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.
