Recurrent Pregnancy LossStillbirth
DOÇENT DOKTOR ZİYA KALEM
İSTİNYE ÜNİVERSİTESİ LİV
BAHÇEŞEHİR HASTANESİ
Miscarriage is the most common complication of pregnancy.
American Society for Reproductive Medicine defines recurrent
pregnancy loss (RPL) as two or more failed pregnancies, not
necessarily consecutive.
5% of couples attempting pregnancy will experience
two miscarriages, and 1% of couples will experience
three or more losses.
Despite a comprehensive evaluation, a cause for RPL can be
discerned in less than half of cases.
In general, a patient and her partner with unexplained RPL have a
75% chance of a successful future pregnancy,
The subsequent loss rate for a patient with antiphospholipid
antibody syndrome may exceed 90% in an untreated pregnancy.
RPL is more likely to occur in couples with similar reproductive
histories, including a prior stillbirth, an anomalous fetus, a delayed
conception, a family history of recurrent miscarriage, a preterm
birth, or a previous child with growth restriction
The limited number of bona fide causes includes structural
chromosome rearrangements and monogenetic abnormalities,
certain uterine anomalies, antiphospholipid antibody syndrome,
and severe endocrine disorders
Genetic Abnormalities
Genetic Abnormalities
MATERNAL AGE–RELATED ANEUPLOIDY
Maternal age is strongly associated with the risk for both SAB and
aneuploidy
Cytogenetic alterations are identified in 50% to 60% of
spontaneous abortion (SAB) specimens.
Common karyotypic abnormalities include autosomal trisomy
(60%), monosomyX (20%), and polyploidy (20%).
The risk for trisomy in a clinically recognized pregnancy increases
from about 2% to 3% for women in their twenties to 25% or more
for women in their forties
A large prospective Danish cohort study tracking 634,272
women through 1,221,546 pregnancies found SAB rates of less
than 12% for women 20 to 29 years old, 15% for those 30 to 34
years old, 24.6% for those 35 to 39 years old, 51% for those 40
to 44 years old, and 93.4% for those older than 44 years.
Women who have had ovarian deficiency, either as a result of
surgery or as a congenital abnormality, have an increased risk for
trisomy 21.
Theories for nondisjunction have been proposed.
- Absent or reduced recombination events
- Abnormal chiasma position or function
- Premature separation of sister chromatids
- Chronic oxidative stress
- Abnormalities in folate metabolism
- Progressive shortening of oocyte telomere length
ROBERTSONIAN AND RECIPROCAL TRANSLOCATIONS
Approximately 3% to 5% of couples who experience RPL have
a balanced structural chromosome rearrangement, as opposed
to the rate of 0.2% in the general population
In couples with RPL; 50% had balancedreciprocal translocations,
24% were robertsonian translocations, and 12% were mosaic for a
female sex chromosome abnormality
The remaining 14% had other types of rearrangements
including pericentric and paracentric inversions
Balanced rearrangements are known to predispose to errors in
meiosis, resulting in abnormal offspring or RPL.
Live birth rate for carriers of a reciprocal balanced translocation
was 63% and 69% among those with a robertsonian translocation.
There is no clear evidence to suggest a difference in risk for RPL
between a maternal or paternal carrier, although men more often
present with infertility.
SINGLE-GENE DISORDERS
Most examples of known single-gene causes of RPL are associated
with second-trimester miscarriage.
Lethal multiple pterygium syndromes are a collection of autosomal
recessive and X-linked recessive disorders that are associated with
fetal death at 14 to 20 weeks (arthrogryposis, hydrocephalus,
hydrops, cystic hygromas, dental anomalies and cutaneous
manifestations, chondrodysplasia punctata type 2, Rett syndrome,
oral-facialdigital type 1, Aicardi syndrome, and Goltz syndrome.).
MALE GENETIC FACTORS
The paternal genome is equally important in fertilization,
embryologic development, and placental function.
USE OF ASSISTED REPRODUCTIVE TECHNOLOGIES
An argument has been proffered that patients with RPL could
benefit from ART, including in vitro fertilization (IVF) with or
without preimplantation genetic screening (PGS) for chromosomal
abnormalities commonly found in abortus specimens.
Although the use of ART is appealing for couples with unexplained
RPL who are desperate for a successful outcome, the prognosis for
live birth in subsequent pregnancy without any intervention is
approximately 75%
Thrombophilias
There are two types of thrombophilia putatively associated with RPL
THROMBOPHILIAS
Inherited thrombophilias
• Factor V Leiden
• Prothrombin gene mutation
• Other
Antiphospholipid antibody syndrome
INHERITED THROMBOPHILIAS
The possible link between inherited thrombophilias and adverse
obstetric outcomes has become a highly debated issue.
Researchers and clinicians hypothesized that women or possibly
fetuses with a genetic predisposition to thromboembolism could
have thrombosis of the uteroplacental circulation and resultant
complications such as preeclampsia, placental abruption, growth
restriction, or fetal loss.
The early literature suggested a causal relationship between
pregnancy loss and FVL.
A meta-analysis of 31 studies reported a modest link between FVL
and first-trimester SAB, with an OR of 2.01 (95% CI, 1.13 to 3.58) but
a stronger association with late (> 19 weeks) nonrecurrent fetal loss
(OR = 3.26; 95% CI, 1.82 to 5.83).
A large case-control study of patients with recurrent stillbirths
beyond 22 weeks showed an even stronger association with FVL (OR
= 7.83; 95% CI, 2.83 to 21.67)
Dudding and Attia conducted a meta-analysis of the link between
FVL and adverse pregnancy events and noted no association with
first-trimester miscarriage but a strong association with two or more
second- or third-trimester fetal losses (OR =10.7; 95% CI, 4.0 to 28.5
Prospective studies have not proven causality between inherited
thrombophilia and miscarriage, so screening and treatment are no
longer recommended
ANTIPHOSPHOLIPID ANTIBODY SYNDROME
The antiphospholipid antibody syndrome (APS) is defined by
both clinical and laboratory criteria
The clinical criteria include a history of deep venous or arterial
thrombosis and characteristic obstetric complications including RPL
Laboratory criteria include the presence of medium to high titers of
IgG/IgM anticardiolipin antibodies, IgG/IgM anti-β2 - glycoprotein-1
antibodies at levels in the 99th percentile or higher, or a lupus
anticoagulant on two or more occasions at least 12 weeks apart.
At least one clinical criterion and one laboratory criterion must
be present for definitive diagnosis.
Persistently high levels of aPLs appear to be associated with
obstetric complications, including fetal loss after 9 weeks’
gestation, abruption, severe preeclampsia, and intrauterine
growth restriction, in about 15% to 20% of affected patients.
Between 5% and 15% of women with recurrent SAB have
documented aPL, compared with 2% to 5% in the general
obstetric population.
In patients with strictly defined APS, the pregnancy failure rate in
untreated pregnancies is up to 90%, with 52% of miscarriages
occurring early (< 10 weeks) and 38% occurring late (> 10 weeks).
TREATMENT OF ANTIPHOSPHOLIPID ANTIBODY
SYNDROME AND INHERITED THROMBOPHILIAS
Proposed interventions include low-molecular-weight heparin
(LMWH), unfractionated heparin, aspirin (81 and 325âmg),
prednisone, and intravenous immunoglobulin (IVIG).
The combination of heparin and aspirin modestly increased the
likelihood of a live birth compared with aspirin alone
Endocrine Disorders
Three endocrine disorders are reported to be associated with RPL.
THYROID DISEASE
Autoimmune thyroid disease is the most common cause of
hypothyroidism, with a reported prevalence of 5% to 20% among
pregnant women.
Normal maternal thyroid function is important for trophoblast
function and maintenance of early pregnancy.
Antithyroid antibodies are more common in women with RPL.
Nonrandomized studies have suggested that levothyroxine
therapy may decrease SAB rates in euthyroid, thyroid-antibody
positive women and in those with subclinical hypothyroidism.
A recent Cochrane Database Review recommends treating
women with subclinical hypothyroidism to reduce the risk for
miscarriage
LUTEAL PHASE DEFECT
A luteal phase defect (LPD) is described as a failure to develop
fully mature secretory endometrium
The prevalence of LPDs among patients with early RPL is reported
to be up to 35%.
Studies of available treatments, including ovulation induction
and progesterone supplementation, intended to reduce the rate of
RPL, have conflicting results.
A Cochrane Review did show that progesterone supplementation
was beneficial in women with a history of three or more
consecutive pregnancy losses (OR = 0.38; 95% CI, 0.2 to 0.7).
For a patient with RPL and an LPD accompanied by
hyperprolactinemia, bromocriptine is a treatment option that
appears to improve live birth rates
POLYCYSTIC OVARIAN SYNDROME
Initial reports suggested that polycystic ovarian syndrome
(PCOS) was associated with recurrent miscarriage, but causal
links between hyperandrogenism, hyperinsulinemia, and RPL
have been difficult to establish.
Those patients with overt diabetes clearly have up to a threefold
increased risk for spontaneous pregnancy loss, so women with
risk factors should be screened by routine
measures and treated accordingly
Uterine Malformations and
Endometrial Abnormalities
Women with müllerian tract anomalies appear to have an
increased risk for RPL.
the prevalence of congenital uterine anomalies is 16.7% among
women with three or more miscarriages
The various theories proposed to account for the association
between uterine anomalies and RPL include decreased
vascularity in the septum, increased inflammation, and a
reduction in sensitivity to steroid hormones
Although reductions in RPL with surgical correction have been
reported in several large series, there have been no prospective
randomized trials to validate this intervention
The presence of myomas, submucous myomas that distort the
uterine cavity have been suggested as causes of recurrent
miscarriage and reduced IVF success rates.
Other uterine defects, such as Asherman syndrome and polyps,
have been posited as causes of recurrent SAB, and descriptive
series suggest improvement in pregnancy outcomes after
hysteroscopic resection
Environmental Factors
CAFFEINE
ALCOHOL
OBESITY
Other Factors Associated with
Recurrent Pregnancy Loss
IMMUNOLOGIC PROCESSES
There are conflicting data with regard to the role of immunologic
mechanisms in RPL.
Maternal antipaternal lymphocytoxic antibodies (i.e.,blocking
antibodies) acted to shield the placenta from a maternal
immune response.
Researchers proposed that excessive human leukocyte antigen
(HLA) sharing or an abnormally high HLA conformity by prospective
parents would lead to the absence of such antibodies
This, in turn, would expose placental antigens to a more cytotoxic
maternal immune response
CELIAC DISEASE
Celiac disease is known to affect other target organs, including
the liver, thyroid, skin, and reproductive tract
Epidemiologic studies suggest an association between celiac
disease and adverse reproductive outcomes, including RPL, low
birth weight, preterm birth, and infertility
OTHER INFECTIOUS AND INFLAMMATORY PROCESSES
Although Chlamydia trachomatis, Ureaplasma urealyticum,
Mycoplasma hominis, human cytomegalovirus, adeno-associated
virus, rubella, herpesviruses, and human papillomaviruses
have been identified more frequently in genital tract cultures
from women with RPL, there are no data establishing an association
between chronic genital tract carriage of bacteria and
recurrent SAB, or data indicating that empiric treatment offers
benefit.
The presence of bacterial vaginosis during the first trimester of
pregnancy has been repeatedly reported as a risk factor for secondtrimester pregnancy loss.
Inherited Bleeding Disorders
Maintaining hemostatic balance is critical for implantation and
pregnancy maintenance
Adverse reproductive outcomes including RPL have been reported
in patients with bleeding disorders , including heritable and
acquired deficiencies of fibrinogen or factor XIII deficiency
An increased risk for miscarriage is reported in patients with
deficient or defective fibrinogen, including diagnoses of
afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemia
Evaluation of Patients with Recurrent Pregnancy Loss
history
physical examination
laboratory assessment (genetic, anatomic, endocrine,
and hematologic studies)
parental karyotypes, karyotyping of miscarriage
specimens, and assessment of the placental
pathology for trophoblast inclusions or chronic
inflammatory processes appear to be reasonable
diagnostic studies
Stillbirth
Epidemiology
Stillbirth, defined as fetal death at 20 weeks or more of gestation,
is one of the most common adverse pregnancy outcomes.
It has been estimated that 98% of all stillbirths occur in low- and
middle-income countries
Maternal age and parity are significant risk factors for stillbirth.
There is a U-shaped relationship between maternal age
and stillbirth
The peak risk period was 37 to 41 weeks.
The risk for stillbirth at 37 to 41 weeks for women 35 to 39 years
old was 1 in 382 ongoing pregnancies, and for women 40 years or
older it was 1 in 267 ongoing pregnancies.
Stillbirth rates are lowest for women with one prior pregnancy
(4.87 per 1000 births).
Multiple gestation and use of assisted reproductive technologies
(ART) are also risk factors for stillbirth.
The stillbirth rate is 2.8-fold higher for twins and 4.8-fold higher for
triplet and higher-order pregnancies compared with singletons
Compared with spontaneously conceived singleton pregnancies,
singleton pregnancies from in vitro fertilization (IVF) or
intracytoplasmic sperm injection (ICSI) procedures had more than
four times the risk for stillbirth (odds ratio [OR] = 4.44; 95% CI,
2.38 to 8.28)
In most studies, previous stillbirth is associated with an increased
recurrence rate of stillbirth (10-fold increased risk for subsequent
stillbirths).
Previous cesarean delivery as a risk factor for stillbirth is
controversial
In pregnancy, obesity increases the risk for hypertension
and diabetes and is an independent risk factor for stillbirth
Pre-pregnancy obesity was associated with a 3.5- to 4.6-fold
increased risk for stillbirth after 37 weeks’ gestation.
Smoking, another modifiable risk factor, has been associated
with a 36% increase in the odds of stillbirth (OR = 1.36; 95% CI,
1.27 to 1.46).
Alcohol use, illicit drug use, low maternal education level, and
lack of or inadequate prenatal care have all been associated with
increased stillbirth rates
Pathogenesis
INFECTION
Infection is believed to be associated with approximately 10%
to 20% of stillbirths in developed countries.
Infectious agents may result in stillbirth by producing direct fetal
infection, placental dysfunction, or severe maternal illness.
The most common is an ascending infection from the vagina into
the space between the maternal decidua and the maternal
chorion.
Maternal systemic infections may also spread hematogenously
and reach the fetus through the placental villi (villitis).
These types of infections typically involve the fetal liver.
Syphilis, which is increasingly uncommon in the United States, is
still responsible for some stillbirths, especially in endemic areas.
Treponema pallidum, the causative agent, can cross the placenta
and infect the fetus after 14 weeks’ gestation, with risk for fetal
infection increasing with gestational age.
Other spirochetal diseases causing stillbirth include leptospirosis
and Lyme disease.
Bacterial pathogens implicated in stillbirth include Escherichia
coli, group B streptococci, Ureaplasma urealyticum, Mycoplasma
hominus, Bacteroides species, Gardnerella, Mobiluncus species,
and various enterococci, which produce ascending infection.
Malaria may be a cause of stillbirth in women who contract a
first infection during pregnancy. Other, less common organisms
associated with fetal death include Toxoplasma gondii and
Listeria monocytogenes.
When parvovirus is responsible for stillbirth, themechanism is
most often destruction of erythropoietic tissue leading to severe
anemia and hydrops.
Other viral pathogens include enteroviruses, such as
coxsackieviruses and echoviruses, as well as cytomegalovirus
(CMV).
MATERNAL MEDICAL CONDITIONS
Hypertensive Disorders
Hypertensive disorders of pregnancy complicate 10% to 16%
of pregnancies and is a significant cause of stillbirth.
9.2% of stillbirths were associated with hypertensive disorders.
Diabetes Mellitus
Diabetes mellitus (DM) affects 2% to 5% of all pregnancies and
is associated with about 4% of stillbirths.
The rate of stillbirth was 1.5% in diabetic pregnancies,
five times that seen in the nondiabetic population, with the
majority occurring between 34 and 40 gestational weeks.
Thyroid Disease
Maternal hyperthyroidism in pregnancy is rare, occurring with
a prevalence of 0.05% to 0.2%.
Graves disease, the most common cause of hyperthyroidism,
results in fetal or neonatal thyrotoxicosis in about 1% of cases
because of the transplacental passage of thyroid-stimulating
immunoglobulins, and it is associated with an increased
stillbirth rate of 7%
Hypothyroidism, both overt and subclinical, is relatively common,
occurring in about 2.5% of pregnancies.
Overt hypothyroidism places women at increased risk for
pregnancy-induced hypertension,51 SGA infants,51 and stillbirth
with a rate of 12/1000 to 20/1000.
An increased stillbirth rate has been noted in euthyroid women
with high serum antithyroid peroxidase (TPO) antibody
concentrations, as seen in Hashimoto thyroiditis.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) has an overall prevalence
of less than 1%, with a stillbirth rate of 40 to 150 per 1000.
Cause of stillbirth is neonatal lupus erythematosus with congenital
atrioventricular (AV) block.
Antiphospholipid antibodies are present in over a third of patients
with SLE and are associated with an increased risk for thrombosis
and damage to the uteroplacental vasculature.
fetal death was more common in those with antiphospholipid
antibodies (38%) than in those without antibodies (16%)
Renal Disease
The association of renal disease with stillbirth depends on the
severity of renal impairment and the presence of hypertension.
There is a positive linear relationship between maternal
creatinine levels and stillbirth rates.
Intrahepatic Cholestasis of Pregnancy
Intrahepatic cholestasis of pregnancy (ICP), the most common
form of noninfectious liver disease occurring in pregnancy, has
been associated with an increased stillbirth rate of 12 to
30/1000 affected pregnancies
ICP is characterized by pruritus and an elevation in serum bile
acid concentration, but the exact mechanism of the associated
stillbirth is unknown.
Thrombophilias
Antiphospholipid antibody syndrome (APS) is an autoimmune
disorder characterized by the presence of antiphospholipid
antibodies, thrombosis, and obstetric complications.
The mechanism of pregnancy loss remains uncertain, but
placental inflammation, thrombosis, and decidual vasculopathy
are involved.
The role in stillbirth of heritable coagulopathies or
thrombophilias that involve deficiencies or abnormalities in
anticoagulant proteins or an increase in procoagulant proteins is
unclear.
CONDITIONS RELATED TO THE FETUS
Red Cell Alloimmunization
More than 50 different red cell antigens have been reported to
be associated with hemolytic disease of the fetus and newborn.
Maternal alloimmunization to non-RhD antigens continues to
contribute to the occurrence of stillbirth.
Platelet Alloimmunization
Chromosomal Abnormalities
Structural Anomalies
Fetomaternal Hemorrhage
Fetal Growth Restriction
Umbilical Cord Pathology
Umbilical cord abnormalities account for 3% to 15% of stillbirths.
Velamentous insertion of the umbilical cord occurs when vessels
insert on the membranes rather than on the placenta.
It may cause stillbirth if it leads to a vasa previa
Umbilical cord occlusion results in cessation of blood flow
to the fetus. The mechanisms whereby cord accidents could lead
to stillbirth include intermittent disruption of blood flow such
as cord prolapse, fetal blood loss through cord hemorrhage,
intrinsic cord abnormalities, and entanglement of the cords in
the case of monochorionic twins
Umbilical cord torsion has been reported as a cause of fetal
death and is seen most frequently at the fetal end of the cord.
Umbilical cord abnormalities accounted for 10% of possible or
probable causes of death and were more common in stillbirths
of greater than 32 weeks’ gestation.
Diagnosis and Evaluation
A complete postmortem evaluation is recommended in all
cases of stillbirth
Autopsy has been found to provide information on a cause of
death in over 30% of cases
Genetic evaluation should be offered in all cases of stillbirth
An abnormal fetal karyotype has been noted in 6% to 13% of
all stillbirths tested
Prevention of Stillbirth
Improved treatment of maternal medical disorders such as diabetes
and hypertension has clearly decreased the risk for stillbirth
in these situations. The risk for stillbirth associated with APS is
decreased with treatment (prophylactic heparin or lowmolecularweight heparin and low-dosage aspirin).