P For APAS Serial Fetal biometry Aspirin FeSO4, CaCO3, MgSO4, Folic acid, MV

S Edema Hematuia

O BP 140/80 on admission, BP spikes of 160/100) Proteinuria on urinalysis and 24 hr urine collection (+) fine, coarse, waxy casts Raised creatinine

A Lupus Nephritis Hypertension

P For Biopsy Albumin transfusion Prednisone and Azathioprine MPPT Multidrug antiHPN

S Easy fatigability Difficulty of breathing

P Serial 2D Echo MPPT

(-) signs of Lupus cardiac Pericarditis tamponade CXR: cardiomegaly 2D echo : mod pericardial effusion, RA and RV wall collapse, fair LV systolic function

S Slightly pale conjunctivae

O On admission, Hgb = 82 mg/dl At PICU, Hgb = 54 mg/dl Retic index 0.05 Direct and Indirect Coombs (-)

A Anemia of chronic disease

P BT of PRBC

S Dyspneic Sitting position Blood-tinged sputum

O Moderate cardiorespiratory distress ABG metabolic acidosis CXR: Bilateral pleural effusion Inhomogenous opacities BLF Pulmonary infiltrates hypoalbumine mia

A Pulmonary edema Pleural Effusion, Bilateral

P Transferred to PICU O2 support Furosemide

O UTI

P Cefuroxime Ceftazidime

1. On admission U/A: pyuria 2. At PICU Blood CS: NG5d Urine CS: Micrococcus luteus U/A: pyuria

Nosocomial sepsis

Ward stay 17 days PICU stay 10 days Discharged on April 15, 2008
Home Meds x Prednisone x Aspirin x Azathioprine x Nifedipine x Methyldopa x Hydralazine x Multivitamins x Folic acid x MgSO4 x Fe

Among retrospective and prospective studies [2]

Lupus flare rates ranges from approximately

20% 60%

Lupus that is active at the onset of pregnancy is activated further during pregnancy

2 Singh, Ajay K. Lupus nephritis and anti-phospholipid activity syndrome in pregnancy. Kidney International. Vol 58. (2000), pp 2240-2254.

Manifestations

No. of Flares (% Total) 27 (69%) 13 (33%) 4 (10%) 4 (10%) 1 (3%) 3 (8%) 1 (3%) 1 (3%)

1st Trimester 3 3 0 0 0 0 0 0

2nd 3rd Postpartum Trimester Trimester 8 2 0 1 1 0 0 0 3 2 0 0 0 1 0 0 13 6 4 3 0 2 1 1

Arthritis Skin lesions Hemolytic anemia LN Thrombocytopenia Fever Hepatitis Serositis

a Some

patients experienced multiple organ involvement during the same flare.

3 Cortez-Hernandez, J., et al. Clinical Predictors of Fetal and Maternal Outcome in Systemic Lupus Erythematosus, a Prospective Study. Rheumatology. 2002; 41: 643-50.

Prednisone (1-2 mg/kg/day) drug of choice for most SLE manifestation Methylprednisone pulse 1g/day fowllowed by oral Prednisone at 0.5-1.0 mg/kg/day severe systemic disease Azathioprine (2 mg/kg/day) for initial mild flare Stress doses of Hydrocortisone for emergency surgery, cesarean section, prolonged labor and delivery

5 Obstetric Emergencies: Management of Lupus Flare. www.obgmanagement.com. May 2006.

Table 2. Evidence for adverse effects of immunosuppressant used in pregnancy and breastfeeding[6]
Whether drug can be used Drug
Hydroxychloroquine/ Chloroquine

Evidence
No increased risk of miscarriage, congenital malformation, stillbirth at doses 200-400 mg/day Cessation increase risk of flare Long half life means stopping does not prevent fetal exposure Metabolized by placenta In high doses have caused cleft palate in experimental animal models and low birth weight in humans Fetus lacks enzyme to convert to active form Fetal and neonatal immunosuppression minimal if dose is <2 mg/kg and maternal white cell count is normal No increase in congenital malformation Prematurity and IUGR trends not significant Small amounts in breastmilk but no adverse effects noted No increase in congenital malformation Increased rates of prematurity related to maternal disease In one case report, a baby received 0.02% of maternal dose via breastmilk Cross the placenta after 32 weeks but with no adverse effects to fetus Increased risk of congenital abnormalities Enterohepatic recirculation Long half life Alkylating agent Teratogenic, fetotoxic Risk of suppression of neonatal hematopoiesis Folate antagonist Teratogenic and Fetotoxic Congenital abnormality in animal studies Human studies limited Long half life of active metabolites Limited experience in human pregnancies but no adverse fetal or neonatal outcomes to date

In pregnancy
Y

In breastfeeding
Y

Prednisone/ Methylprednisone Azathioprine

Ciclosporin

Tacrolimus

If benefits outweigh potential risks Y with caution Y N

IVIG Mycophenolate mofetil

Y N (stop 6 weeks before conception) N (stop 3 months before conception) N (stop 3 months before conception and give Folic acid 5 mg daily) N (use cholestyramine to increase clearance preconception) Limit to severe disease

Cyclophosphamide

Methotrexate

Leflunomide

Biologic agents Etanercept, Infliximab, Adaluminab, Rituximab

Probably avoid

6 Mackillop, Lucy H., et al. Pregnancy plus Systemic Lupus Erythematosus. BMJ.2007; 335: 93336.

Whether drug can be used Drug Prednisone/ Methylprednisone Evidence

Metabolized by placenta In high doses have caused cleft palate in experimental animal models and low birth weight in humans Fetus lacks enzyme to convert to active form Fetal and neonatal immunosuppression minimal if dose is <2 mg/kg and maternal white cell count is normal

In pregnancy Y

In breastfeeding Y

Azathioprine

6 Mackillop, Lucy H., et al. Pregnancy plus Systemic Lupus Erythematosus. BMJ.2007; 335: 93336.

Rule: To treat the lupus flare before irreparable maternal harm occurs Use of other new line immunosuppressive drugs

Benefits must be outweighed by potential

risks

No conclusive data suggest pregnancy termination will ameliorate lupus flare.

5 Obstetric Emergencies: Management of Lupus Flare. www.obgmanagement.com. May 2006.

counseled on appropriate timing of planned pregnancy

remission of at least 6 months and preferably more

than 12 months and minimal or no need of immunosuppressives

Risks to patient and fetus are discussed in detail The following baseline investigations are obtained at the start

CBC Urea, creatinine, electrolytes Liver function tests ANA, anti dsDNA, aPL, anti-Ro/anti-La

Mackillop, Lucy H., et al. Pregnancy plus Systemic Lupus Erythematosus. BMJ.2007; 335: 93336.

follow-up frequency is dependent on disease activity hydroxychloroquine is given to prevent flares Low dose aspirin is administered to prevent preeclampsia If APLS positive or history of thrombosis or fetal loss, treatment with heparin or LMWH and low dose aspirin

Mackillop, Lucy H., et al. Pregnancy plus Systemic Lupus Erythematosus. BMJ.2007; 335: 93336.

fetus is regularly monitored by obstetrician using Doppler UTZ

20 weeks, a detailed morphology scan is

done Regular growth scans at 28, 32 and 36 weeks is done If with anti-Ro and anti-La, fetal heart pulsed Doppler echocardiography at 18 weeks and 3rd trimester

Delivery method and timing depends on obstetric indications

Mackillop, Lucy H., et al. Pregnancy plus Systemic Lupus Erythematosus. BMJ.2007; 335: 93336.

Nutrition management
Megavitamin therapy adequate dietary intake Breastfeeding is contraindicated when

taking the following drugs: mycophenolate, cyclophosphamide, methotrexate and leflunomide Breastfeeding is appropriate if the maternal dose of prednisone is <30 mg/d, to take her medications just after breast-feeding
Ferris, Ann M., et al. Nutritional consequences of chronic maternal conditions during pregnancy and lactation: lupus and diabetes. American Journal of Clinical Nutrition. 1994; 59 (suppl): 465S-73S.

Spontaneous abortion Preeclampsia IUGR Fetal death rate Preterm delivery

Thromboembolism Lupus nephritis Renal failure Antiphospholipid syndrome Active disease at conception First presentation of SLE at pregnancy

7 Molad, Yair. Sytemic Lupus in Pregnancy. Current Opinion in Obstetrics and Gynecology.2006; 18: 613-617.

Mortality Full term delivery Preterm delivery Abortion Total 2 (5%) 12 (28%) 8 (19%) 22 (52%)

Survival #% 16 (38%) 4 (10%) 0 20 (48%)

Total 18 (43%) 16 (38%) 8 (19%)

8 Valdez, Corazon, et al. Systemic Lupus Erythematosus in Pregnancy: a 23-year review. Acta Medica Philippina

Table 5. Diagnostic criteria for the antiphospholipid syndrome Antiphospholipid antibodies plus at least one of the following: y Arterial or venous thrombosis y Three or more miscarriages (at <10 weeks gestation) y Fetal death (at >10 weeks gestation with normal fetal morphology)

Prevalence = 37% In the Fetus

fetal death (early or late), intrauterine growth

retardation, premature delivery and dysmaturity.

In pregnant women
repeated abortions , risk of unexpected intrauterine

deaths, venous/arterial thrombosis, thrombocytopenia, pregnancy-induced hypertension, chorea, multi-system organ failure and post-natal depression

Singh, Ajay K. Lupus nephritis and anti-phospholipid activity syndrome in pregnancy. Kidney International. Vol 58. (2000), pp 2240-2254.

generalized photosensitive rash thrombocytopenia and anemia giant cell hepatitis with severe cholestasis isolated complete heart block or cardiomyopathy If the fetus has an abnormal echocardiogram (dexamethasone and plasmapharesis have been suggested

Singh, Ajay K. Lupus nephritis and anti-phospholipid activity syndrome in pregnancy. Kidney International. Vol 58. (2000), pp 2240-2254.

On regular follow up to Rheuma, Renal, Perinatology Maintained on Prednisone, Azathioprine, Aspirin, megavitamin Controlled hypertension Normal fetus on serial scans EDC: Aug. 26, 2008the Awaiting APAS Father is alienating the patient.

Whether pregnancy does exacerbate SLE is a controversial issue. Women with SLE can have successful pregnancies. In the care of lupus pregnant patient, the most diffiucult dilemma is saving both the mother and the unborn child.