2.  To discuss how pregnancy affects SLE in increasing lupus flare rates  To discuss the effects of SLE on maternal and fetal outcome in pregnancy  To discuss management of Lupus flare in pregnancy  To discuss ethical issues on the case

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

5. Target Organ Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Target Organ Neurologic disorder Hematologic disorder Immunologic disorder Antinuclear antibody Diagnosed case of Systemic Lupus Erythematosus since Aug. 2007 1997 Revised Classification Criteria for Systemic Lupus Erythematosus [1] 1 Kliegman, Robert, M.D., et al. Nelson’s Textbook of Pediatrics. 18 th ed. USA: Sanders, 2007, pp. 1015-191

6. 1 yr PTA (+) alopecia, (+) malar rash 9 mo PTA (+) 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

7. 9 mo PTA (+) fever (+) discoid rash (+) oral ulcers (+) R eyelid swelling (+) joint pain and swelling of hands Consult at PGH OPD Rheuma

8. 2 mo PTA Pregnant discontinued Prednisone No consult done 1 wk PTA (+) persistence of cough (+) bipedal and periorbital edema 4 d PTA (+) persistence of edema (+) 2 pillow orthopnea (-) PND, palpitations, chest pain

9. 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

10. Prednisone (1 mkd) 7 mo PTA (-) alopecia, oral ulcers, eyelid swelling, malar rash arthritis (-) proteinuria Prednisone tapered 5 mo PTA Lost to follow-up but asymptomatic

11. 2 mo PTA Pregnant discontinued Prednisone No consult done 2 wks PTA (+) fever (+) cough (-) dyspnea Meds: Paracetamol Bromhexine syrup

12. 1 wk PTA (+) persistence of cough (+) bipedal and periorbital edema 4 d PTA (+) persistence of edema (+) 2 pillow orthopnea (-) PND, palpitations, chest pain

13. 2 d PTA (+) easy fatigability (+) difficulty of breathing (+) vomiting (+) epigastric pain (+) diarrhea (+) tea-colored urine (+) oliguria Rheuma clinic consult PAY

14.  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

15.  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

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

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

18.  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

19.  (+) BCG  (+) OPV – 3 doses  (+) DPT – 3 doses  (+) Hepa B – 3 doses  (+) measles

20.  At par with age  G1P0, (+) pregnancy test in February,  (+) spotting in February, (-) vaginal discharge  LMP: Dec 3, 2007, 30 days interval, 4 days duration, 3 pads/day, (+) dysmenorrhea  2 nd child from a brood of 9  Mother is a 39 y/o,housewife.  Father is 45 y/o, nurse at PGH PICU. Developmental History Personal/Social History Obstetrics/Menstrual History

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

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

23.  2 nd child from a brood of 9  Mother is a 39 y/o,housewife.  Father is 45 y/o, nurse at PGH PICU.

24.  Home › living with parents and siblings › good relationship with them (closest to her older sister)  Education › incoming 1 st year college student, taking up BS Psychology › She didn’t finished first year due to her illness › plans to finish her study and work to help her parents

25.  Education › incoming 1 st year college student, taking up BS Psychology › She didn’t finished first year due to her illness › plans to finish her study and work to help her parents.

26.  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 › doesn’t smoke

27.  Drugs › Denies illicit drug use › occasional beverage drinker › doesn’t smoke

28.  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

29.  Suicidal ideations › when scolded by parents › felt very sad when she was diagnosed with SLE

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

31.  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

32.  Chest and Lungs: Equal chest expansion, no retractions, (+) clear breath sounds, (-) crackles/wheeze  Cardiovascular: adynamic precordium, distinct HS, tachycardic, normal regular rhythm, AB at 5 th 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

33.  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

34.  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

35. 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)

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

37. 1. Pregnancy 2. SLE Nephritis, Hypertension Pericarditis Anemia 3. Pulmonary edema, noncardiogenic Pleural Effusion, B 4. Infection

38. SOAP Amenorrhea LMP: Dec 3, 2007 Sexual intercourse Pregnancy Test (+) UTZ: Pregnancy Uterine 17 2/7 weeks, good cardiiac and somatic acrtivities Pregnancy Uterine 17 2/7 weeks by early UTZ, NIL t/c APAS For APAS Serial Fetal biometry Aspirin FeSO4, CaCO3, MgSO4, Folic acid, MV

39. SOAP Edema Hematuia BP 140/80 on admission, BP spikes of 160/100) Proteinuria on urinalysis and 24 hr urine collection (+) fine, coarse, waxy casts Raised creatinine Lupus Nephritis Hypertension For Biopsy Albumin transfusion Prednisone and Azathioprine MPPT Multidrug anti- HPN

40. SOAP Easy fatigability Difficulty of breathing (-) signs of cardiac tamponade CXR: cardiomegaly 2D echo : mod pericardial effusion, RA and RV wall collapse, fair LV systolic function Lupus Pericarditis Serial 2D Echo MPPT

41. SOAP Slightly pale conjunctivae On admission, Hgb = 82 mg/dl At PICU, Hgb = 54 mg/dl Retic index 0.05 Direct and Indirect Coomb’s (-) Anemia of chronic disease BT of PRBC

42. SOAP Dyspneic Sitting position Blood-tinged sputum Moderate cardiorespiratory distress ABG metabolic acidosis CXR: Bilateral pleural effusion Inhomogenous opacities BLF Pulmonary infiltrates hypoalbumine mia Pulmonary edema Pleural Effusion, Bilateral Transferred to PICU O2 support Furosemide

43. SOAP 1.On admission 2.At PICU U/A: pyuria Blood CS: NG5d Urine CS: Micrococcus luteus U/A: pyuria UTI Nosocomial sepsis Cefuroxime Ceftazidime

44.  Ward stay – 17 days  PICU stay – 10 days  Discharged – on April 15, 2008 › Home Meds  Prednisone  Aspirin  Azathioprine  Nifedipine  Methyldopa  Hydralazine  Multivitamins  Folic acid  MgSO4  Fe

45.  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.

46. Manifestations No. of Flares (% Total) 1 st Trimester 2 nd Trimester 3 rd Trimester Postpartum Arthritis27 (69%)38313 Skin lesions13 (33%)3226 Hemolytic anemia4 (10%)0004 LN4 (10%)0103 Thrombocytopenia1 (3%)0100 Fever3 (8%)0012 Hepatitis1 (3%)0001 Serositis1 (3%)0001 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.

47.  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.

48. Table 2. Evidence for adverse effects of immunosuppressant used in pregnancy and breastfeeding[6] Whether drug can be used DrugEvidenceIn pregnancyIn breastfeeding Hydroxychloroquine/ Chloroquine 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 YY Prednisone/ Methylprednisone Metabolized by placenta In high doses have caused cleft palate in experimental animal models and low birth weight in humans YY Azathioprine 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 YY Ciclosporin No increase in congenital malformation Prematurity and IUGR trends not significant Small amounts in breastmilk but no adverse effects noted Y If benefits outweigh potential risks Tacrolimus 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 Y Y with caution IVIGCross the placenta after 32 weeks but with no adverse effects to fetusYY Mycophenolate mofetil Increased risk of congenital abnormalities Enterohepatic recirculation Long half life N (stop 6 weeks before conception) N Cyclophosphamide Alkylating agent Teratogenic, fetotoxic Risk of suppression of neonatal hematopoiesis N (stop 3 months before conception) N Methotrexate Folate antagonist Teratogenic and Fetotoxic N (stop 3 months before conception and give Folic acid 5 mg daily) N Leflunomide Congenital abnormality in animal studies Human studies limited Long half life of active metabolites N (use cholestyramine to increase clearance preconception) N Biologic agents Etanercept, Infliximab, Adaluminab, Rituximab Limited experience in human pregnancies but no adverse fetal or neonatal outcomes to date Limit to severe diseaseProbably avoid 6 Mackillop, Lucy H., et al. Pregnancy plus Systemic Lupus Erythematosus. BMJ.2007; 335: 93336.

49. Whether drug can be used DrugEvidence In pregnancy In breastfeeding Prednisone/ Methylprednisone Metabolized by placenta In high doses have caused cleft palate in experimental animal models and low birth weight in humans Y Y Azathioprine 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 YY 6 Mackillop, Lucy H., et al. Pregnancy plus Systemic Lupus Erythematosus. BMJ.2007; 335: 93336.

50.  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.

51.  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.

52.  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.

53.  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 3 rd trimester  Delivery method and timing depends on obstetric indications Mackillop, Lucy H., et al. Pregnancy plus Systemic Lupus Erythematosus. BMJ.2007; 335: 93336.

54.  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.

55.  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.

56. MortalitySurvival #%Total Full term delivery 2 (5%)16 (38%)18 (43%) Preterm delivery 12 (28%)4 (10%)16 (38%) Abortion8 (19%)0 Total22 (52%)20 (48%) 8 Valdez, Corazon, et al. Systemic Lupus Erythematosus in Pregnancy: a 23-year review. Acta Medica Philippina

57.  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 Table 5. Diagnostic criteria for the antiphospholipid syndrome Antiphospholipid antibodies plus at least one of the following:  Arterial or venous thrombosis  Three or more miscarriages (at <10 weeks’ gestation)  Fetal death (at >10 weeks’ gestation with normal fetal morphology) Singh, Ajay K. Lupus nephritis and anti-phospholipid activity syndrome in pregnancy. Kidney International. Vol 58. (2000), pp 2240-2254.

58.  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.

59.  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.

60.  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.