Fawaz Edris MD, RDMS, FRCSC, FACOG, AAACS RECURRENT PREGNANCY LOSS Fawaz Edris MD, RDMS, FRCSC, FACOG, AAACS

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 Abnormal implantation: 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 Intrauterine adhesions 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 Other uterine anomalies 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 Hyperprolactinemia 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 Personal habits 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 Infection 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 Celiac disease 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) Hysterosalpingogram (HSG) 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 MRI 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 Thyroid peroxidase antibody More important in ♀ with clinical manifestations but even in asymptomatic Thyroid peroxidase antibody

OVARIAN RESERVE D3 FSH +/- D3 E2 in ♀ of any age or ¼ 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 Suspected immunologic dysfunction 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 Hyperprolactinemia Thrombophilia 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 Progesterone 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: Pregnancy issues hCG CC Increased risk of : IUGR PTD No increased risk of: PIH GDM

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