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REPRODUCTIVE ISSUES AND
RHEUMATIC DISEASES
By
Walaa F. El Bazz
MD
Prof of Internal Medicine, Rheumatology&
Immunology
Al Azhar University (Girls)
 Rheumatic diseases occur ↑ in F, childbearing yrs.



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This confirmed conviction sex hormone have important
role in disease development and course.
During pregnancy, hormonal changes↑ free steroid
hormones; glucocorticoids, progesterone and estrogen,
induces changes in functions of immuno-competent cells
B cells, T cells and monocytes.
Clinical symptoms of immune-mediated RDs are
modified related to pathophysiological process; some
improve, others unchanged or worsen.
Cutolo M, Capellino S, Straub RH:Estrogens in rheumatic diseases: friend or
.
foe? Rheumatology 2008;47 Suppl. 3:iii2-5

Pregnancy outcome may be threatened by severe organ
involvement and presence of autoantibodies.
 Rare diseases with anecdotal pregnancy experience,
like vasculitides, pose problems in management.
 Fetal and neonatal effects of maternal autoantibodies
are well known, but the long-term outcome of those
children is still insufficiently studied.
 Likewise, causes of impairment of fertility in RDs patients
need more investigation, specialy in males.
Immunomodulatory effects of oestrogens


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(A) S. estrogens in physiological
conc.are implicated in maturation
of Th cells (Th0) into Th1-type.
In pharmacological conc.( high),
they mainly support the
maturation of Th0 T cells into
Th2 type and B-cell activation.
(B) pregnancy, ↑ s. estrogen
shift to a Th2 response ,
therefore classical Th1-driven
diseases such as RA are
improved in 50–75%, classical
Th2-driven diseases as SLE may
be negatively influenced
(complications in 40–70%)
Physiologic Adaptation In Pregnancy May Influence the
Course Of Rheumatic Diseases
I – Volume & BP changes:

Patients with rheumatic disease are not able to
tolerate ↑ intravascular volume.

Vascular bed of patients may lack sufficient
compliance to accommodate ↑ fluid volume.

Subclinical myocarditis, valvulitis, pericarditis 
cong cardiomyopathy, valvular insufficiency,
constrictive pericarditis.
II – coagulation changes:

Normal pregnancy 
* ↓ survival of platelets
* ↑ plasma fibrinogen
* ↑ factor VIII
* ↑ platelet production
  no change in P platelets.

Thrombocytopenia  uncomplicated pregnancy.

Rheumatic diseases with pregnancy:
Activated coagulation system.
thrombocytopenia
Immunologic changes in pregnancy:
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↓ Cell mediated immunity
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↓ T cell / B cell ratios
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↑Treg – helper T cell ratios
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↓ lymphocyte – monocyte ratios
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↓ cutaneous, humoral immune response  due
to ↓ leucocytes, chemotaxis, ↓ adhesion
molecules
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↑ Ig – secreting cells but ↓ inflammatory
response.

Pregnancy specific proteins: alpha feto protein, B1
glycoprotein, alpha 2 macroglobulin  suppress in vitro
lymphocyte function.
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↑ Endogenous corticosteroids  ↓ lymphocyte function.

IL1, IL3, TNF alpha, IFN gamma, GM-CSF  critical to
sustain pregnancy.

Pmncs show an increase in anti-dsDNA and IL-10
in response to estrogen.

Cric IC (in rheumatic diseases) + local levels of
cytokines may be constitutively or secondary abnormal.

C3, C4, CD50 are falsely normalized or ↑ in pregnancy
(pregnancy ↑ synthesis, Rh disease ↑ activation, ↓
synthesis)

CD4+CD25+FOXP3+ Tregs suppress immune responses
and supporting maternal tolerance towards the fetus.
Hormonal changes:

Estrogen up-regulate & androgens down-regulate T cell
response, Ig synthesis.

Sex hormones can regulate IL1, IL2, IL6, TNF alpha 
worsen rheumatic disease state.

Also rheumatic diseases affect them  deterimental to
maintenance of pregnancy.
Does Pregnancy Influence Coarse Of
Rheumatic Disease?

Pregnancy induce abnormalities similar to rheumatic diseases
1. Erythema.
2. Hair loss.
3. Arthralgia.
4. CV, pulmonary compromise.
5. Anaemia.
6. Thrombocytopenia.
7.HTN, proteinuria.
So if ttt is directed to 1ry disease, not to complications of
pregnancy  harmful.
Does Rheumatic Disease Affect
Pregnancy?

Rheumatic diseases ↓ fertility (Debate).
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RA  high frequency in nullipara.
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Scleroderma  subnormal fertility.
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NSAID  ↓ fertility.
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Anaemia, fever  ↓ fetal growth.
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TTT of renal, pulmonary, cardiac dysfunction  affect
fetal outcome.
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Continuous medications  may be harmful to fetus.

Maternal antibodies  may cause fetal illness.
Antiphospholipid Syndrome
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10% of female with past history of recurrent fetal loss.

2 – 3 % of apparently normal pregnant females  low
titre of aPL, high titre  0.2%

aPL may present in infections, HIV, HCV, lyme disease,
enteric diseases.
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B2 glycoprotein, cofactor for pathogenic aPL.
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1ry, 2ry APS  ↑ mid pregnancy fetal loss.

Presence of high titre of IgG, IgM, IgA (less)aCL, LA.
antiB2 glycoprotein, thrombocytopenia  ↑ fetal loss
Effect of pregnancy on APS
 No
evidence of ↑ or ↓ thrombotic events.
 May
be due to anticoagulation for
sake of fetus.
 Postpartum
 ↑ incidence of stroke, MI,
ischemic myopathy.
↑
Thrombocytopenia  remit after labour.
Effect of APS on pregnancy

Early pregnancy  N., after 15 ws  ↓ fetal growth,
bradycardia, ↓ fetal motion, ↓ amniotic fluid  ↓ placental
size  fetal death.

Different aPL-mediated pathogenic mechanisms (i)
placental thrombotic events; (ii) placental inflammatory
events following local C activation; (iii) direct aPL effect on
trophoblast cells inducing defective placentation.

2ryAPS ↑ pre-eclampsia triggered by placental dysfunction
↑ its severity  HELLP syndrome  plasmapharesis.

Genetic polymorphisms, dysregulation of angiogenic factors
 maternal endothelial cell dysfunction (placental dysfunct)

A recent study showed that cell-free, fetal nucleic acids
(DNA and mRNA), released by the placental trophoblast,
↑ in cases with early-onset pre-eclampsia, correlated
with disease severity but not in cases with normal
pregnancy outcome.

No specific histological pattern, C activation was
detected for abortive placentas /at term.

aPL compete with placental anticoagulant proteins
annexin V  coagulation in placenta.

Fetal loss proportionate to titre of IgG aCL, previous fetal
loss (20%SR)
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Tans-placental passage of APL  Infants will not have
APS
Management

If aCL IgG, M+ve  no serial test, if –ve  serial test once/trimester 
platelet count/month.

High titre IgG, M aCL:
- Primigravida,multipara with recent live born  low dose aspirin
or no ttt except thrombocytopenia.
- multipara with preg failure > 15 ws  aspirin to concieve then
heparin 5000 bid during all pregnancy. LMWH  more safe,
effective.

Low titre aCL IgG, M:
- primigravida , multipara with no fetal loss  no ttt.
- Multipara with prior pre-eclampsia, IUGR, HTN, renal D  l d
aspirin after 1st trimester.
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SC heparin or LMWH in therapeutic dose  female with
prior thrombotic events
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Continue aspirin heparin or warfarin postpartum  3 ms
or more (thrombotic event (No contraceptive pills.)

Many live born infants  premature or GR  failure of
breast feeding.
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Breast feeding  allowed aCL Ig, LA, aspirin transmitted
 no complications, heparin not transmitted  allowed.

20% of pregnancies still experience poor outcome
despite conventional treatment. ↑ the dose of LMWH, or
adding either steroids, HCQ or IVIG.
SLE & pregnancy
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SLE is commoner in females child bearing period.
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Drug induced SLE is rare in pregnant females.
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Pregnancy can cause SLE flare mainly 2nd - 3rd trimester
or at perperium.
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↑ Renal flares in pregnant SLE patients .
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Recent study↓↓ in renal function similar to those in
non-pregnant patients with LN In SLE.
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Identify flare of SLE during pregnancy is difficult as
pregnancy induce thrombocytopenia, proteinuria.
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The presence of:

New or increased rash
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Lympadenopathy
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Arthritis
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Fever
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Ant ds DNA titre increase
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Indicate SLE flare > pre-eclampsia.
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Thrombocytopenia in pregnant females:
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APS
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Active SLE
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Pre-eclampsia
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ITP (less common) remit after delivery.
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Anaemia of LE  ↑dueto pregnancy dilutional anaemia
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Proteinuria
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SLE nephritis.
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Pre-eclampsia.
Normal C3, C4  pre-eclampsia.
Decrease C3, C4  nephritis.
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Joints  non inflammatory effusion during pregnancy.
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Active arthritis  active SLE.
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Neurologic manifestation  induced or exacerbate in
pregnancy.
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Some develop stroke postpartum usually APS.
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Lupus nephritis  predispose  pre-eclampsia.
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Patients with preserved renal function, minimal
hypertension  good pregnancy outcome.
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Thrombocytopenia is not independent predictor of fetal
death.
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Neuro-psychiatirc disease  little direct effect on
outcome, ?? fetal injury from hypoxia during seizures,
sedation or addiction from anticonvulsants.

Prematurity, IUGR, fetal death  common in SLE
related to disease severity, APS.

High clinical activity and abnormal serology (complement
or anti-dsDNA)  predictive of a poor obstetric outcome.
Women with SLE have ↓levels of DHEA,further reduced
by ttt with prednisone. In clinical trials, DHEA suppleme
was helpful both for disease activity and for BMD.
 Estrogen substitution in post-menopausal women↑
mild/moderate, not significantly severe flares .
 Oral contraceptive (OCP) is an established risk factor for
SLE particularly, recently use, suggesting an acute
effect in a susceptible women.
 OCPs do not increase flares in women with established
SLE that is inactive or only moderately active.

Neonatal lupus
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Ant Ro, Ant La present in 30% SLE patient  child with
neonatal lupus. 1–2%.
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Maternal HLA DRW3 increase risk.
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The risk of recurrence is 15–20%; unfortunately high
dose IVIGs are not effective in reducing this risk .

A typical skin rash, transient photosensitivity that
resolves spontaneously within 6 ms.
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Congenital heart block most common presentation(85%),
thrombocytopenia, liver abnormalities, hemolytic anemia.

All are reversible except heart block, neonatal
lupus  identified at 23 ws  ttt.
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Dexamethazone or Betamethazone,
plasmapharesis  inverse incomplete heart
block, myocarditis, heart failure.
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After delivery cardiac lesion no progression.
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Early delivery indicated, decrease cardiac
function, congestive heart failure.
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CHB  permanent pace maker
Management

Prednisolone 30 – 60  drug of choice.
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Hydroxychloroquine benign in pregnancy.
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Small dose of aspirin  APS, prevent pre-eclampsia
with lupus nephritis.
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NSAIDs  spasm of ductus arteriosus, prolonged
labour, peripartum bleeding.

Neuropsychiatric lupus  non pregnant.

Cyclophosphamide  not used due to teratogenicity.
Rheumatoid Arthritis
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Common  female: male (3: 1).

All races (1%) population
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Unknown cause, HLA DR4, DR1, familial.
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Insidious onset, periods of remission & exacerbation with systemic
manifestation, ↓ wt, fever, lymphadenopathy.
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Articular & extra-articular manifestation
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Articular: proliferative synovitis  erosion of cartilage, bone 
permanent deformity  variable prognosis.

Management: a lot of medication
Retrospective and prospective studies  48% RA
improves (DAS-28), 41% flares after delivery.
 Improvement of disease activity, post-partum flare not
associated with changes in ACPAs or RF levels.
 Women -ve for ACPA and RF more likely to improve
during pregnancy .
 Higher disease activity during pregnancy was associated
with lower birth weight
 Gestational age at delivery of patients using prednisone
is shorter, and delivery more often premature .
 Affected joints that influence obstetric care, hips, knees

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Associated osteoporosis  fracture with rough handling
the patient
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↑↑levels of fetal Mc were found in the circulation of
women with RA who improved during pregnancy.

Decades after birth fetal Mc persists in the mother and
maternal Mc in offspring. RA Women have no RA-risk
alleles were recently reported to harbour Mc with RA-risk
alleles signif. more than healthy women. Thus, Mc could
contribute to both health and disease

RA patients, circulating Tregs ↑during pregnancy and ↓
post-partum as healthy women (unable to suppress
effectively the pro-inflammatory cytokine response).

Pregnancy restores Treg function creating an antiinflammatory cytokine milieu in 3rd trimester time of maximal
improvement of disease activity.

Pregnancy  ameliorates disease due to ↑ endogenous
corticosteroids, pregnancy specific proteins ptnA  antiinflal

Remission may be due to maternal fetal HLADQ DR
disparity..

Postpartum is time of ↑ risk for new cases of RA.
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RA joints  more unstable

C1 – C2 sublaxation is common and need special concern
during labour.

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A preponderance of 16α-hydroxylated estrogen
metabolites observed in RA SF is unfavourable in
synovial inflammation enhance cell proliferation
including synoviocytes [2].
17β-oestradiol taken during HRT rapidly increase
estrone sulphate after conversion in adipose tissue by
aromatases, pro-inflammatory effects to the inflamed
RA synovial tissue [1].
Management

To conceive  stop some DMARDs due to potential
fetal toxicities of DMARDs.

Azathioprine, hydroxychloroquine  used without ill
effect. Some case reports of fetal harm.

Cyclophosphamide, MTX  contraindicated early in
pregnancy, used in severe, late cases

Moderate dose of aspirin – low dose corticosteroids 
safest

Little is known about NSAIDs during pregnancy

aCL IG ant SSA/Ro, anti. SSB/La  rare in RA.

Labour need team work, obstetrician & rheumatologist.

Identify joint disabilities, range of motions, her
permissible activities (hip, knee, neck).
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Potential risk of fracture, cord compression (forced
motion)

If no free motion of neck, hip, knees  Cesarean
section.

TMJ affection prevent wide opening of mouth  need
special anesthesiologist familiar to these cases

Special techniques & equipments for
transporting patient to delivery suite

No special risks to fetus other than those related
to maternal ttt

Counseling of parents can be optimistic

If medication permit  breast feeding is possible
but arthritis of shoulders, elbows, hands, wrists
 discomfort to the mother
Systemic Sclerosis

Incidence 1: 10000.

Female > male (3: 1)

Age 20 – 40 years.

Raynoud’s phenomenon present in 90%, edema of
hands, face then tight thinning of skin of affected areas,
hypopigmentation, hyperpigmentation.

Oesophageal dismotility, GERD, pulmonary fibrosis,
duodeno-jejunal dilatation, cardiac dysrythmia, PH, HTN,
hyperreninaemic RF  renal crisis needs ACE inhibitor
 reverse RF to normal.

Prognosis is affected by systemic afection.

Diagnosis is clinically, skin biopsy, +ve ANA, antiScl 70,
ACL (uncommon).

CREST syndrome  anticentromer antibodies.

No effective ttt  vasodilator
* Ca channel blockers, immuno-suppressors
* corticosteroids  for myositis, haemolytic anaemia.
* ACE inhibitors  life saving in renal crisis.
* Diuretics is dangerous  ↓ COP in patients with PH,
renal crisis.
EFFECT OF SScON PREGNANCY

Pregnancy losses occurred in 4% of SSc women
 Prematurity (25%),IUGR the most prominent adverse
outcome
 Pre-eclampsia and hypertension less common 1.5% .
 Pregnancy outcomes were similar in limited and diffuse
SSc.
 Skin involvement stable in 69% of women, RP improved
in 40%, GERD worsened in 24%, spirometry and echo
remained stable in 72%, 98%.
 Renal crisis was less observed.
 Uncomplicated, successful pregnancies, provided the
disease is stable and organ damage mild.
Management during pregnancy

Fertility before & after disease  normal.

High miscarriage rate in severe late scleroderma.

Patient may tolerate pregnancy well or poorly  vascular,
visceral disease. (non distensible vascular bed, preexisting renal, cardiac, pulmonary insufficiency)

GERD oesophageal dismotility  ↑ disabling disease 
H2 blocker, prokinetic drug, Oesoph. stricture  dilatation.

Renal scleroderma  bad prognosis, so gestation is
contraindicated/ interrupted.

ACE inhibitors contraindicated, except if renal hypertensive
crisis occur.

Patients with atonic small bowel  N pregnancy with
parentral nutrition.

Pregnancy success rate is normal

Wound healing  normal.

Anesthesia; intubation  difficult  small opening of the
mouth.

Emergency use of ACE inhibitor for HTN, oliguria, whatever
its cause.
Dermatomyositis & polymyositis

Female predominate.

Peak of onset  25y (25 – 50)

Malignancy may be associated with older group.

Chronic disease, remission, relapse with proximal Ms
weakness, pulmonary fibrosis, weakness of respiratory
muscles  aspiration  respiratory failure (danger in
late pregnancy)

↑ creatinine kinase, aldolase, AST, EMG.

Skin ms biopsy, +ve ANA, +ve antiJo-1 (antihistidyl tRNA
synthase antibody)  association with pulmonary
disease + poor prognosis to ttt.

Corticosteroids, immune suppressive MTX, azathioprine,
IV Ig  safe with pregnancy.
During pregnancy:

Uncommon 14% of patients get disease in chiild
bearing peroid.

Muscle fatigue +respiratory impairment  greatest risk
for pregnant. No antibodies cross placenta to fetus  ms
weakness.

Pulmonary fibrosis compromise maternal respiratory
reserve especially in late pregnancy.

Ms strength, respiratory function monitored during
pregnancy & delivery.

Uterine ms contraction Normal in labor but m weakness
for pushing in 3rd stage may be limited factor

Risk for fetus is due to mother’s ttt and complication
during pregnancy.
DRUGs AND PREGNANCY
 During
pregnancy, HCQ, low-dose
glucocorticoids and AZA can be safely
used. Pulse i.v. steroids can be given in
cases of severe SLE or vasculitis flares.
CYC, MTX and MMF are contraindicated
during pregnancy and lactation



Exposure to anti-TNF therapies, especially if this occurs
at the time of conception or during the first trimester, is
not associated with↑ risk of adverse pregnancy and
foetal outcomes.
INF, ADA are found in cord blood in the 2nd and 3rd
trimester transport across the placenta at birth and for up
to 6 months thereafter. • Due to the absence of the Fc
fragment, certolizumab (CZP) has the lowest level of
placental transfer
There are increasing reports of pregnancies in women
exposed to rituximab prior to or during pregnancy 60%
live births (76% full-term deliveries) and 21% in first
trimester miscarriages

Exposure to rituximab during the 2nd and 3rd trimester
results in transient B-cell lymphopenia in the child but the
longterm effects on immune system development remain
unknown. Safe to stope.
 Data on other biologic therapies, including anakinra,
abatacept, tocilizumab and belimumab, are scarce.
 Breast-feeding Glucocorticoids, azathioprine,
hydroxychroquine, and sulfasalazine are generally
considered as safe. There is limited data on
breastfeeding and the use of biologics
HOME MESSAGE




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Pregnancy is a state of↑↑ concentration of sex hormones
and cross-talk between mother and fetus.
Throughout pregnancy, the hormonal, biochemical and
immunological equilibrium in the mother changes 
tolerance to the semi-allogeneic fetus.
Female gonadal hormones exert an important role in the
aetiology and course of chronic inflammatory
/autoimmune diseases.
Epidemiological, immunological and clinical evidence
shows that menstrual cycle, pregnancy, menopausal
status and OCPs are significant influencing factors.

Optimum disease control, remission or low disease
activity before pregnancy is the requirement for good
outcomes.
 Previous complicated pregnancies, renal disease,
irreversible organ damage, anti-Ro/SSA and aPL and
high doses of glucocorticoids increase the risk of
complications.
 Pregnancy is contraindicated in women with
symptomatic pulmonary hypertension, heart failure,
severe restrictive pulmonary disease, severe chronic
renal failure, recent high disease activity and recent
arterial thrombosis.
 There is a need for a change “cautions against
pregnancy” to “embraces pregnancy” through the
individualised, pre- and post-conceptual, multidisciplinary care.
REFRENCES
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NEVERTIRE TO STUDY AND TO TEACH OTHERS
Thank you
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