SLEと妊娠

妊娠とSLE

13年11月14日木曜日

妊娠とSLE
OBSTETRICAL AND GYNECOLOGICAL SURVEY 2011;66:639-653

•

SLEは妊娠可能年齢の女性で好発する疾患であり,
SLEのマネージメント, 妊娠中の管理は重要.
•

SLE患者における妊娠はHigh-riskと見なす.
妊婦死亡率は20倍, 帝王切開リスクがOR 1.7, 早産リスクがOR 2.4,
子癇発作リスクがOR 3.0.
また, 出血, 血栓, 感染リスクも上昇する事が分かっている.

•

また, 妊娠中にSLEが再燃する事もあり, 再燃率は13.5~65%と様々だが,
妊娠による症状が再燃症状をマスクする可能性もあり,
気付かれにくい.

•

妊娠自体が再燃リスクを増加させるという報告もあれば,
リスクにならない報告もあり, 妊娠がリスクとなるかどうかは議論があるところ


TABLE 2
Assessment of lupus flares in pregnancy
Feature

Findings Indicative of a Lupus Flare

Findings of Normal Pregnancy That Can Mimic a Flare

Clinical

Active rash of lupus
Inflammatory arthritis
Lymphadenopathy
Fever Ͼ38°C (not related to
infection or drug)
Pleuritis
Pericarditis

Erythrocycle sedimentation rate

Increased

Anemia

Hemoglobin Ͻ10.5 gm/dL

Thrombocytopenia
Urinalysis
Proteinuria
dsDNA antibodies
Complement

Platelet count Ͻ95,000
Hematuria or cellular casts
͓Ն͔300 mg/d
Rising titers
͓Ն͔25% drop

Fatigue
Arthralgias
Bland effusions of knees
Myalgias
Malar and palmar erythema
Postpartum hair loss
Carpal tunnel syndrome
Edema of hands, legs, and face
Mild resting dyspnea
18 – 46 mm/h Ͻ20 weeks’ gestation
30 –70 mm/h ͓Ն͔20 weeks’ gestation 17
Hemoglobin Ͼ11 gm/dL during first 20 weeks’ gestation
Hemoglobin Ͼ10.5 gm/dL h after 20 weeks’
gestation18
Mild in approximately 8%19
Rare hematuria from vaginal contamination
Ͻ300 mg/d
Negative or stable titers
Usually increased


•

SLE再燃の症状と, それをマスクする可能性がある妊娠による症状


otein should be a
in synthesis also
n result in higher
mponents as well
ad to a substantial
entation rate in a

ia from lupus gloficult. Both may
ia, hypertension,
on in renal funcdition, the 2 con-

•

TABLE 5
Differentiation of active lupus nephritis from preeclampsia
Active Lupus Nephritis
Hypertension
Proteinuria
Urinary sediment
Uric acid
DNA antibody levels
24-h urine calcium
Complement levels
Soluble FMS-like
tyrosine kinase 1

Preeclampsia

Onset before 20 weeks Onset after 20
weeks
Ն300 mg/d
Ն300 mg/dL
Active
Inactive
Յ5.5 mg/dL
Ͼ5.5 mg/dL
Rising
Stable or
negative
Ն195 mg/d
Ͻ195 mg/d
Ն25% drop
Normal
Normal
Elevated

ループス腎炎の活性化と子癇発作の違い


TABLE 6
Differentiation of microangiopathies in lupus pregnancy
Features*
Usual time of onset
Fever
Abdominal pain and other
symptoms
Jaundice
Central nervous system
involvement
Lung involvement
Elevated liver enzymes
Elevated bilirubin
Hepatic infarcts
Hypertension
Proteinuria
DIC
Microangiopathic hemolytic
anemia
Thrombocytopenia
Hypoglycemia
ADAMTS-13 Ͻ5%

HELLP†
Ͼ34 weeks, including postpartum
Absent
60%– 80%
5%–10%
40%– 60%
Rare
100%
50%– 60%
With antiphospholipid
antibodies
80%
90%–95%
5%–56%
50 –100%
Usually Ͼ20,000
Absent
Absent

AFLP‡
Ͼ27 weeks
25%–32%
35%–50%
40%–90%
30%– 40%
Rare
100%
100%

50%
30%–50%
73%
15–20%
None initially
Common
Absent

TTP§

CAPS¶

Late second to early
third trimester
20%–50%
Common

Second or third trimester
or postpartum
10%
Common

Rare

Not reported
60%

66%
Rare
Usually mild
100%

73%
Not reported
Not reported
Not reported

20%–75%
Common
Rare
100%

Not reported
Common
20%
With concomitant HELLP

Usually Ͻ20,000
Absent
33%–100%

60%
Absent
Not reported

Adapted from references.98–101
†
Hemolysis, elevated liver enzymes, and low platelets.
‡
Acute fatty liver of pregnancy.
§
Thrombotic thrombocytopenic purpura.
¶
Catastrophic antiphospholipid antibody syndrome.

•

SLE患者の妊娠で生じ得る Microangiopathyの鑑別


•

子癇発作はSLEの妊婦の13-35%で生じる.
一般の妊婦では5-8%であり, 2-3倍のリスク.
•

特に受胎時に活動性のループス腎炎がある例で頻度が高い.
他のリスク因子は, 20mg/d以上のPSL使用, 肥満, PLT低下, 高血圧, 腎疾患.

•

死産, 流産リスクは19%. その55%は妊娠中期で生じる.
•

•

蛋白尿>500mg/d, 抗リン脂質抗体症候群, PLT低下, 高血圧がリスク因子.

早産や子宮内発育遅延(IUGR)は33%[8-63], 9%[2-40]と高頻度.
•

妊娠初期にループス腎炎や高血圧があるとリスクが上昇.
他には受胎時や妊娠初期に活動性があるSLEがある場合,
抗リン脂質抗体症候がリスクとなる.


•

活動性のあるループス腎炎例が最も妊娠合併症のリスク.
•

このような患者では流産, 死産が8-36%の頻度
(妊娠前にループス腎炎がある患者群での統計)
妊娠中に活動性のループス腎炎(+)例では52%に及ぶ.

•

受胎時にCre>2.8mg/dLとなっている群では,
妊娠成功率はわずか20-30%しかない.

Postgrad Med J 2001;77:157–165


•

新生児ループスはSLE妊婦の3.5-8%で合併.
•

母体中の抗SS-A抗体, SS-B抗体が胎児に移行し, 発症する.
典型的には新生児の皮疹, 日光過敏で発症し, 6-8ヶ月で改善する.
他にはPLT低下, 心筋炎, 肝炎等を合併しえる.

•

最も重篤な合併症は子宮内Heart block(1度∼3度)で,
抗SS-A抗体陽性妊婦の2~7%で合併し, 20%で繰り返す.

•

抗SS-A, B抗体陽性の妊婦では, 妊娠中にHydroxychloroquineを
使用することで心臓の障害のリスクが低下する可能性がある.


•

Lupus anticoagulant

BLOOD, 18 JULY 2013 x VOLUME 122, NUMBER 3
There were significantly more patients with a

history of TEs in the
LAC-positive group compared with
(LAC)による妊娠合併症のリスクpatients in2013;122(3):341-347
Blood. the LAC-negative
group (33.9% vs 2.9%; P 5 .001; 95% CI for the difference, .238-.382;
Table 1. Distribution of diagnoses among LAC-positive and
OR, 21.2; 95% CI, 8.8-51.1). There were significantly more LACLAC-negative patients
positive patients with a history of stillbirth (38.0% vs 7.1%; P , .001;
LAC negative,
LAC positive,
95% CI, .283-.477;340 (%) 95% CI, 4.2-17.5) and significantlyCI)
OR, 8.6;
fewer
Diagnosis
n5
n 5 62 (%)
P (95%
with a history of >2 early spontaneous losses (28.0% vs 71.8%;
SLE
66 (19.4)
13 (21.0)
NS
P , .001; 95% CI, .287-.569) compared with LAC-negative patients,
1° APS
0 (0)
24 (38.7)
,.001 (0.322-0.452)
respectively (Table 2). Significantly more LAC-positive women had
SLE/APS
3 (0.9)
13 (21.0)
,.001 (0.147-0.255)
pregnancies complicated by IUGR (8.0) HELLP,.001 (0.489-0.755)
and
compared with
Early RPL
238 (70.0)
5
LAC-negative women, but no apparent difference in the frequency
Other
33 (9.7)
7 (11.3)
NS
of preeclampsia was observed between the 2 groups. There was no
RPL, early recurrent pregnancy loss; NS, not significant; SLE/APS, lupus with
secondary APS.

Table 2. Distribution of clinical events among LAC-positive and
LAC-negative patients

test results (Figure 1): 62 (2.7%) had repeatedly tested positive for
LAC negative, LAC positive,
LAC; 31event
(1.4%) tested positive for LAC(%) only 1Poccasion and
on
Clinical
n 5 340 (%)
n 5 62
(95% CI)
subsequently tested negative; 43 (1.9%) tested positive with no
TE (idiopathic)
4 (1.2)
10 (16.1)
,.001 (0.085-0.182)
subsequent tests, as they were lost to 11 (17.7) ,.001 (0.113-0.217)
follow-up; and 2121 (94.0%)
TE (with risk factor*)
6 (1.8)
tested negative for LAC at (7.1) once. (38.0) ,.001 (0.283-0.477)
$1 stillbirth
23/326 least 19/50
$2 early SA

234/326 (71.8)

14/50 (28.0)

,.001 (0.287-0.569)

IUGR
3/326 (0.9)
9/50 (18.0)
,.001 (0.119-0.223)
Comparison of LAC-positive and LAC-negative patients
HELLP

TE; thrombotic event

1/326 (0.3)

6/50 (12.0)

,.001 (0.077-0.157)

Preeclampsia
6/326 (1.8)
.186 (20.087-0.003)
Patients in the LAC-positive group3/50 (6.0)significantly older than
were
$1
230/326 (70.6)
thoselive birth LAC-negative group36/50 (72.0) 40 .972 (20.149 to 0.121)
in the
(median,
vs 37 years, reNo adverse obstetric
31/326 (9.5)
5/50 (10.0)
.884 (20.092 to 0.082)
spectively; P , .001, Mann-Whitney rank-sum test). No difference
events
was observed in the prevalence of patients with SLE in either group
SA, spontaneous respectively) (Table 1). However, there were
(21.0% vs 19.0%, abortion.
*Predisposing events for
significantly more patientsthrombosis: oral contraception, surgery, and postwith either primary or secondary APS in
partum period.
the LAC-positive group (60% vs 1%) and significantly more patients

妊娠中にSLEが増悪する理由

•

妊娠中では徐々に性ホルモン(Estrogen)が上昇する
•

Estrogenは免疫活性を賦活化し, 自己免疫疾患のリスクを上昇させる.
Estrogenは特に妊娠後期でより増加するため,
SLE患者において, 妊娠後期は再燃のリスクが上昇する.


SLEが妊娠に及ぼす機序

•

胎盤の血管障害が原因の1つ
•

脱落膜の血管障害, 血栓形成,

塞を生じ,

胎盤重量は通常と比べて減少する.
これは抗リン脂質抗体の有無にかかわらず, SLE妊婦で広く認められる所見
胎盤の障害は過凝固状態, 高血圧, 免疫由来の血管損傷により生じる.
•

補体の活性化が子癇発作, 死産, 流産, IUGRに関与する
•

抗リン脂質抗体はTrophoblastに作用し, 補体を活性化させ,
胎盤障害を引き起こす. その結果胎児に影響がでる.

•

SS-A, B抗体の胎盤通過性により, 胎児ループスを引き起こす


SLE患者における妊娠

•

SLE患者はループス腎炎, もしくは活動性SLEによる無月経症,
Cyclophosphamide使用が無い限り, 妊娠は可能.
•

Cyclophosphamideはパルス療法, 経口療法に限らず,
副作用として卵巣不全を来す.
使用時の年齢, 総量にもよるが, 恒久的な卵巣不全は11-59%で生じる.

•

GRH agonist(leuprolide 3.75mg, 各Cyclophosphamide投与の2wk前に投与)で
卵巣不全を予防する方法もあるが, 効果のほどは不明で,
Estrogen値を上昇させる事で血栓リスクにもなり得るので注意.

•

薬剤使用前の卵巣冷凍保存という方法もある.



•

避妊も重要なSLE患者のマネージメント
•

妊娠に適さない時期は避妊が重要であり,
教育や妊娠計画をたてる事が重要.

•

経口避妊薬はEstrogenを含み, SLE再燃のリスクになるかもしれないが,
RCTでは再燃のリスクは証明されていない.
Studyには活動性Lupusは除外されており,
安定した患者群での投与が望ましい.


SLE患者における妊娠計画

•

受胎のタイミングは少なくとも6ヶ月は病状が安定し,
投薬内容も安定した後に行う.
リスクアセスメント
過去の妊娠の合併症の確認
病状活動性と侵襲臓器の確認

奇形リスクのある免疫抑制剤
MTX, leﬂunomide, mycophenolate,

薬剤調節

cyclophosphamideは受胎の3ヶ月前

SS-A/B抗体, 抗リン脂質抗体の確認

には中断する必要がある.

Low-Risk妊娠
安定病期
低活動性
臓器障害無し

通常の産科で問題無し


薬剤調節

Low-Risk妊娠
安定病期
低活動性
臓器障害無し

通常の産科で問題無し

薬剤調節

妊娠は不適格
重度の肺, 心臓, 腎, CNS障害

妊娠を延期する

症候性の肺高血圧症

活動性のループス腎炎

重度の子癇発作の既往

最近の重度の再燃歴, Stroke

(ヘパリン投与下で)

High-RIsk妊娠
活動性のループス腎炎, 最近の重度の再燃
抗リン脂質抗体(+)で, 流産 or 血栓症歴(+)
抗SS-A, B抗体陽性 or 新生児ループス既往

High-RIsk妊娠
活動性のループス腎炎, 最近の重度の再燃
抗リン脂質抗体(+)で, 流産 or 血栓症歴(+)
抗SS-A, B抗体陽性 or 新生児ループス既往

抗SS-A/B抗体陽性例では,
毎月のlab評価: CBC, 生化, UA, 補体, DNA抗体

16wk~出産まで胎児の

UA, 尿検査(Prot/Cre)

Mモード心エコーをフォローする

胎児エコー; <13wkで胎齢を評価,
16-20wkで胎児異常を評価,

抗リン脂質抗体陽性例

その後3-4wk毎に成長を評価

+ 流産, 血栓症の既往の場合

臍帯動脈Doppler velocimetryを26wkから毎週施行

→ アスピリン + LMWH

26-28wkより毎週Fetal surveillance testを施行
32-40wkは毎週診察

抗リン脂質抗体陽性例

再燃が生じた場合はもっと小まめにフォロー

+ 流産, 血栓症の既往が無い場合
→ アスピリンのみ.


Lupus and Pregnancy Y CME Review Article

外来でのモニタリング

647

TABLE 4
Monitoring of the pregnant lupus patient
Type of Monitoring

Timing During Gestation

Testing

Clinic visit: obstetrician

Conception to 20 weeks: monthly
20 –28 weeks: every 2 weeks
28 weeks to delivery: every week

Clinic visit: rheumatologist
Laboratory

Monthly
Initial assessment

Standard prenatal visit
Standard registration and 28 week labs
Assessment at each visit for signs and symptoms
of lupus
Clinical assessment
Complete blood count
Chemistry panel
Serum urate level
Urinalysis
Spot or 24-h urine protein-to-creatinine ratio
C3, C4, CH50
dsDNA antibodies
SS-A and SS-B antibodies
Cardiolipin antibodies
Lupus anticoagulant assay (e.g., Russell viper
venom test)
Complete blood count
Chemistry panel
Serum urate level
Urinalysis
C3, C4, CH50
dsDNA antibodies
24-h or spot urine protein to creatinine ratio if urine
dipstick positive
Assessment of crown-rump length
Fetal anatomy scan
Monitoring for fetal growth disturbances and
oligohydramnios

Monthly

Sonography

Fetal surveillance

Fetal m-mode echocardiography
(in setting of maternal SS-A
(Ro) and/or SS-B (La)
antibodies)

7–13 wk
16 –20 wk
Then every 4 weeks (or every 3
weeks in setting of preeclampsia or suspected IUGR)
At 26 –28 weeks, and then weekly
until birth
Weekly beginning at 16 weeks
and continuing till delivery

IUGR indicates intrauterine growth retardation.

Nonstress test to start at 28 weeks
Biophysical profile to start at 26 weeks
Fetal umbilical artery Doppler velocimetry to start at
26 weeks
Assessment for heart block


•

SLEで使用する可能性がある薬剤と妊婦への影響
Lupus and Pregnancy Y CME Review Article
645

TABLE 3
Use of drugs in lupus pregnancy
Drug

FDA Pregnancy-Risk
Category

Nonsteroidal anti-inflammatory
drugs (NSAIDs)
Hydroxychloroquine

C

Nonfluorinated corticosteroids
(e.g., prednisone,
methylprednisolone)
Fluorinated corticosteroids (e.g.,
betamethasone and
dexamethasone)
Intravenous pulse
methylprednisolone
Leflunomide

B

C

May lead to constriction of fetal
ductus arteriosus.
Considered safe in doses used to
treat lupus
Associated with a small risk of orofacial clefts

Recommendation for Use During
Pregnancy
Avoid, especially in third
trimester
Continue to prevent lupus flares
Treatment of severe flares

C

Cross the placenta

Use only if intent is to treat fetus

B

May reach the fetus

Treatment of severe flares

X

High rate of fetal anomalies in rodent studies but 9.3% in registry
of rheumatoid arthritis patients (compared with 13% for
control RA group and 3.5% for
healthy women)70
Estimated congenital anomaly rate
of 10%–15% with doses used for
rheumatic disease.71 Discontinue
at least 3 menstrual cycles before
attempting to conceive
Use in first trimester associated with
malformations and miscarriage

Contraindicated

Methotrexate

X

Cyclophosphamide

D


Maternal and Fetal Outcomes
Related to Use During Pregnancy

Contraindicated

Use only when mother’s life is at
risk and other options

Cyclophosphamide

D

Cyclosporine

C

Azathioprine

D

Intravenous immunoglobulin

C

Mycophenolate mofetil

D

Bisphosphonates

C

Warfarin

X

Rituximab

C

Use in first trimester associated with
malformations and miscarriage
Use in second and third trimesters associated with growth
retardation, suppression of fetal
hematopoiesis, impaired neurological development.
No increased risk of congenital
anomalies. May be associated
with increased rates of prematurity. Often used during pregnancy
by women with organ transplants
May be associated with IUGR
Studies in women with multiple
sclerosis and antiphospholipid
antibody syndrome have not revealed any fetal risk.
Increased risk for congenital anomalies, including facial dysmorphia
and malformation of the ears
Cross the placenta; effects on neonatal bone metabolism are
unknown.
Teratogenic in the first trimester
Associated with transient B-cell depletion in fetus if administered to
mother in second or third trimester

Use only when mother’s life is at
risk and other options
exhausted.

May be used for treatment of
lupus

Long track record of use in lupus pregnancies
May be used for certain lupus
manifestations

Contraindicated

Discontinue before conception

Switch to heparin before
May be used for certain lupus
manifestations

FDA pregnancy-risk categories: A, no risk in adequate controlled trials of pregnant women; B, no risk to fetus demonstrated in animal
reproduction studies or adverse effect noted in animal studies but no risk evident in controlled trials of pregnant women; C, no data in
humans are available and animal studies either positive for fetal risk or have not been conducted; D, evidence of human fetal risk exists,
but the potential benefit outweighs the potential risk to the fetus; X, risk associated with the use of the drug clearly outweighs any
positive benefit.72,73
IUGR indicates intrauterine growth retardation.



•

妊婦へ使用可能な薬剤は,
•

ステロイド(PSL, mPSL等), Hydroxychloroquine, Cyclosporine, IVIG,
Bisphosphonate, Rituximab程度.

•

PSLは≤10mg/dまで減量したほうが良い
(高血圧や子癇発作のリスクとなる可能性がある.)

•

アザチオプリンは胎児の肝臓では代謝されず,
活性化されないため, どうしても免疫抑制剤が必要な場合は,
アザチオプリンもしくはシクロスポリンを考慮する.


授乳婦の管理

•

SLEで使用する殆どの薬剤は母乳に移行する.
•

アスピリンは24h以内に0.1-21%胎児に移行してしまう.
母乳中のピーク濃度は血中のピークの2時間後.
胎児におけるアスピリンの代謝は低下しており,
中毒症状が生じる可能性があり,
授乳婦におけるASA投与は可能な限り避ける or 低用量が推奨.

•

NSAIDの濃度は高くなりにくいため,
Ibuprofen, Indomethacin, Naproxenは安全に投与可能とされているが,
黄疸がある新生児では核黄疸リスクが上昇するため, 避けるべき.



•

ステロイド(PSL)は母乳へ少量移行するが,
乳児への影響はほぼ無い為に投与可能.
•

PSLが20mg/dを超えるようならば,
内服後4時間程空けて授乳することを推奨する専門医もいる

•

•

デキサメサゾン, ベタメサゾンではデータ不明.

Hydroxycholoroquineも少量母乳に以降するが,
乳児への影響は少ないとされている.
•

•

ただし, 蓄積する可能性もあり, 注意して使用する

細胞毒性のあるCyclophosphamide, Azathioprine, Cyclosporin A, MTX
は母乳へ移行し, 有害の為に授乳婦では使用できない.


授乳のSLEへの影響

•

Prolactinは妊娠中期∼後期に上昇し,
高Prolactin状態は授乳していれば出産後数ヶ月は持続する.
•

Prolactinは免疫賦活作用をもつため,
SLEの活動性亢進のリスクになり得る.

•

ただし, 明確なEvidenceは無い.


SLEと妊娠

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