RECURRENT PREGNANCY LOSS

INTRODUCTION
Emotionally traumatic, similar to stillbirth or neonatal death Etiology is often unknown Primary or secondary

Live birth occurred at some time in secondary Better prognosis with secondary

DEFINITION

3 consecutive losses of clinically recognized pregnancies < 20 week gestation Ectopic, molar, and biochemical pregnancies not included 15 % experience sporadic loss of clinically recognized pregnancy 2 % experience 2 consecutive losses 0.15 x 0.15 = 0.0225 = 2 % 0.4 to 1 % experience 3 consecutive losses 0.15 x 0.15 x 0.15 = 0.003 = 0.3 % observed frequency is higher than expected by chance alone

RISK FACTORS AND ETIOLOGY

Only in 50 %, the cause can be determined Etiological categories:

Uterine Immunologic Endocrine Genetic Thrombophilic

Environmental

UTERINE FACTORS
Acquired or congenital anomalies Congenital anomalies: 10 -15 % in with RPL vs. 7 % in all

Abnormal implantation:
vascularity (septum) inflammation (fibroid) sensitivity to steroid hormones

SEPTATE UTERUS
Most common Poorest outcome Miscarriage > 60 % Fetal survival with untreated cases 6 to 28 % The longer, the worse The mechanism

Not clearly understood

Poor blood supply poor implantation

LEIOMYOMA
Submucous The mechanism

Their position Poor endometrial receptivity Degeneration with increasing cytokine

production

OTHER UTERINE CAUSES

Endometrial polyps
Rx: Polypectomy

Intrauterine adhesions
Curettage for pregnancy complications (4/52) Traumatize basalis layer granulation tissue Insufficient endometrium to support fetoplacental

growth Menstrual irregularities (hypomenorrhea, amenorrhea), cyclic pelvic pain, infertility.

OTHER UTERINE CAUSES

Cervical insufficiency
Recurrent mid-trimester loss

Other uterine anomalies

Impaired uterine distention

IMMUNOLOGIC FACTORS

Antiphospholipid syndrome (APAS)

5 - 15 % of with RPL may have APAS

Other immunological factors

Not well defined

ENDOCRINE FACTORS

Luteal phase defect

Progesterone is essential for implantation and

maintenance of pregnancy
A defect in C.L. impaired progesterone

production
Controversies: Does this defect really exists? If it does, is related to miscarriage? No consensus on method of diagnosis No consensus on method of treatment

ENDOCRINE FACTORS

Diabetes mellitus
Poorly controlled early (and late) loss No risk with well-controlled
Mechanism Hyperglycemia Maternal vascular disease Immunologic factors (possible)

ENDOCRINE FACTORS

Insulin resistance
No strong evidence
PCOS Miscarriage 20 - 40% vs. baseline rate 10 - 20%

Mechanism is unknown LH, Testosterone, and androstenedione adversely affect the endometrium

ENDOCRINE FACTORS

Thyroid disease and antibodies

Poorly controlled hypo- or hyper-thyroidism Infertility & pregnancy loss
thyroid antibody, even if euthyroid. No strong evidence

Hyperprolactinemia
Rx successful pregnancy (86 vs. 52%)

BUT, need correct diagnosis

At what level to treat?

GENETIC FACTORS

RPL in 1st degree relatives of with unexplained RPL

Shared HLA types, coagulation defects, immune

dysfunction, other undefined heritable factors

Chromosomal rearrangements
5 % of couples with RPL have major

chromosomal defects (vs. 0.7 %)

Balanced translocation or an inversion

Even if present, may not be the cause

complete evaluation of RPL is indicated

THROMBOPHILIA

Thrombosis on maternal side of the placenta impair placental perfusion

Late fetal loss, IUGR, abruption, or PIH

Relationship with early loss is less clear

large and contradictory literature
May be restricted to specific defects not

completely defined, or presence of multiple defects

MISCELLANEOUS

Environmental chemicals & stress

Anesthetic gases (nitrous oxide), formaldehyde,

pesticides, lead, mercury

Sporadic spontaneous loss No evidence of associations with RPL

Personal habits
Obesity, smoking, alcohol, and caffeine Association with RPL is unclear
May act in a dose-dependent fashion or synergistically to

sporadic pregnancy loss

Exercise
does not sporadic or RPL

MISCELLANEOUS

Male factor
Trend toward repeated miscarriages with

abnormal sperm (< 4% normal forms, sperm chromosome aneuploidy)

ICSI

Paternal HLA sharing not risk factor for RPL Advanced paternal age may be a risk factor for miscarriage (at more advanced age than females)

Infection
Listeria, Toxoplasma, CMV, and primary genital

herpes Cause sporadic loss, but not RPL

MISCELLANEOUS

Decreased ovarian reserve

Quality and quantity of oocytes decrease with unexplained RPL have a higher D3 FSH

and E2 than with known cause

Celiac disease
Untreated & even subclinical, associated with

pregnancy loss, menstrual disorders, and infertility

Treatment prevent these problems

No evidence that it causes RPL

CANDIDATES FOR EVALUATION

Evaluate and Rx 2 or 3 consecutive losses Most have good prognosis for a successful pregnancy, even when no Dx or Rx The minimum workup:

Complete medical, surgical, genetic, and family

history Physical examination

HISTORY

GA & characteristics (anembryonic pregnancy, live embryo) of all previous pregnancies

RPL typically occurs at a similar GA Most common causes of RPL vary by trimester
Chromosomal & endocrine earlier than anatomic or

immunological causes

Uterine instrumentation intrauterine adhesions Menstrual cycles regularity endocrine dysfunction Galactorrhea, Headache, Visual disturbances hyperprolactinemia

HISTORY

Thyroid related symptoms Hx of congenital or karyotypic abnormalities heritable Was cardiac activity detected? If not suggests chromosomal abnormality Does F.Hx display patterns of disease consistent with strong genetic influence? consanguinity Exposure to environmental toxins Hx venous thrombosis thrombophilia or APAS Information from previous laboratory, pathology, and imaging studies

PHYSICAL EXAMINATION
General physical Signs of endocrinopathy (hirsutism, galactorrhea, thyroid) Pelvic organ abnormalities (uterine malformation, cervical laceration)

LABORATORY EVALUATION

Karyotype (Parental)
Low yield & limited prognostic value only if

the other work-up was negative

Karyotype (Embryonic)
Not really needed
May consider after 2nd loss If abnormal karyotype + normal parents bad

luck

UTERINE ASSESSMENT

Sonohysterography (SIS)
More accurate than HSG Differentiate septate & bicornuate uterus

Hysterosalpingogram (HSG)
Does not evaluate outer contour Not ideal for the cavity

Hysteroscopy
Gold standard for Dx + Rx intrauterine lesions Cannot differentiate septate from bicornuate Reserved for when no Dx is made

UTERINE ASSESSMENT

Ultrasound
Presence and location of uterine myomas Associated renal abnormalities

MRI
Differentiate septate from bicornuate

Hysteroscopy, laparoscopy, or MRI second-line tests when additional information is required

APAS
Dx: one lab & one clinical criteria are met Clinical criteria: Venous or arterial thrmobosis RPL Laboratory criteria Lupus anticoagulant Anticardiolipin antibody (IgG and IgM)

Medium or high titers of both Low to mid positive can be due to viral illness

Repeat twice, 6-8 weeks apart

THROMBOPHILIA
Contradictory literature Evaluate if loss > nine weeks + evidence of placental infarction or maternal thrombosis

THYROID

TSH +/- FT4 & FT3

More important in with clinical manifestations

but even in asymptomatic

Thyroid peroxidase antibody

OVARIAN RESERVE
D3 FSH +/- D3 E2 in of any age or would be missed Clomiphene challenge test

NONE USEFUL TESTS

Routine cervical cultures for Chlamydia, Mycoplasma & vaginal evaluation for BV & toxoplasmosis serology ANA Screening for DM Immune function (HLA typing, etc) Progesterone level (Single or multiple) Endometrial biopsy

MANAGEMENT

Prognosis for successful future pregnancy is good

live birth rates after normal and abnormal

diagnostic evaluations, 77 and 71 percent, respectively

Emotional support is important and enhance success

PARENTAL KARYOTYPE ABNORMALITY

Refer for genetic counseling

Information for probability of a chromosomally

normal or abnormal conception

May undergo prenatal genetic studies

Amniocentesis
CVS IVF with PGD

UTERINE ABNORMALITIES

Managed hysteroscopically
Septum, adhesions, submucosal myoma

Cervical cerclage
Second trimester loses

MANAGEMENT

Antiphospholipid syndrome
Aspirin & Heparin

Suspected immunologic dysfunction

Several immunologic Rx advocated None effective Some are harmful

DM
Controlled at least 6/12 prior to conception

Thyroid
Hyper and Hypo thyroid should be controlled Euthyroid with peroxidase antibody may benefit

from treatment

MANAGEMENT

Polycystic ovary syndrome

No agreed upon protocol
Metformin just as effective when stopped at

diagnosis of pregnancy or 12/52 gestation

Hyperprolactinemia
Normal levels play important role in maintaining

early pregnancy (in RPL)

Thrombophilia
Anticoagulation if loss > 9/52

UNEXPLAINED RPL
50% of RPL remain unexplained Prognosis is still good

>50 % live birth even without intervention

UNEXPLAINED RPL

Lifestyle modification
Eliminating use of tobacco, alcohol, and caffeine &

reduction in BMI (for obese women).

Progesterone
Widely used but studies on its efficacy are lacking Vaginally or IM

Human menopausal gonadotropin

Correcting LPD or creating thicker endometrium Clinical experience supports the efficacy

IVF +/- PGD

Mixed results Promising

UNEXPLAINED RPL

Useless interventions:
hCG CC

Pregnancy issues
Increased risk of : IUGR PTD No increased risk of: PIH GDM

Thank you