Systemic lupus erythematosus in Pregnancy

Systemic lupus erythematosus in Pregnancy

• SLE is known to increase the risk of spontaneous miscarriage; it can also cause fetal growth restriction and increased rates of sudden intrauterine death, pre-eclampsia and preterm delivery

Pre-pregnancy counselling :

• The presence of anti-Ro/La and 
  antiphospholipid antibodies should  be determined. 
  These antibodies are associated with congenital heart block 
  and neonatal cutaneous lupus syndrome. 
  Antiphospholipid 
  antibodies are present in about 30% of women with SLE and 
  are associated with arterial and venous thrombosis, recurrent 
  miscarriage, fetal growth restriction, fetal loss and preterm 
  delivery due to uteroplacental insufficiency.
• Quiescent disease, without associated antiphospholipid syndrome (APS), hypertension or renal involvement the risks of miscarriage/stillbirth and fetal growth restriction are not significantly increased
• The risk of miscarriage and stillbirth in pregnancies complicated by lupus varies in the literature from 6–35% and from 0–22%
• The great concern are women with SLE and associated pulmonary arterial hypertension who wish to conceive: maternal mortality rates have been quoted as being as high as 33%
• Women should  be advised not to conceive during a period of active disease, particularly with lupus nephritis, because of worse maternal and fetal outcomes
• Counsel women with SLE for increased risk of pre-eclampsia, preterm delivery and fetal growth restriction
• In active lupus nephritis with worsening renal function, increasing proteinuria and hypertension,it may be necessary to use such treatments as cyclophosphamide and mycophenolate mofetil, which are associated with congenital malformations if used in the first trimester,
• Pregnant women with active SLE/lupus nephritis or anti-Ro/La/antiphospholipidantibodies should be considered as a higher risk group and managed in tertiary centre
• If severe disease, patients need hospitalisation
• For patients with stable disease, 4-weekly reviews of disease activity and regular assessment of fetal growth, blood pressure and proteinuria are acceptable.
• For those women who are anti-Ro/La positive the fetal heart rate should be monitored and recorded at each visit and fetal echocardiography assessments made at 18–20 and ~28 weeks of gestation
• Women who have had a previous venous thromboembolism  should receive thromboprophylaxis with low molecular weight heparin throughout pregnancy and for 6 weeks postpartum 
• The risk of an SLE flare in pregnancy is increased with active disease in the 3–6 months prior to conception, with the majority of flares occurring after the 20th weeks of pregnancy
• Most flares are  managed expectantly with medical management and adjustments to drug therapy
• At every antenatal visit, measure the BP, test the urine for proteinuria,  and quantify the proteinuria by PCR or 24 hour urine proetien estimation.
• The features of lupus nephritis include hypertension and proteinuria with or without haematuria and renal impairment
• The presence of hematuria or red cell casts as well as a rise in anti-dsDNA titres or a fall in complement levels help to distinguish this from pre-eclampsia
• In cases of lupus nephritis that fail to respond to increasing dosages of steroids and azathioprine, and where there is a deterioration of renal function and/or hypertension, other immunosuppressive drugs may be considered, such as mycophenolate mofetil or tacrolimus. Such management decisions should be undertaken in consultation with nephrologists and rheumatologists.
• Premature rupture of membranes is also regarded as being more frequent in pregnancies complicated by SLE; rates vary and are generally quoted as ~20% and is common in women who are on steroids

SLE and fetal risks

• Increased rates of miscarriage,
• Increased risks of congenital heart block, fetal growth restriction and increased rates of preterm delivery 
• Scanning at least every 4 weeks to screen for fetal growth restriction in those women at risk is generally accepted and fetal echocardiography referral should be arranged for those with anti-Ro/La antibodies
• Doppler studies can be used to estimate placental function
• A uterine artery Doppler should be first carried out at 20 weeks and repeated 4 weeks later if any abnormality is found
• A raised pulsatility index or diastolic notching are associated with increased risk for developing  pre-eclampsia, as they can indicate underlying placental dysfunction
• Congenital heart block is associated with maternal anti-Ro/La autoantibodies.
• usual presentation is a fixed fetal bradycardia of 60–80 beats per minute on ultrasound scan.
•  It occurs in 2–3% of fetuses of women with the anti-Ro/La antibody 
• CHB is associated with significant perinatal morbidity and mortality, with about half of infants requiring pacing by the first year of life. 
• Congenital heart block develops between 18– 28 weeks of gestation and fetal echocardiography should be performed around this period to detect it. Hydrops fetalis can occur in utero and is thought to be due to the degree of endomyocardial fibrosis and associated myocarditis.

Neonatal lupus rash

• lesions are  commonly seen on the face and scalp 
  and appear typically after ultraviolet exposure in the first 
  2 weeks of life, but can appear  up to 3–6 months postpartum

Drug treatment in SLE

• Glucocorticoids, mainly in the form of prednisolone, are frequently but not exclusively used as one of the first-line treatments in pregnancy
• Women on moderate to high dosages of steroids should should be screened regularly for gestational diabetes.
• Immunosuppressants  that are used and are generally considered safe during pregnancy include azathioprine and hydroxychloroquine. There is no  need to discontinue them during pregnancy

Postpartum management

• To consider thromboprophylaxis
• Manage hypertension

• 
  

Autoimmune disorders and pregnancy

The implications of autoimmunity and pregnancy
Two decades ago, it was suggested that women with autoimmune diseases avoid pregnancy due to inordinate risks to the mother and the child. In contrast, newer epidemiological data demonstrated that advances in the treatment of autoimmune diseases and the management of pregnant women with these diseases have similarly improved the prognosis for mother and child.
In particular, if pregnancy is planned during periods of inactive or stable disease, the result often is giving birth to healthy full-term babies without increased risks of pregnancy complications.

Nonetheless, pregnancies in most autoimmune diseases are still classified as high risk because of the potential for major complications.

These complications include disease exacerbations during gestation and increased perinatal mortality and morbidity in most autoimmune diseases, whereas fetal mortality is characteristic of the anti-phospholipid syndrome (APS).

In this review, following topics are discussed , including issues of hormones, along with potential long-term effects of the microchimerism phenomenon.

With respect to pregnancy and autoimmune diseases, epidemiological studies have attempted to address the following questions:

1) Is it safe for the mother to become pregnant or are there acute or chronic effects of pregnancy on the course of the disease?

2.Does the disease alter the course and/or the outcome of a pregnancy and thereby represent an inordinate risk for the fetus and infant? And do new therapeutic and management approaches improve the pregnancy outcomes in women with autoimmune diseases? 3) Does passage of maternal autoantibodies represent a risk to the child? 4) Do pregnancy, parity, or other factors influencing hormonal status explain the female predominance of many autoimmune diseases, and is the pregnancy effect related to microchimerism?
 Answering these questions has taken on additional importance in recent decades as women in western countries now frequently choose to delay pregnancies and have some or all of their pregnancies after disease onset.

In this a primary focus is placed on APS, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D).

This indicates that women in their childbearing years are
frequently affected.
3.1.1. Pregnancy morbidity
The specific pregnancy morbidity criteria for APS are

 a) one or more unexplained deaths of a morphologically normal fetus at or
beyond the 10th week of gestation;

b) one or more premature births of a morphologically normal neonate before the 34th week of gestation because of either eclampsia or severe preeclampsia or
placental insufficiency; or
c) three or more unexplained consecutive spontaneous abortions before the 10th week of gestation in the absence of anatomic, hormonal or chromosomal causes.
This highlights one of the major differences between APS and other
autoimmune diseases: whereas other autoimmune diseases may
affect the course of pregnancy, pregnancy morbidity is a manifestation
and a defining feature of APS. While late fetal loss is
considered to be more characteristic of APS, recurrent early fetal
loss is more common.
Before the advent of treatment, the prognosis for pregnancies in
APS patients was dismal, with only 10% or less of all pregnancies
resulting in live births, although others have reported
somewhat better outcomes. It has become common practice to
treat pregnant APS patients or SLE patients with aPL even in the
absence of clinical manifestations of APS with low-dose aspirin
alone or in combination with heparin, but considerable controversy
remains as to the most appropriate approach. Since the
introduction of such preventive regimens, the pregnancy outcome
among women with APS has improved dramatically. Interestingly, there were
significant differences in the distribution of fetal losses. Mexican,
Ecuadorian, and Colombian women with APS experienced early
pregnancy loss significantly more often than their European
counterparts, whereas their late pregnancy loss rate was lower, the
latter reaching statistical significance only in patients with pAPS
. During a further 5 years of follow-up, the live birth rate in
the European cohort improved significantly to 76.2%, with early and
late pregnancy losses occurring in 17.1% and 6.7% of pregnancies,
respectively. This is consistent with numerous other studies
showing success rates of 70- 80% in pregnancies of women with
APS who receive aspirin alone or in combination with heparin or
other preventive regimens.
While the pregnancy outcome has improved significantly in
recent years, the complication rates remain high.

Typical complications in women with APS are preeclampsia/eclampsia, intrauterine growth restriction (IUGR), premature rupture of membrane,
Cesarean delivery and premature delivery, the latter being
primarily due to preeclampsia/eclampsia or placental insufficiency.
Overall, the reported rates of preeclampsia range between 0 and
51% and those for preterm delivery between 32 and 65%.

The Euro-Phospholipid study revealed preeclampsia in 9.5%, eclampsia
in 4.4%, premature rupture of membranes in 2.0%, and post-partum
cardiopulmonary syndrome in 0.5% of pregnancies

An analysis of nationwide obstetric hospitalization data in the USA
similarly showed that women with APS had a significantly
increased frequency of hypertensive disorders (13.0%), IUGR (5.1%),
premature rupture of membranes (1.8%) and cesarean delivery
(44.6%) compared to the general obstetric population [21]. Women
with APS were significantly older, but even after adjusting for age,
their risk of these pregnancy complications remained significantly
elevated. There are indications that the complication rates, particularly
for preterm delivery, giving birth to an SGA baby and
preeclampsia, are higher in women who have thrombotic manifestations
of APS.

Possible effects of pregnancy morbidity on the disease course
From the limited available data, it is difficult to determine
whether recurrent pregnancy loss represents a risk factor for
subsequent thrombosis in APS patients. One of the few prospective
studies examining this issue used a definition of 2 miscarriages as
recurrent pregnancy loss and compared patients with aPL with or
without clinical manifestations of APS [23]. In this investigation,
miscarriages were not significantly associated with the subsequent
occurrence of thrombosis, whereas a history of vascular disease
constituted a risk factor for subsequent miscarriages. This is
consistent with other observations, including the finding from the
Euro-Phospholipid cohort, where only 2.5% of women with
exclusively obstetric APS manifestations at study begin developed
a thrombotic event during 5 years of follow-up.These
findings are in marked contrast to the results of a retrospective
analysis of data from three tertiary referral centers in the USA on
65 patients whose only clinical manifestation for the diagnosis of
APS was recurrent pregnancy loss. This subgroup of APS
patients was found to be at high risk of subsequent thrombosis,
particularly when not continuously treated with low-dose aspirin
for the prevention of thrombotic events. Specifically, the nonaspirin-
treated group of 34 patients had 20 events, including
7 venous thromboses, 5 strokes, and 5 transient ischemic attacks,
during a mean follow-up of w8 years, resulting in an event rate of
7.4/100 patient-years, whereas the aspirin-treated group had an
event rate of 1.3/100 patient-years. Mean duration from initial
pregnancy loss to clinical event was 4.2 years. Of note, pregnancy
and the post-partum period may also represent a time of particular
susceptibility to catastrophic APS (for more details, the reader is
referred .

Table 6
Neonatal diseases caused by maternal autoantibodies.
Neonatal disease Maternal disease Causative antibody Proportion of antibody-positive
pregnant women
% Affected neonates of
antibody-positive mothers
Neonatal lupus syndrome SLE, SS, RA, other connective tissue
diseases, or asymptomatic
Anti-SSA/SSB 1-2% Up to 52%
Neonatal autoimmune
thrombocytopenia
Immune thrombocytopenic purpura Anti-platelet 0.1% 10%
Neonatal autoimmune neutropenia Autoimmune neutropenia Anti-neutrophil 1:50,000
Neonatal Graves' disease Graves' disease Anti-TSHa receptor 0.1- 0.4%
Autoimmune hemolytic anemia
of infancy
Autoimmune hemolytic anemia Anti-erythrocyte 1e2:100,000 Very rare
Pemphigus Anti-desmoglein 1:50,000 10e40%
Myasthenia Myasthenia gravis Anti-acetylcholine receptor 1:10,000e2:10,000 10e20%
Hypothyroidism Anti-thyroid 10e15% 0.32e0.56/100,000b
Neonatal APS Primary or secondary APS or
asymptomatic
aPL 2% 30e37%
a TSH thyroid-stimulating hormone receptor.