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RECURRENT PREGNANCY LOSS. INTRODUCTION  Emotionally traumatic, similar to stillbirth or neonatal death  Etiology is often unknown  Primary or secondary.

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Presentation on theme: "RECURRENT PREGNANCY LOSS. INTRODUCTION  Emotionally traumatic, similar to stillbirth or neonatal death  Etiology is often unknown  Primary or secondary."— Presentation transcript:


2 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

3 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

4 RISK FACTORS AND ETIOLOGY  Only in 50 %, the cause can be determined  Etiological categories: Uterine Immunologic Endocrine Genetic Thrombophilic Environmental

5 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

6 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

7 LEIOMYOMA  Submucous Submucous  The mechanism Their position Poor endometrial receptivity Degeneration with increasing cytokine production

8 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.

9 OTHER UTERINE CAUSES  Cervical insufficiency Recurrent mid-trimester loss  Other uterine anomalies Other uterine anomalies Impaired uterine distention

10 IMMUNOLOGIC FACTORS  Antiphospholipid syndrome (APAS) 5 - 15 % of ♀ with RPL may have APAS  Other immunological factors Not well defined

11 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

12 ENDOCRINE FACTORS  Diabetes mellitus Poorly controlled  early (and late) loss ○ No ↑ risk with well-controlled Mechanism ○ Hyperglycemia ○ Maternal vascular disease ○ Immunologic factors (possible)

13 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

14 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?

15 GENETIC FACTORS  ↑ RPL in 1 st 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

16 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

17 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

18 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

19 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

20 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

21 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

22 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

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

24 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 2 nd loss If abnormal karyotype + normal parents  “bad luck”

25 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

26 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

27 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

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

29 THYROID  TSH +/- FT4 & FT3 More important in ♀ with clinical manifestations but even in asymptomatic  Thyroid peroxidase antibody

30 OVARIAN RESERVE  D3 FSH +/- D3 E2 in ♀ of any age or ¼ would be missed  Clomiphene challenge test

31 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

32 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

33 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

34 UTERINE ABNORMALITIES  Managed hysteroscopically Septum, adhesions, submucosal myoma  Cervical cerclage Second trimester loses

35 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

36 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

37 UNEXPLAINED RPL  50% of RPL remain unexplained  Prognosis is still good >50 % live birth even without intervention

38 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

39 UNEXPLAINED RPL  Useless interventions: hCG CC  Pregnancy issues Increased risk of : ○ IUGR ○ PTD No increased risk of: ○ PIH ○ GDM

40 Thank you

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