Autoimmune connective

tissue diseases and

pregnancy

Elisabetta Greco, MD
Rheumatology, Allergology and Clinical Immunology Unit
University of Rome Tor Vergata
elisabetta.greco@uniroma2.it
 Autoimmune connective tissue diseases and pregnancy
• Rheumatic diseases occur preferentially in women, often during
childbearing age.
• The interaction of pregnancy and rheumatic diseases is varied.
• Risks for the mother and the child differ in regard to the presence of
organ manifestations, organ damage, disease activity, presence of
specific autoantibodies and therapy.
• Adverse pregnancy outcomes -> recurrent miscarriage, intrauterine
growth restriction and fetal demise.
• Pregnancy complications -> hypertension, preeclampsia, premature
delivery and side effects of therapy.
Maternal-fetal
interface

M. Østensen et al. Best Practice & Research Clinical Obstetrics and Gynaecology 29 (2015) 658-670
 • Rheumatoid
arthritis
• Behçet disease

 Ankylosing
spondylitis
 Takayasu Arteritis

o SLE

M. Østensen et al. Autoimmunity Reviews 11 (2012) A437–A446

 RA
• Improves spontaneously during pregnancy in a majority of patients
(especially in seronegative patients).
• Improvement starts often already in the first trimester with a reduction of
pain, stiffness and joint swelling and reaches a maximum in the third
trimester.
Spondyloarthritis
• Inflammatory arthritis with few joints involved or with inflammation of
the spine like ankylosing spondylitis (AS) do not show improvement
during pregnancy.
• Most women with AS remain active and need control of pain and stiffness
in the spine throughout pregnancy.
 SLE
• SLE is active at some stage during pregnancy in about 50% of
the patients:
- 60-70% of lupus women do experience mild to moderate
disease symptoms (skin, joints and hematological involvement).
- 10-25% experience severe organ flares (kidney, lung, CNS).
• Active SLE during pregnancy:
- increases the rate of negative outcomes two-to fourfold (10-
30% pregnancy loss)
- is a key predictor also for preterm delivery, like high dose (>15-
20 mg/d) of corticosteroids.
• High titers of aPL, presence of triple positivity
(aCL, LAC, Ab b2GPI) are as LAC, and associated
with a high risk of adverse pregnancy outcomes.
• Pregnancy complications -> pregnancy loss,
intrauterine growth restriction (IUGR),
preeclamptic toxemia (PET), HELLP syndrome,
placental abruption, stillbirth and premature
delivery.
- PET has been reported to occur in about 1/3 of
patients with APS (often with early onset before 34 APS
weeks of gestation)
- IUGR is high ranging from 15% to 40% indicating
placental insufficiency.
 Active rheumatic disease?

Severe organ involvement?

Antiphospholipid
antibodies?
Checklist for risk
Anti-Ro/SSA and
pregnancy anti-La/SSB?

Previous pregnancy
complication?

Ongoing therapies
 Severe pulmonary hypertension

Severe restrictive lung disease (FVC<1)

Circumstances in
Severe heart failure
which women should
be advised against Chronic renal failure (stage 4-5)
pregnancy
Active disease

Women with APS with recurrent preeclampsia or

HELLP despite therapy with aspirin and heparin
Anti-Ro/SSA and /or anti-La/SSB positive
patients
• The transplacental transfer of maternal
autoantibodies to SSA/Ro and SSB/La from the
beginning of the second trimester can lead to
neonatal lupus syndromes.
• Congenital heart block (damage of the conduction
system of the fetal heart) -> most vulnerable period
being between week 18 and week 26 of gestation.
• 2-5% of children develop CHB
 Strategy in anti-Ro/SSA and /or anti-La/SSB
positive patients
• Pre-emptive therapy
- HDQ -> reduces risk of recurrence of CHB
- High doses of fluorinated glucocorticoids are frequently administered when
an AV block is detected in an anti-Ro/SSA-positive mother. However, their
efficacy is controversial.
• Fetal heart rate must be monitored regularly between week 18 and 28
• Fetal echocardiography
- in case of suspected fetal dysrhythmia
- from 16-26 of gestation (especially in women with a previously affected
child)
- no standardised protocols
 Preeclampsia screening and prophylaxis
• Preeclampsia screening
‒ Maternal characteristics (weight, height, mean arterial pressure)
‒ Biophysical assessment of placental function using Doppler-
ultrasonography in maternal and fetal arteries.
‒ Angiogenic factors (sFlt-1/PIGF)
• Preeclampsia prophylaxis
‒ LDA
‒ Calcium supplementation (?)
‒ Vitamin D supplementation (?)
‒ Statins (?)
 As soon as pregnancy is recognized….
• A complete clinical and laboratory assessment should be made.
• Frequent clinical evaluation for monitoring of arterial blood pressure
and proteinuria after 20 weeks.
• Regular assessment of fetal growth, starting with ultrasound for correct
dating in the first trimester, can predict whether the fetus is at risk.
• Doppler flow techniques evaluating the uteroplacental and umbilical
circulation help predict complications such as preeclampsia and IUGR,
starting at week 20.
• Serial fetal echocardiography between weeks 18 and 28 is
recommended for detecting early incomplete heart block and
myocarditis in SSA and SSB positive mothers.
 Key messages
• Pre-conception counselling is important to discuss
possible problems, to identify features implicating a high
risk for mother and/or fetus and to plan the appropriate
treatment.
• Pregnancy should be postponed in case of active or early
stages of disease.
• aPL, anti-Ro/SSA and anti-La/SSB should be measured
before a planned pregnancy.
 Recommendations for CYC in pregnancy
and breastfeeding

• CYC is teratogenic and gonadotoxic, therefore it should

only be considered in pregnancy in life-/organ-
threatening maternal disease.
• There is no evidence to recommend the use of CYC in
breastfeeding (D)
• Paternal exposure to CYC is not recommended (D).
 Recommendations for MMF in pregnancy
and breastfeeding
• MMF remains contraindicated during pregnancy (D).
• Treatment with MMF should be stopped at least 6
weeks before a planned pregnancy (D)
• No data exist on excretion into breast milk, therefore
breastfeeding is not recommended (D).
• Based on very limited evidence, MMF is compatible
with paternal exposure (D)
 Recommendations for MTX in pregnancy
and breastfeeding
• MTX at any dose should be avoided in pregnancy and stopped 3 months
in advance of conception (D).
• Women treated with low-dose MTX within 3 months prior to conception,
folate supplementation (5 mg/day) should be continued prior to and
throughout pregnancy (B).
• In the case of accidental pregnancy on low-dose MTX, the drug should be
stopped immediately, folate supplementation (5 mg/day) continued and a
careful evaluation of foetal risk carried out by local experts (D).
• MTX cannot be recommended in breastfeeding because of theoretical
risks and insufficient outcome data (D)
• Based on limited evidence, low-dose MTX may be compatible with
paternal exposure (D).
 Recommendations for LEF in pregnancy
and breastfeeding
• LEF may not be a human teratogen but it is still not recommended in
women planning pregnancy ©
• Women on LEF considering pregnancy should stop and undergo
cholestyramine washout before switching to alternative medication
compatible with pregnancy (C)
• Therefore, if accidental conception occurs on LEF, the drug should be
stopped immediately and cholestyramine washout given until plasma levels
are undetectable ©
• Breastfeeding is not recommended (D).
• Based on very limited evidence, LEF may be compatible with paternal
exposure (D).
 Recommendations for corticosteroids in
pregnancy and breastfeeding

• Prednisolone is compatible with each trimester of pregnancy (A)

• Prednisolone is compatible with breastfeeding (D)
• Prednisolone is compatible with paternal exposure (D)
• Methylprednisolone has rates of placental transfer similar to
prednisolone with equivalent anti-inflammatory effects at 80% of
prednisolone dose and would therefore be expected to be
compatible with pregnancy, breastfeeding and paternal exposure
(D).
 Recommendations for HCQ in pregnancy
and breastfeeding

• HCQ remains the antimalarial of choice in women

planning a pregnancy with rheumatic disease in need of
treatment and should be continued during pregnancy
(A).
• HCQ is compatible with breastfeeding (D).
• Men should not be discouraged from taking HCQ while
trying to conceive (D).
 Recommendations for SSZ in pregnancy
and breastfeeding

• SSZ with folate supplementation (5 mg/day) is compatible

throughout pregnancy (C).
• SSZ is compatible with breastfeeding in healthy, full-term infants
(D)
• Men taking SSZ may have reduced fertility. There is no evidence,
however, that conception is enhanced by stopping SSZ for 3
months prior to conception unless conception is delayed >12
months when other causes of infertility should also be considered
(D).
 Recommendations for AZA in pregnancy
and breastfeeding

• AZA is compatible throughout pregnancy at <2 mg/kg/day

(B)
• Is compatible with breastfeeding (D)
• Is compatible with paternal exposure (D)
 Recommendations for CSA in pregnancy
and breastfeeding
• CSA is compatible throughout pregnancy at the lowest
effective dose (B)
• Mothers on CSA should not be discouraged from
breastfeeding (D)
• Based on limited evidence, CSA is compatible with
paternal exposure (D).
 Recommendations for IVIG in pregnancy
and breastfeeding

• IVIG is compatible with pregnancy (A)

• IVIG is compatible with breastfeeding (D)
 Recommendations for anti-TNF
medications in pregnancy and
breastfeeding

• Infliximab (IFX) may be continued until 16 weeks and etanercept (ETA) and
adalimumab (ADA) may be continued until the end of the second trimester (D).
• To ensure low/no levels of drug in cord blood at delivery, ETA and ADA should
be avoided in the third trimester and IFX stopped at 16 weeks. If these drugs
are continued later in pregnancy to treat active disease, then live vaccines
should be avoided in the infant until 7 months of age.
• Certolizumab pegol is compatible with all three trimesters of pregnancy and
has reduced placental transfer compared with other TNF inhibitors (D).
• Based on limited evidence IFX, ETA and ADA are compatible with paternal
exposure (D)
 Risk factors for impaired female fertility
• Age related fertility (>35y)
• High disease activity (shown for RA, SLE)
• Organ damage (renal insufficiency, lupus nephritis)
• Drugs
- Risk of reversible infertility: NSAIDs, Prednisone >7.5 mg/die
- Risk of irreversible infertility: Cyclophosphamide
Anti-thyroglobulin (aTG) and thyroid peroxidase (aTPO), ANA, anti-laminin,
anti-prothrombin antibodies and anti-saccharomyces cerevisiae antibodies
(ASCA) have been associated to impaired fertility.
 Ovarian stimulation can result in high concentrations of
estradiol, exceeding physiological levels, with a risk for
ovarian hyperstimulation syndrome (capillary leak-syndrome
and raised hematocrit which increases the risk of
thrombosis).

Assisted The risk can be reduced by using stimulation protocols with

gonadotropin-releasing hormone (GnRH) antagonists and
reproductio ovulation induction with GnRH agonists which almost
n completely avoids ovarian hyperstimulation syndrome. This
protocol requires a cryopreservation of all fertilized oocytes
and an interval of at least one month before embryo transfer.

Friendly ovarian stimulation, single embryo transfer,

avoidance of ovarian hyperstimulation, administration of
coadjuvant therapy and use of natural estrogen or
progesterone through a non-oral route may constitute the
safest approach
 Take home messages
RDs differ in their response to pregnancy.

RD with predominant joint involvement, few organ manifestations, and few autoantibodies rarely
impair pregnancy outcomes.
aPL or APS increase risk of miscarriage, preeclampsia, IUGR, fetal death, and prematurity.

SSA/Ro, SSB/La antibodies predispose to neonatal lupus syndromes and CHB.

Active disease at conception, renal disease, aPL, and high-dose corticosteroids predict complications
in RD pregnancies.
Assessment of maternal and fetal risks is a prerequisite for preconceptional counseling.

Adjustment of medication instead of global drug withdrawal in the first trimester is appropriate.

Interdisciplinary care and management is a prerequisite for successful pregnancy outcomes