Recurrent

Pregnancy Loss

Definition

of 3 or more spontaneous and

consecutive pregnancies
RCOG Guideline No. 17, May 2003

of 2 or 3 or more consecutive pregnancy

losses
ACOG Practice Bulletin No. 24, Feb 2001

Incidence
15 to 20%
The most widely accepted rate of loss for a
"single spontaneous abortion
80% (4 in 5) of spontaneous abortions
occur in the first trimester of pregnancy
RPL affects 2-4% of reproductive age
couples
Stephenson M, Kutteh WH. Evaluation and management of recurrent
early pregnancy loss. Clin Obstet Gynecol 2007

Number of Patients with RPL

UP-PGH, High Risk Clinic
January-March 2011

Risk
Factors
MAJOR RISK FACTORS
Gestational age of the pregnancy
Maternal age
Past obstetrical history

Risk
Factors
GESTATIONAL AGE
Abnormalities present in
70%
5.6%

1st trimester losses

2nd and 3rd trimester losses

RPL based on Gestational age

UP-PGH, High Risk Clinic
January-March 2011

Risk
Factors
MATERNAL AGE

RPL rate

Under 30y/o

14 %

Above 40y/o

40%

The Practice Committee of the American Society for Reproductive Medicine.

Aging and infertility in women. Fertil Steril 2006

Maternal age
UP-PGH, High Risk Clinic
January-March 2011

N= 17

Risk
Factors
PAST OBSTETRICAL HISTORY
Primigravid

4-5%

Poor OB History

24%

Gravidity
UP-PGH, High Risk Clinic
January-March 2011

N=17

Genetic Factors

Genetic
Factors
56% Trisomy 16, 22 and 15
20% Polypoid
18% Monosomic for chromosome X
4% Unbalanced translocations

Causes of RPL
Parental Karyotyping
Recommendations
ACOG
Couples with RPL should be tested for parental balanced
chromosome abnormalities
Level C
RCOG
All couples with a history of RPL should have peripheral blood
karyotyping performed and a (+) finding should prompt referral to
a clinical geneticist
Level IV grade C

Causes of RPL
Cytogenetic analysis of the products of conception
Recommendations
RCOG
In all couples with a history of RPL, cytogenetic
analysis of the products of conception should be
performed if the next pregnancy fails
Level IV grade C

Anatomical Factors

Anatomical
Factors

Congenital uterine anomalies

unicornuate and bicornuate uteri

Fundal filling defects or intrauterine

abnormalities in the upper two-thirds
of the uterine cavity
fibroids and polyps greater than 1.0 cm
septa greater than 1.0 cm wide and 1.0 cm
deep
Ashermans syndrome adhesions.

Diagnostic factors identified in 1020 women with 2 vs 3 or more recurrent pregnancy losses
Jaslow, Carney, Kutteh MD et al, Fertility and Sterility Vol. 93, No. 4, March 1, 2010
2010 American Society for Reproductive Medicine, Published by Elsevier Inc.

Anatomical
Factors
Diagnostics
Hysterosalpingogram (HSG)
2-D pelvic ultrasound +/- Sonohysterography
3D Ultrasound
Laparoscopy
Hysteroscopy

Causes of RPL
Anatomical Factors
Recommendations
All women with RPL should have a pelvic
ultrasound to assess uterine anatomy and
morphology
Women with RPL and a uterine septum should
undergo hysteroscopic evaluation and resection

Hormonal Abnormalities

Hormonal
Abnormalities

Generally considered luteal phase defects

Result from inadequate progesterone
effect on the uterine endometrial lining
PCOS
36 56% of RPL
levels of androgen
No known therapy in decreasing the risk of pregnancy loss in
women with RPL

Causes of RPL
Hormonal Abnormalities
Recommendations
ACOG

An association between the luteal phase defect and RPL is controversial. LPD should be
confirmed by endometrial biopsy

Luteal phase support with progesterone is of unproven efficacy

Level B

RCOG

Polycystic ovary morphology itself does not predict an increased risk of future pregnancy
loss among ovulatory women with a history of RPL who conceive spontaneously
Level III grade B

Prepregnancy suppression of high LH concentration among ovulatory women with RPL

and PCOS does not improve the live birth rate
Level Ib grade A

There is insufficient evidence to evaluate the effect of progesterone supplementation in

pregnancy to prevent a miscarriage
Level Ia grade A

There is insufficient evidence to evaluate the effect of hCG in pregnancy to prevent a

miscarriage
Level Ib grade A

Metabolic Abnormalities

Metabolic Abnormalities
Thyroid disease
2% of women with midtrimester loss were
hypothyroid

Diabetes mellitus
if well-controlled, it is NOT associated with
recurrent pregnancy loss

Causes of RPL
Metabolic Disorders
Recommendations
ACOG
Tests for glucose intolerance, thyroid abnormalities and anti-thyroid
antibodies are not recommended in the evaluation of otherwise
normal women with RPL
Level C

RCOG
Routine screening for occult DM and thyroid disease with oral glucose
tolerance test and thyroid function tests in asymptomatic women
presenting with RPL is uninformative
Routine screening for thyroid disease in women with RPL is not
recommended
Level III grade B

Infectious Diseases

Antiphospholipid syndrome (APS): Where does it come from?

Sherer, Blank, Shoenfeld et al, 2007 Elsevier Ltd.

Infectious
Causes
Microbial infection Positive cervical
cultures
Chlamydia trachomatis
Mycoplasma hominis
Ureaplasma urealyticum

Diagnostic factors identified in 1020 women with 2 vs 3 or more recurrent pregnancy losses
Jaslow, Carney, Kutteh MD et al, Fertility and Sterility Vol. 93, No. 4, March 1, 2010
2010 American Society for Reproductive Medicine, Published by Elsevier Inc.

Causes of RPL
Bacterial Vaginosis
a risk factor for 2nd trimester miscarriage and preterm delivery
association with 1st trimester miscarriage is inconsistent

For women with history of previous preterm birth,

detection and treatment of BV in early pregnancy may
prevent a further preterm birth
Cochrane review 2000 Level 1A grade A

Hematologic cause
Thrombophilia
Factor V Leiden gene mutation
deficiency of protein C, protein S and
antithrombin III

Immunologic Causes

Reproductive Immune Failure

Syndrome

CATEGORY I Alloimmune
CATEGORY II APAS
CATEGORY III ANA Positive
CATEGORY IV Antisperm
antibodies
CATEGORY V Natural kiler cells
and embryotoxic cytokines, organ
specific antibodies

Antiphospholipid
Antibody Syndrome

Antiphospholipid Antibody
Syndrome
most common acquired cause of
hypercoagulability
associated with :
fetal loss
thrombosis
autoimmune thrombocytopenia
elevated levels of antiphospholipid
antibodies

Antiphospholipid Antibody
Syndrome

Considered as the autoimmune cause of RPL

Involves two antibodies:
Lupus anticoagulant (LAC)
Anti-cardiolipin antibody (ACA)

7%
15%

AntiphospholipidAntibody
Syndrome
LAC + ACA

THROMBOSIS

FETAL LOSS

Diagnosis of APAS
1. Clinical Criteria

Recurrent Vascular Thrombosis

arterial, venous, or small vessel thrombosis in any tissue or organ confirmed by:
imaging, doppler studies, histopathology

1 unexplained death 10th week AOG

1 premature birth 34th week of gestation because of:

Severe preeclampsia or eclampsia
Severe placental insufficiency

3 consecutive spontaneous abortions

< 10th week of gestation excluding the following as causes:
Maternal anatomic or hormonal abnormalities
Maternal and paternal chromosomal abnormalities

Sapporo, 1998

2. Laboratory Criteria
Anticardiolipin Antibodies (ACA /aCL)
ACA IgG or IgM by ELISA
medium to high titers ( i.e 40 GPL or 40 MPL or > 99th
percentile ) on two or more occasions at least 12 weeks apart
by
and / or

Lupus Anticoagulant (LAC or LA):

phospholipid dependent coagulation tests + 2
occasions at least 12 weeks apart
Kaolin Clotting Time (KCT),
Dilute Russel Viper Venom Time (DRVVT)
activated Partial Thromboplastin Time (aPTT)

11th International Congress on APAS, Sydney Australia, Nov. 2004

APAS screen
UP-PGH, High Risk Clinic
January-March 2011

Laboratory Criteria
Anti-2 glycoprotein-1 antibody IgG and
or IgM isotype in serum or plasma
( in titer >99th centile) present on two or
more occasions at least 12 weeks apart
measured by ELISA according to
recommended procedures.

11th International Congress on APAS, Sydney Australia, Nov. 2004

Anti-2 GP1
Anti-2 GP1 antibodies are independent risk
factors for
Thrombosis ( Evidence level II)
Pregnancy complications ( Evidence level I)

In 3-10% of APS patients, Anti-2 GP1 may be

the only test positive ( Evidence level 1)

AntiphospholipidAntibody
Syndrome

Definite Antiphospholipid Antibody

Syndrome should fulfill
>1 clinical and
>1 laboratory criteria

Unexplained RPL
50% or more of couples with RPL despite
detailed investigation remains unexplained
75% prognosis for a successful future
pregnancy with supportive care alone
Women with unexplained recurrent
miscarriage have an excellent prognosis for
future pregnancy outcome without
pharmacological intervention if offered
supportive care alone
Level IV grade C

RPL

Genetic

Karyotyping
Genetic
counselling
Options for
adoption

Anatomic

HSG,
hysteroscopy

UTZ, MRI
Surgical
correction

Endocrine

TSH screen if
symptomatic
PCOS:
Progesterone

Infectious

Cervical
cultures

Thrombophilia

If postive
Give Heparin

Immunologic

APS screen
Co-managed:
Immunolgist
Hematologist

ASA + Heparin

Management

Referred to Immunology
UP-PGH, High Risk Clinic
January-March 2011

Management
1. Medical treatment includes heparin,
low-dose aspirin, and
immunoglobulins
2. Active attempt to search for other
causes of RPL
3. Management of RPL should also
include extensive counseling for the
patient and her family

Therapeutics
Anticoagulation alone may be
sufficient in most cases.
Aspirin
Heparin

Therapeutics
Aspirin
Start Aspirin 80-100 mg daily at least a month
prior to conception and throughout pregnancy
once pregnancy test is positive.
ASA given preconception is an independent
and significant prognostic factor associated
with a good outcome .
Continued post delivery as primary
prophylaxis if the patient is not breastfeeding.
Carmona F et al Am J Reprod Immunol 2001; 46: 274-279

Therapeutics
Heparin
Added once pregnancy test is positive, or
positive for a fetal heartbeat at
prophylactic doses.
Discontinued once the patient is in labor.
Epidural anesthesia is avoided if heparin
and ASA are still being given together
because of the risk of bleeding.
Resumed 12 hours after delivery and
maintained up to 2 weeks postpartum

Correlation of treatment with

Outcomes
TREATMENT

LIVE BIRTH RATE

Any treatment overall

None
Aspirin alone
Prednisone alone
Heparin alone
Prednisone + ASA
Prednisone +Azathioprine
IVIg

67.0%
13.6%
78.0%
31.0%
92.0%
59.0%
46.0%
85.0%

Treatment
UP-PGH, High Risk Clinic
January-March 2011

Women considering
pregnancy should be
counseled regarding the
course of the disease and its
complications.

Work up: 1 Trimester

st

Baseline CBC, platelet count, blood

typing and urinalysis
Platelet count weekly 3x, then every
trimester
Encourage anti-stasis exercises,
regular walks

Work-up: 2nd and 3rd

Trimester
Biometry every 2-4 weeks for interval
growth from 2nd trimester onwards
and observe for:
IUGR
Signs of abruptio placenta
Subchorionic hemorrhages
Placental infarctions
Oligohydramnios
Premature aging of the placenta

Monitoring: 2nd and 3rd

Trimester
Doppler Velocimetry of uterine and
umbilical arteries at 20 weeks and
monthly thereafter
An abnormal umbilical and uterine artery
doppler velocity waveform is an
independent prognostic factor predictive of
adverse outcome
Carmona F et al Am J Reprod Immunol 2001; 46: 274-279

Monitoring:2nd and 3rd

Trimester
BPP NST at 32 weeks and weekly
thereafter
Non-reassuring FHR patterns complicate
50% of all successful APAS pregnancies
resulting in early delivery
Branch et al 1992, Lima et al1996

Monitor for preterm labor

Branch et al 1992, Lima et al 1996

Monitoring:2nd and 3rd

Trimester
Individualize frequency of monitoring if
with complications
Prospective studies of pregnant women
with APAS:
Rate of thrombosis 5%
(Branch et al,
1992)
Rate of stroke

12%
(Lima et al, 1996)

Complications of Treatment
Bleeding: hematuria,gum bleeding,epistaxis
Withold heparin and ASA
Reverse effect of Heparin with protamine sulfate
if life threatening bleeding

Heparin-induced Thrombocytopenia
Monthly platelet count

Osteoporosis, from Heparin, Prednisone

Calcium 1,500 mg with Vitamin D daily
Bone densitometry at 6th month

Hyperacidity, from Aspirin, Prednisone

May give antacids

Plan and Mode of Delivery

Prevent excessive bleeding during
delivery
Discontinue ASA two weeks prior to
delivery e.g. 34 or 35 weeks
If on Low molecular weight heparin, shift
to unfractionated heparin a week before
delivery/ term (uncertain wash-off time)
Discontinue unfractionated heparin 6 to
12 hours before CS

Plan and Mode of Delivery

Co-manage with Immunologist and Hematologist
If delivery is urgent but patient still on ASA and
full heparinization prepare the following:

Platelets
Fresh frozen plasma
Packed RBC
Transfuse platelets and FFP before giving anesthesia for
CS or during labor
Evaluate need to reverse heparin effect with protamine
sulfate

Minimize risk of thrombosis during labor (DVT,

Pulmonary embolism, MI)

Route of delivery
UP-PGH, High Risk Clinic
January-March 2011

Post partum Management

Heparin 12 hours postpartum
up to 4 weeks postpartum.

Post Partum Care

Goals:
Prevent thrombosis
Counsel for the next pregnancy
Counseling for future risk of
thrombosis: reassess need for
anticoagulation

Counseling for Next

Pregnancy

No oral contraceptives which

are thrombogenic
Advise pre-conceptional
anticoagulant treatment

The End