RECURRENT MISCARRIAGE

SYNDROME Fahad zakwan

Other names1.Recurrent fetal loss

2.Recurrent miscarriage

3.Recurrent abortions

4.Recurrent pregnancy loss

5.Habitual abortion

INTRODUCTION•Emotionally traumatic, similar to stillbirth or neonatal death•Etiology is often unknown (in 40-50% of cases)•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 or fetal weight less than 500g.Ectopic, molar, and biochemical pregnancies

not included

1-2 % of couples experience this

RISK FACTORS AND ETIOLOGY

• Only in 50 %, the cause can be determined

• Etiological categories:1. Uterine

2. Immunologic

3. Endocrine

4. Genetic

5. Thrombophilic

6. Environmental

UTERINE FACTORS(10-15%)CONGENITAL ANOMALIES

1. Septate uterus

2. Bicornuate uterus

3. Unicornuate

4. Didelphytic uterus

5. Cervical incompetency

ACQUIRED1. Myoma2. Intrauterine

adhesions3. Cervical

incompetence

SEPTATE UTERUS

•Most common

•Poorest outcome

•Miscarriage > 60 %

•The longer the septum, the worse

LEIOMYOMA•Submucous

•The mechanism•Their position•Poor endometrial receptivity•Degeneration with increasing cytokine production

•Endometrial polyps

•Intrauterine adhesions•Curettage for pregnancy complications or infection•Traumatize basalis layer :Insufficient endometrium to support fetoplacental growth

•Cervical insufficiency/incompetence•Recurrent mid-trimester loss

“Generally all uterine causes of RPL of RPL cause second trimester loss.”

trimester loss.”

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 corpus luteum (C.L). impaired progesterone production

•Diabetes mellitus•Poorly controlled early (and late) loss•No ↑ risk with well-controlled

•Mechanism•Hyperglycemia•Maternal vascular disease

•Insulin resistance

•PCOS•Miscarriage 20 - 40% vs. baseline rate 10 -20%•Mechanism is unknown•↑ LH, Testosterone, and rostenedioneadversely affect the endometrium

•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

GENETIC FACTORS•Paternal chromosomal rearrangements

•Maternal•5 % of couples with RPL have major

chromosomal defects (vs. 0.7 %)•Balanced translocation or an inversion

•Usually causes first trimester miscarriages.

THROMBOPHILIA

•Thrombosis on maternal side of the placenta impair placental perfusion•Late fetal loss, IUGR, abruption, or PIH

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

•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

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

HISTORYGA & 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

HISTORYThyroid related symptoms Hx of congenital or karyotypic abnormalities heritableWas cardiac activity detected? If not suggests

chromosomal abnormalityDoes F.Hx display patterns of disease consistent with strong

genetic influence? consanguinity Exposure to environmental toxinsHx venous thrombosis thrombophilia or APASInformation 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)•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

• 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 thrombosis

• 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

Other 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 depends

on:• Number of prior loss.• The cause• Maternal age• Prior successful pregnancy

• 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 may be used

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

• 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 ?

UNEXPLAINED RPL

• 50% of RPL remain unexplained

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

Thank you