CHAPTER I

INTRODUCTION
Recurrent pregnancy loss (RPL) is always a traumatic experience for the patient,
and also the most difficult areas in reproductive medicine. According to the Royal
College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline No. 7 In
2011, miscarriage is the spontaneous loss of a pregnancy before the fetus reaches 24
weeks gestation.3 World Health Organization (WHO) recommends that in developing
countries, where the gestational age is often difficult to determine, the loss of pregnancy
when the fetus weighs under 500g is used to determine miscarriage. 1 Ideally, a threshold
of three or more consecutive miscarriages should be used for epidemiological studies
while clinical evaluation may proceed following two first-trimester pregnancy losses.
RPL affects 0.5-1% of couples. 5 This figure turned out to be twice the incidence that may
occur by chance, thus showing that there is an abnormality that can occur. It has been
found that the factors that could cause RPL including cytogenetic factors, anatomical
factors, antiphosopholipid syndrome, thrombophilias, hormonal or metabolic disorders,
infectious, autoimmune, sperm quality and lifestyle issues. 1
Only little consensus exists on the investigation should be done to find the
etiology of RPL along with effective treatment, and only a few are evidence-based. 1 This
paper aims to discuss the definition, epidemiology, etiology, investigation and
management in RPL.

CHAPTER II
LITERARY REVIEW
2.1 Definition
For the purposes of determining whether evaluation for RPL is appropriate,
pregnancy is defined as a clinical pregnancy documented by ultrasonography or
histopathological examination. 2 Williams Obstetrics 23rd edition defines RPL as three or
more consecutive pregnancy losses at 20 weeks or less with fetal weight less than 500
grams.5 World Health Organization (WHO) recommends to developing countries where
the gestational age is often difficult to determine, the loss of pregnancy when the fetus
weighs under 500g was used to determine miscarriage.1 Controversy has existed on the
number of miscarriages required to define RPL.

According to the Royal College of

Obstetricians and Gynecologists (RCOG) Green-top Guideline No. 7 in 2011,

miscarriage is defined as the spontaneous loss of a pregnancy before the fetus reaches 24
weeks of gestation. RPL is therefore defined by three or more consecutive misscariages. 3
In contrast, the American Society for Reproductive Medicine (ASRM) in 2012 has
defined RPL as a distinct disorder defined by two or more failed clinical pregnancies.
Jaslow et al, evaluated more than 1000 women with RPL and their study found no
difference in the frequency of abnormal diagnostic factors between women with two and
those with three or more miscarriages, and argued that full evaluations should be offered
to women who have experienced at least two consecutive losses. Ideally, a threshold of
three or more consecutive miscarriages should be used for epidemiological studies while
clinical evaluation may proceed following two first-trimester pregnancy losses. 1 The
difficulty on handling RPL is for the clinician is to distinguish sporadic miscarriage of
RPL. Self-reported miscarriage are often inaccurate. In a case study, only 71% reported
miscarriages patients themselves could be verified through medical records. Therefore, to
determine whether the evaluation for RPL is required, the pregnancy must be defined as
clinical pregnancies recorded by ultrasound or histopathology examination. 2
RPL is a traumatic experience for the patient, and also the most difficult areas in
reproductive science. To date, there is little consensus on the necessary investigations to
identify the causes and management of effective, and very few are evidence based. 1
2

2.2 Epidemiology
RPL affects 0.5-1% of couples attempting to have children.

Identified causes

such as uterine malformations, antiphospholipid antibodies, parental cytogenetic

anomalies, endocrine disturbances and infection accounted for only 20-50% of RPL.

The risk of miscarriage increases with younger gestational age, with the majority
occuring in the first trimester. The prevalence of miscarriage increases with increasing
maternal age, this occurs due to increased chromosomal abnormalities, possibly due to
decreased oocyte quality, and decreased uterine and ovarian function. Increased paternal
age is also a risk factor for miscarriage. The highest risk of miscarriage in couples where
women over 35 and men over 40 years. The patients obstetric history may also increase
the risk of miscarriage. Retrospective and prospective studies have shown that the risk of
recurrent miscarriage increases after each miscarriage. RPL usually occurs at the same
gestational age. 1
Tabel 1: Risk of miscarriage at specific gestational ages 1

Gestation
Before 6 weeks
6-10 weeks
After10 weeks

Risk of miscarriage (%)

22-57
15
2-3

Tabel 2: Miscarriage rate according to maternal age 1

Maternal age at conception (years)

20-24
25-29
30-34
35-39
40-44
>45

Miscarriage rate (%)

9
11
15
25
51
75

Tabel 3: Risk of miscarriage according to obstetric history 1

Consecutive pregnancies
First pregnancy
After 1 miscarriage
After 2 miscarriage

Risk of miscarriage (%)

5-13
14-21
24-29
3

After 3 miscarriages

31-45

2.3 Etiology
It has been found that the factors that could cause RPL including cytogenetic
factors, anatomical factors, thrombophilic factors, antiphosopholipid syndrome,
immunologic factors, endocrine factors, environmentral factors, infection, male factors,
and unexplained RPL.
2.3.1

Cytogenetic Abnormalities
60% of miscarriage are associated with sporadic chromosomal anomalies,
especially trisomy partly related to age. In miscarriage with normal
karyotypes, multiple morphological abnormalities in the fetus were
diagnosed with transcervical embryoscopy. The risk of sporadic
miscarriage between 6-12 weeks of gestation in women less than 35 years
old is 9% -12%. This risk is increased in women over 35 years due to a
very significant increase of the incidence of trisomy pregnancy. In women
over 40 years, the risk of miscarriage sporadic reached 50%. Aneuploidy
risk at any age is lower in women with RPL compared experiencing
sporadic miscarriage.

The most common genetic cause of RPL is a

balanced reciprocal or robertsonian translocation. Other structural

abnormalities include chromosomal inversions, insertions, mosaicisms.
However, single gene defects such as seen in cystic fibrosis or sickle cell
anemia are seldom associated with RPL

2.3.2 Anatomical abnormalities

2.3.2.1 Congenital uterine anomalies
Congenital uterine malformations caused by disorders of
Mllerian duct development, fusion, canalization, and septal
resorption. Congenital anomalies of the uterus often cause miscarriage
in the second trimester, and in patients with RPL, the contribution of
4

congenital uterine anomalies are not clear. Septate uterus is uterine

abnormality most frequently associated with RPL with the worst
reproductive outcomes with the possibility of miscarriage more than
60%. A longer septum gives worse prognosis. 1
Figure 1.1: Disoders of mullerian duct development

2.3.2.2 Leiomyoma
The more important factor that plays a role in the
relationship between fibroids and fertility is more towards the
location rather than the size of the fibroids. The fibroids can
change the shape of the uterine cavity such as submucosal and
intramural fibroids with an intracavity component was found to
increase the risk of miscarriage. One study found that intramural
fibroids can decrease the implantation in each cycle. A metaanalysis showed a decrease in the pregnancy rate with in vitro
fertilization (IVF), also with women with intramural fibroids that
does not change the shape of the cavity. 1
Figure 1.2 Uterine fibroid locations

2.3.2.3 Intra-uterine adhesions

Adhesion can occur due to intra-uterine trauma, such as
Asherman's syndrome that is caused by endometrial curettage. This
can cause miscarriage because the endometrium is not sufficient
for the development of the fetus, but there are no prospective
studies that may explain the relationship. In the developing
countries,

intra-uterine

adhesions

can

be

caused

genital

tuberculosis. 1

Figure1.2 Intrauterine adhesions

2.3.2.4 Cervical incompetence (insufficiency or dysfunction)

Cervical

incompetence

may

cause

repeated

mid-trimester

miscarriage. 1
2.3.3 Thrombophilic factors
It is hypothesized that thrombophilic disorders can cause thrombosis of the
utero-placental vasculature (spiral arteries and intervillous space) due to an
increase in a hemostatic response. The subsequent impaired placental
perfusion may lead to RPL, fetal death, pre-eclampsia, intra-uterine growth
retardation (IUGR), and placental abruption. 1
Inherited thrombophilia is a genetic condition in which there is an
increased risk of venous thrombosis. The various types are:

Factor V leiden (FVL) mutation

Prothrombin G202110A gene mutation (PGM)
Protein S deficiency
Protein C deficiency
Antithrombin deficiency
Of the cases of inherited thrombophilia, 50-60% are due to the

FVL mutation and PGM. The literature on the association between

maternal inherited thrombophilia and RPL and mostly contradictory.
2.3.4 Autoimmune factors

According to the RCOG, antiphospholipid syndrome is the most

important cause of RPL that can be cured. This syndrome is the only
autoimmune disease in which abortion is part of the diagnostic criteria.
Antiphospholipid antibodies (APAS), lupus anticoagulant, anticardiolipid
antibodies (ACAS) and anti-B2-glycoprotein I antibodies attack the
phospholipid-binding plasma proteins.1
Disorders of pregnancy can occur in the form of:

More than 3 consecutive miscarriages can not be explained

under the age of 10 weeks gestation

More than one dead fetus with normal morphology after 10

weeks' gestation
More than one preterm births under 34 weeks' gestation
because

of

pre-eclampsia,

eclampsia

or

placental

insufficiency. 1
Figure 1.3 Antiphospholipid antibodies against the placenta

Antiphospholipid antibodies against trophoblasts has many effects

towards the placenta, including the inhibition of the differentiation of
villous cytotrophoblasts, extravillous cytotrophoblast invasion into
decidua, induction of apoptosis syncytiotrophoblast, and the initiation of
maternal

inflammatory

pathways

on

the

surface

of

the

syncytiotrophoblast. 2
2.3.5 Allo-immune factors
The Hypothesis that some cases of RPL may be due to the failure
of maternal allo-immune recognition of the pregnancy has never been
proven. There is also no evidence to support the hypothesis that HLA
incompatibility between couples may lead to RPL.1
2.3.5.1 HLA Incompatibility
The human conceptus is a semi-allograft and hence
antigenically foreign to the mother. Therefore the process of
implantation may include mechanisms to prevent allograft
rejection, but once the immunological tolerance becomes
imbalanced, RPL may occur. The human leucocyte antigen (HLAG) seemed to play a major role in immune suppression at the
maternal-fetal interface and placental angiogenesis. HLA-G is
mainly expressed in extravillous trophoblasts (EVTs) of decidual
tissue, and has suppressive effects on NK cells, CD4+ and CD8+ T
cells, B lymphocyctes and antigen presenting cells such as
macrophages and dendritic cells. This interaction was essential for
9

the maternal-fetal immune balance needed for optimal trophoblast

invasion during implantation and placentation.
Recent evidences have indicated that HLA-G played an
important role in the pathogenesis of RPL. Although there were
some controversies, the overall picture in recent years was that
reduced or aberrant HLA-G expression (such as HLA-G
polymorphism) was associated with RPL. Complications during
pregnancy, such as preeclampsia, miscarriage, IUGR, and
premature birth were associated with low or undetectable levels of
soluble HLA-G in the maternal blood circulation. However, studies
that have examined the association between HLA-G 14-bp
insertion/deletion

polymorphism

and

RPL

have

showed

inconsistent, even contradictory results. 5

In a comprehensive meta analysis by Wei Fan et al (2013),
it is shown that there was insufficient evidence to demonstrate a
conclusive association between HLA-G 14-bp insertion/deletion
polymorphism with the risk RPL, whereas a significant
heterogeneity was evident across the individual studies. The
subgroup analysis indicated that there was a significant association
between HLA-G 14-bp insertion/deletion polymorphic variation
and RPL risk in patients with three or more miscarriages. 5
2.3.5.2 Uterine natural killer (NK) cells
Some patients with RPL may lack essential component of
the networks that provide immunological protection for the
embryo. Uterine NK cells appear to regulate placental and
trophoblast growth and local immunomodulation, and control
trophoblast invasion. The relationship between uterine NK cells
and pregnancy outcome in patients with RPL is still under
investigation. 1
2.3.5.3 Granulocyte-macrophage colony stimulating factor (G-CSF)

10

G-CSF is a cytokine with an important regulatory role in

embryo implantation and subsequent development. G-CSF
deficiency in pregnancy adversely impacts on fetal and placental
development. Recent studies has shown that the highest quality
oocytes come from follicles with the highest levels of G-CSF.
Research has been done to investigate the effectiveness of
administering G-CSF in preventing embryo death in women with
RPL. Most of the data show that G-CSF may be effective in the
treatment of unexplained RPL. However further studies are needed
to confirm the effectiveness of this treatment.
2.3.6 Endocrine factors
2.3.6.1 Diabetes Mellitus
Several studies have found that the value of glycosylated
hemoglobin (HbA1C) is high (> 8%) in early pregnancy can
increase early pregnancy loss and congenital malformations. There
is no risk of miscarriage in women with well-controlled diabetes
mellitus. 1
2.3.6.2 Polycystic ovarian syndrome (PCOS)
Recent studies have shown that reproductive outcome did
not differ between patients diagnosed with PCOS and healthy
controls. The two groups had similar live birth and miscarriage
rates.1
2.3.6.3 Thyroid antibodies and disease
There are many conflicting reports, and evidence is still
lacking with regard to the role of thyroid disease. Although the
mechanism is still unclear, it was found that increased serum
thyroid antibodies (thyroid peroxidase or thyroglobulin) are
associated with spontaneous RPL. Hyperthyroidism (Graves'
disease) can cause miscarriage, premature contractions, low fetal
weight, and perinatal mortality. Hypothyroidism can cause

11

infertility and miscarriage in the first trimester, as well as perinatal

morbidity and mortality. 1
2.3.6.4 luteal phase defect and deficiency of progesterone
A functional corpus luteum is essential for successful
implantation and maintenance of early pregnancy, primarily
through progesterone production. A luteal phase defect (defect in
corpus luteum function) with insufficient progesterone production
results in endometrial development unsuitable for embryonic
implantation and is associated with RPL. The existence for this
luteal phase defect is controversial, whether or not it is related to
RPL, mainly because there are inconsistencies in diagnosis and
management. There is no evidence that could be found in literature
regarding a possible association of anti-Mullerian hormone
deficiency and RPL. 1
2.3.7 Environmental factors
No high quality evidence shows the relationship between RPL and
occupational factors, stress, chemical exposure to light, smoke, or
caffeine. Medium-heavy alcohol consumption may increase the risk of
sporadic miscarriage. Physical activity does not increase the risk of RPL.
Recent retrospective study found that obesity is a risk factor for infertility,
miscarriage sporadic, RPL, and pregnancy complications. 1
2.3.8 Infection
No infectious agent has been proven to cause RPL. Ureaplasma
urealyticum, Mycoplasma hominus, chlamydia, Listera monocytogenes,
Toxoplasma gondii, rubella, cytomegalovirus, herpes virus, and other less
frequent pathogens have been identified more frequently in vaginal and
cervical cultures and serum from women with sporadic miscarriages.
However, there are no convincing data that infections cause recurrent
pregnancy loss, therefore there are no clear indications for routinely
testing these organisms for RPL evaluation. Therefore, use of any
antibiotics are nit supported by evidence.2 Pregnancies complicated by
12

untreated syphilis may lead to RPL if it remains untreated in the

subsequent pregnancy, this usually presents with recurrent mid-trimester
miscarriage with a macerated fetus. Genital tuberculosis may cause
implantation failure or early embryonic rejection, leading to RPL and
ectopic pregnancy. 1
2.3.9. Male factors
Standard semen parameters, including sperm morphology, do not
appear to be predictive of RPL. Sperm aneuploidy and DNA
fragmentation have been studied in couples with RPL. Abormal DNA
fragmentation may be seen in advanced paternal age or result from
correctable environmental factors, such as exogenous heat, toxic
exposures, varicoceles, or increased reactive oxygen species in semen.
Although increased rates of sex chromosome disomy have been seen in
sperm from the male partner in couples with recurrent miscarriage,
cytogenic analysis of the products of conception from couples with RPL
does not reveal an increased rate of sex chromosome aneuploidy, thus
suggesting that such cytogenetically abnormal sperm may be selected
against during fertilization. Therefore routine testing for spermploidy or
DNA fragmentation is not recommended.
2.3.10 Unexplained recurrent pregnancy loss
No apparent causative factor is identified in 50%-70% of couples
with RPL. However is it important to emphasize to patients with
unexplained RPL that chance for a future successful pregnancy can exceen
50%-60% depending on maternal age and parity.
2.4 Diagnosis
They who suggested to take the medical examinations are woman who had two or
three miscarriage in a row.
2.4.1
History Taking
Comprehensive evaluation to establish the diagnosis should be
made, including about the history of her disease . Some questions
13

including age, obstetrics history, gynecology history, past medical

history and hereditary diseases, including family illness, a history of
previous surgery, genetic disorders, and social status .
Besides history taking, physical examination are also required
precise

and

meticulous.

complete

history

of

previous

miscarriages events is important, including gestational age when

past miscarriage occurs. When a miscarriage in the second
trimester, any information that could support or rule out the
possibility of cervical incompetence, whether or not the fetus is
macerated and good discovery in the evaluation of uterine
abnormalities, all of them should be reviewed and recorded in the
medical record. The results of investigations that have been done
before, including blood tests, pathology and imaging should also be
obtained.
Table 4. Evaluation of a woman with RPL

14

Here

are

some

methods

to

investigate

the

occurrence of RPL :
Karyotiping
Karyotiping from the conseptionals products
Cytogenic analysis should be carried out on the products of
conception in all patients with RPL. Normal karyotype
usually

indicates

better

prognosis

for

the

next

pregnancy.4 Structural rearrangements of chromosomes in

the fetus can be inherited or sporadic, and is an indication
for karyotyping parents. The role of pre - implantational
genetic diagnosis ( PGD ) with IVF has been reviewed and
has been found not to be cost effective in the management
of RPL.5 In patients with RPL, spontaneous birth rate was
15

50 % ; with PGD miscarriage rate may be decreased , but

only 33 % of women who get pregnant after a cycle of PGD
/ IVF .
Karyotyping from parentals peripheral blood
Proper selective parental karyotyping performed in cases
where chromosomal abnormalities identified in the results
conception.4

Conception

should

be

noted

that

the

investigation is expensive and has limited prognostic value,

low yields for detect any disorders, and it is not an
effective routine to perform karyotyping of all couples with
RPL. The aim is to detect the balance of reciprocal or
Robertsonian translocation, or mosaicism bias that is not
inherited

by

the

balance

on

the

fetus.

However,

chromosomal abnormalities found in the peripheral blood

of the parents are indirect indicators and limited for fetal
karyotype .
Uterus Assessment
According to the RCOG , all women with RPL in the first
trimester or with one or more of the second trimester
should perform a pelvic ultrasound examination to assess
the uterus anatomy.4 After that , if there is a suspicion of
uterine

anomalies,

further

investigations

may

be

performed to confirm the diagnosis, using hysteroscopy,

laparoscopic or pelvic three-dimensional ultrasound. Other
diagnostic

modalities

are

sonohysterography,

hysterosalpingography and magnetic resonance imaging

( MRI ). MRI is rarely used because it is more expensive.
Hysteroscopy is seen as the gold standard for the diagnosis
of intrauterine anomalies, most disorders can also be
treated

during

the

examination

procedure.6

Sonohysterography provides a description of the internal

contours of the uterus, as well as the outer surface and the
16

walls of the uterus. In one study, sonohysterography

provide

more

accurate

results

when

compared

to

hysterosalpingography.7
Hereditary Thrombophilia
Testing for hereditary thrombophilia in women with a
history

of

idiopathic

RPL

is

still

controversial.

No

randomized clinical trials with placebo control to establish

the effectiveness of anticoagulation therapy in preventing
RPL quality. Evidence to help guide the process of
screening is also limited conditions.
According to the American College of Obstetricians and
Gynecologists

Practuce

Bulletin

No.

124,

hereditary

thrombophilia testing is not recommended for women with

a history of RPL or placental abruption, because it is
unclear whether anticoagulation reduces recurrence (level
B recommendation).8 Screening with fasting homocysteine
levels or methylenetetrahydrofolate reductase mutation
analysis also not recommended (level B recommendation).
Examinations should be done is to assess the FVL and
PGM, and antithrombin, protein C and protein S deficiency
(level of recommendation C). Screening it self is still
controversial, and only useful if the results will affect
management

decisions,

and

not

for

the

treatment

indicated for other risk factors.

RCOG recommends that women with RPL in the second
trimester, should be screened for hereditary thrombophilia.
Including tests for FVL, PGM and protein S deficiency (level
D recommendation) .4 It is based on the results of a metaanalysis of retrospective studies that show a strong
association between miscarriage in the second trimester
and hereditary thrombophilia.
Antiphospolipid Syndrome
17

All

women

with

RPL

should

be

screened

for

antiphospholipid syndrome before the next pregnancy. 9

This test included to test the ACA IgG and IgM, and lupus
anticoagulant ( LA ); testing should be done twice, with a
distance of 6-8 weeks, to rule out false positive results.
Diagnosis of antiphospholipid syndrome requires at least
two positive results both for LA or ACA IgG or IgM. Women
with a positive test result and the second negative test
result should have a third test to confirm the diagnosis.
False-positive results may be due to infection, suboptimal
methods of sample collection and preparation, and the lack
of standardization of laboratory testing.
The cause of infection
A recent review article concludes that most patients with a
history of RPL is not affected by the treatment of extensive
infections.10 Exception of the untreated syphilis .
Thyroid function
Thyroid function should be assessed in women who have a
history

of

thyroid

manifestations.

The

disease
American

or

with
Thyroid

the

clinical

Association

recommends measurement of serum thyroid- stimulating

hormone in pregnant women with the following conditions:
11

Symptoms of thyroid disease

From the area that known as iodine drficiency
History of thyroid disease in family or personal
Thyroid peroxides antibody +
Type 1 diabetes
History of premature birth or miscarriage
History of head and neck radiation
Morbid obesity
Infertility
Age over 30 years
Screening in women without symptoms of subclinical
thyroid disease is controversial. When screening for thyroid
18

disease of all women planning a pregnancy is not

recommended, because there is no data to confirm that
the screening had significant results. However, certain
researchers recommend measuring thyroid peroxidase
antibodies in patients with RPL or premature birth, in which
no other cause can be identified.12
Evaluation of ovarian reverse
Taking blood sample to measure the follicle- stimulating
hormone ( FSH ) level on day 3 of the menstrual cycle can
be considered in the evaluation of RPL in women of all age
groups. In a retrospective analysis comparison, serum FSH
day 3 or estradiol, or both, was found to increase as much
as 58 % of women with idiopathic RPL.13
Defect in luteal phase
There is no standard method for diagnostic that available
to assess the actual occurrence and effect of luteal phase
defect. Endometrium biopsy is not recommended, because
studies have shown that it does not predict the fertility
status.

Measurement

of

serum

progesterone

also

unreliable, and can not predict the final outcome of

pregnancy.14
Enforce the medical diagnosis
Laboratory tests may be indicated in women with clinical
manifestations or a history of medical disorders that lead
to RPL
Table 5. Evidence-based approach to the work-up of couples with RPL, to identify a possible underlying
cause

19

Table 6. Controversial factors in the work-up and management of RPL

2.5 1Management
Treatments for recurrent miscarriage is based on the etiology.
However, all couples must be treated sensitively , sympathetic , and
with the proper emotional support. The best practice is to refer the
couple to a specialist clinic.
2.5.1

Anatomical
Correction of septate defect in particular may have beneficial effects and should
be considered in woman with RPL. Clinical management with Asherman
syndrome or intrauterine synechiae, uterine fibroids, and uterine polyps remain
controversial, some data showed that surgical treatment did not reduces the risk of
20

pregnancy loss. Cerclage cervix is recommended to be done at

gestational
2.5.2

age

14-16

incompetence.
Autoimmune
Women with persistent

weeks

lupus

in

the

case

anticoagulant,

of

cervical

anticardiolipin

antibodies and hereditary trombophilia can be treated with low dose aspirin (81 mg) and enoxaparin (40 mg subcutaneously),
2.5.3

during subsequent pregnancies.

Alloimmune
Immunomodulatory treatments for RPL in the setting of one or more finding have
not been proven effective. Treatment with intravenous immunoglobulin (IVIG)
has also been proposed for unexplained pregnancy loss. However, several trials
and meta-analyses conclude that IVIG is ineffective for primary RPL, thus this

2.5.4

treatment is not recommended.

Endocrine
In women with PCOS, the risk of RPL may be reduced by giving
1700 mg metformin daily. Ultrasound examination can also be
carried out to assess the presence of PCOS and uterine
abnormalities.
Any disorder that associated with thyroid hormone can be
detected and treated with ease. First we try to maintain the TSH
values in 4.0-5.0 mIU/L, but if the TSH was not in the range, we
can maintain it by giving thyroid hormone replacement. As for
women who are suspected of suffering from diabetes mellitus,
glucose and hemoglobin AIC monitoring can be done.

2.5.5

Infections
Routine serological tests, cultures cervical and endometrial
biopsy to detect the presence of infection in women with a
history of RPL is not recommended. Evaluation should be
performed only on those who are clinically suffering from
cervicitis, chronic or recurrent bacterial vaginosis or complaints

2.5.6

of pelvic infection.
Unexplained etiology
21

Aspirin and low-molecular-weight heparin are prescribed for

woman with unexplained RPL, with the goal of improving the rate
of live births.
Table 7. Therapeutic Interventions for RPL based on Etiology

Generally, as many as 70-75 % of women who had a history of

RPL can be successful in the next pregnancy, except in those with
impaired or incompetent cervix antiphospholipid antibodies.
Table 8. Suspected cause of RPL

Table 9. Treatment for RPL

Etiology
Anatomical15

Treatment
Transabdominal
Cervicoisthmus

Outcome
- 25% had two successful
Cerclage

(TCC) has been advocated as

a

treatment

for

second-

consecutive
pregnancies after TCC
- Fetal survival after this
22

trimester

miscarriage

and

procedures was 85,2%

prevention of early preterm

labour in selected woman
with

previous

failed

transvaginal cerclage and/or a

very short and scarred cervix
81 mg aspirin once daily - Rate of miscarriage 9%
- Live birth 91%
orally
plus
LMWH
- Rate of pre-eclampsia
enoxaparin
40
mg
7%
subcutaneously / day
5 mg folic acid daily before Live birth rate of woman

Antiphospolipid
Syndrome16,17,18

conception, low dose aspirin, treated with enoxaparin

40 mg/day of enoxaparin was 86% compared with

Hormonal disorder

19,20

subcutaneously

29% woman taking low

Progesterone

dose aspirin alone

No
statistically

supplementation 10 mg/day

difference in the risk of

miscarriage

between

control and trial group

(OR 0,38, 95% CI 0,2Metformin

0,7)
supllementation Diminished

1700-3000 mg/day in woman of

PCOS

until

the

fetal

entire restriction,

pregnancy

incidences
growth
preterm

labor, early pregnancy

loss and increased live

Alloimmune

21,22

birth rates.
IVIg 500mg/kg/month until Live birth

rate

was

18-20 weeks of gestation, 14,7%

approximate total dose of
Unexplained RPL

23,24

150-180 g
80 mg of aspirin daily plus - 54,5% gave birth to live
subcutaneous

nadroparin

infant
23

(2850 IU)

- Woman who pregnant,

live birth rates were
69,1%

24

CHAPTER III
CONCULSION
RPL is spontaneous abortion that occurs three times or more in a row. This
situation is a problem that requires special attention. Etiology of RPL is cytogenetic
factors , anatomical , antiphosopholipid syndrome, thrombophilias , hormonal or
metabolic disorders , infectious , autoimmune , sperm quality and lifestyle issues .
Some proper handling and safe to overcome the incidence of RPL had been
discovered. Since a woman is diagnosed RPL, she should do some medical
examination to prevent the miscarriages and eventually gave birth to the fetus is
viable. Some tests that could be done including genetic examination, anatomy,
endocrinology and immunology factors. Generally the management of RPL is based
on the underlying etiology. Examination using ultrasound can help review the
development of the fetus in the uterus.

25

REFERENCES
1. Niekerk, Elzan C Van, Igno Siebert, and Theunis Frans Kruger. An Evidencebased Approach to Recurrent Pregnancy Loss. South African Journal of
Obstetrics and Gynaecology S Afr J OG 19.3 (2013): 61-5.
2. Evaluation and Treatment of Recurrent Pregnancy Loss: A Committee Opinion.
Fertility and Sterility 98.5 (2012): 1103-111. American Society for Reproductive
Medicine.
3. The Investigation and Treatment of Couples with Recurrent Firsttrimester and
Second-trimester Miscarriage. Green-top Guideline No. 173 (2011): 1-18. Royal
College of Obstetricians and Gynaecologists.
4. Cunningham, F Gary, et al. 2010. Obstetri Williams 23rd ed. USA : The McGrawHill Companies, Inc.
5. Fan Wei, Shangwei Li, Zhongying Huang, Qiong Chen. Relationship between
HLA-G polymorphism and susceptibility to recurrent miscarriage: a meta analysis
of non family based studies. J Assist Reprod Genet (2014) 31: 173-184.
6. Homer HA, Li TC, Cooke ID. The septate uterus: A review of management and
reproductive

outcome.

Fertil

Steril

2000;73(1):1-14.

[http://dx.doi.org/10.1016%2FS0015-0282%2899%2900480-X]
7. Soares SR, Barbosa dos Reis MM, Camargos AF. Diagnostic accuracy of
sonohysterography, transvaginal sonography, and hysterosalpingography in
patients with uterine cavity diseases. Fertil Steril 2000;73(2):406-411.
[http://dx.doi.org/10.1016%2FS0015-0282%2899%2900532-4]
8. Lockwood C, Wendel G. Committee on Practise Bulletins Obstetrics. Practice
Bulletin No. 124: Inherited thrombophilias in pregnancy. Obstet Gynecol
2011;118:730-740. [http://dx.doi.org/10.1097%2FAOG.0b013e3182310c6f]
9. Vinatier D, Dufour P, Cosson M, Houpeau JL. Antiphospholipid syndrome and
recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol 2001;96(1):37-50.
[http://dx.doi.org/10.1016%2 FS0301-2115%2800%2900404-8]
10. Petrozza
JC.
Recurrent
early
pregnancy
loss.
January

2011.

http://www.emedicine.medscape.com (accessed 24 August 2015).

11. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American
Thyroid Association for the diagnosis and management of thyroid disease during

26

pregnancy

and

postpartum.

Thyroid

2011;21(10):1081-1125.

[http://dx.doi.org/10.1089%2Fthy.2011.0087]
12. Alexander EK. Thyroid autoantibodies and pregnancy risk. Nat Rev Endocrinol
2011;7(9):501-502. [http://dx.doi.org/10.1038/nrendo.2011.116]
13. James D, Steer PJ, Weiner CP, Gonik B. High Risk Pregnancy Management
Options. 4th ed. St Louis: Saunders, 2011:75-87.
14. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin.
Management of recurrent pregnancy loss. No. 24, February 2001. Int J Gynaecol
Obstet

2002;78(2):179-190.

[http://dx.doi.org/10.1016%2FS0020-

7292%2802%2900197-2]
15. Anthony GS, Walker RG, Cameron AD, Price JL, Walker JJ, Calder AA.
Transabdominal cervico-isthmic cerclage in the management of cervical
incompetence. Eur J Obstet Gynecol Reprod Biol 1997;72:12730.
16. Mohamed KAA, Saad AS. Enoxaparin and aspirin therapy for recurrent
pregnancy loss due to anti-phospholipid syndrome (APS). Middle East Fertility
Society Journal 2014. 19 ed. 176-182.
17. Carp H,Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in
women with consecutive recurrent miscarriages and hereditary thrombophilia. J
Thromb Haemost 2003;1:4338.
18. Gris JC,Mercier E,Qur I, Lavigne-Lissalde G, Cochery-Nouvellon E,Hoffet M,
et al. Low-molecular weight heparin versus low-dose aspirin in women with one
fetal loss and constitutional thrombophilic disorder.Blood 2004;103:36959.
19. Haas DM,Ramsey PS. Progestogen for preventing miscarriage. Cochrane
Database Syst Rev 2008;(2):CD003511.
20. Jakubowicz DJ, Iuorno MJ, Jakubowicz S,Roberts KA,Nestler JE. Effects of
metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin
Endocrinol Metab 2002;87:5249.
21. Ata B, Tan SL, Shehata F, Holzer H, Buckett W. A systematic review of
intravenous immunoglobulin for treatment of unexplained recurrent miscarriage.
Fertil Steril 2011;95:10805
22. Stephenson MD, et al. Intravenous Immunoglobulin and Idiopathic Secondary
Recurrent Miscarriage: A Multicentered Randomized Placebo-Controlled Trial.
NCBI, Hum Reprod. 2010 Sep; 25(9): 2203-2209.
23. Kaandorp SP, et al. Aspirin plus heparin or aspirin alone in women with recurrent
miscarriage. The New England Journal of Medicine. 2010; 362 : 1586-96.
27

24.

Clark P,Walker ID, Langhorne P,Crichton L,Thomson A, Greaves M, et

al.; Scottish Pregnancy Intervention Study (SPIN) collaborators. SPIN (Scottish

Pregnancy Intervention) study: a multicenter, randomized controlled trial of lowmolecular-weight heparin and low-dose aspirin in women with recurrent
miscarriage. Blood 2010;115:41627.

28