early recurrent pregnancy loss

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Recurrent Early Pregnancy Loss: 

Recurrent Early Pregnancy Loss Dr Jody Mbuilu P., MD O&G/ MPH South Africa August 2011 Recurrent early pregnancy loss

Overview : 

Overview Early pregnancy loss is frustrating and heart wrenching (sudden Heart twist!) for both patient and physician. Is unfortunately the most common complication in human gestation: 75% of all women trying to conceive. Most of these lost are unrecognized and occur before or with the next expected menses. Of those that are recognized, 15-20% result in spontaneous abortions (SABs) or ectopic pregnancies Recurrent early pregnancy loss

Overview : 

Overview Up to 5% of couples trying to conceive have 2 consecutive miscarriages and 1% of couple have 3 or more consecutive losses Early pregnancy loss is defined as the termination of pregnancy before 20 weeks’ gestation or with a fetal weight of <500g Recurrent early pregnancy loss

Incidence : 

Incidence Most studies demonstrate a spontaneous miscarriage rate of 10-15% However the true rate of early pregnancy loss is close to 50% because of the high number of chemical pregnancy (BHCG +) that are not recognized in the 2-4 weeks after conception Most of these pregnancy failure are due to gamete failure Wilcox et al. in 1988: 221 women followed up during 707 total menstrual cycles. A total 198 pregnancies were achived . Recurrent early pregnancy loss

Incidence : 

Incidence Of these, 43 (22%) were lost before the onset of menses, and another 20 (10%) were clinically recognized losses The likehood for SABs increases with each successive miscarriage Recurrent early pregnancy loss

N Engl J Med. 1988 Jul 28;319(4):189-94. Incidence of early loss of pregnancy. Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC.SourceEpidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC : 

N Engl J Med. 1988 Jul 28;319(4):189-94. Incidence of early loss of pregnancy. Wilcox AJ, Weinberg CR, O'Connor JF, Baird DD, Schlatterer JP, Canfield RE, Armstrong EG, Nisula BC.SourceEpidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC We studied the risk of early loss of pregnancy by collecting daily urine specimens from 221 healthy women who were attempting to conceive. Urinary concentrations of human chorionic gonadotropin ( hCG ) were measured for a total of 707 menstrual cycles with use of an immunoradiometric assay that is able to detect hCG levels as low as 0.01 ng per milliliter, with virtually 100 percent specificity for hCG in the presence of luteinizing hormone. Our criterion for early pregnancy--an hCG level above 0.025 ng per milliliter on three consecutive days--was determined after we compared the hCG levels in the study group with the levels in a comparable group of 28 women who had undergone sterilization by tubal ligation. We identified 198 pregnancies by an increase in the hCG level near the expected time of implantation. Of these, 22 percent ended before pregnancy was detected clinically. Most of these early pregnancy losses would not have been detectable by the less sensitive assays for hCG used in earlier studies. The total rate of pregnancy loss after implantation, including clinically recognized spontaneous abortions, was 31 percent. Most of the 40 women with unrecognized early pregnancy losses had normal fertility, since 95 percent of them subsequently became clinically pregnant within two years Recurrent early pregnancy loss

Etiology : 

Etiology The etiology of early pregnancy is varied and often controversial More than 1 etiologic factor is often present The most common causes of recurrent miscariages are: Genetic - Aneuploidy, chromosomal … Immunologic - autoimmune causes, alloimmune… Anatomic - incompetent cervix, polyps, fibroma Infectious - brucellosis, chlamydia , HIV Environmental - smoking, alcohol, caffeine Endocrine - diabetes, luteal phase deficiency Hematologic - abnormal homocystein metabolism Recurrent early pregnancy loss Most common!

Genetic causes: 

Genetic causes 50% of all 1 st trimester SABs are cytogenetically abnormal The rate of normal (euploid) and abnormal (aneuploid) abortuses increases with maternal age Chromosomal abnormality may be numerical (aneuploidy) or structural Aneuploidy: meiotic non disjunction Recurrent early pregnancy loss

Genetic causes: 

Genetic causes Autosomal trisomy : 50 % of the cytogenetical abnormal abortuses in the 1 st trimester Specific trisomy : 16 (30%) of all trisomy 21 Down syndrome (1/3 survive to term) Monosomy X (turner syndrome) Parental chromosome abnormalities Recurrent early pregnancy loss

Genetic causes: 

Genetic causes For couple who have SABs due to suspected genetic cause, the standard of care is to offer a genetic counseling Woman older than 35 years: routine amniocentesis Analysis of abortuses after 2 SABs is useful and cost-effective: ? Parental chromosome abnormality… PGS + transfer of normal embryo! Recurrent early pregnancy loss Management

Immunologiccauses : 

Immunologiccauses Recurrent pregnancy loss is associated with several autoimmune diseases 1. Antiphospholipid (APL) antibody syndrome (APS) explain 10-20% of early losses Three classes of clinically significant APL antibodies: Anticardiolipin (aCL) Lupus anticoagulant (LAC) Anti-β2 glycoprotein Recurrent early pregnancy loss

Immunologic causes : 

Immunologic causes APS is diagnosed when medical, obstetrical and appropriate laboratory finding are present. Clinical criteria Vascular thrombosis Pregnancy morbidity (see next slide) Laboratory criteria Recurrent early pregnancy loss

Immunologic causes : 

Immunologic causes APS is diagnosed when medical, obstetrical and appropriate laboratory finding are present. Clinical criteria Vascular thrombosis Pregnancy morbidity 3 or more unexplained consecutive miscariages with anatomic, genetic and hormonal causes excluded 1 or more unexplained death of a morphologicaly normal fetus at or after 10 weeks 1 or more premature birth of morphologically normal neonate at or before 34 weeks gestation, associste with severe preeclampsia or severe placenta insufficiency Laboratory criteria Recurrent early pregnancy loss

Immunologic causes : 

Immunologic causes APS is diagnosed when medical, obstetrical and appropriate laboratory finding are present. Clinical criteria Laboratory criteria aCL antibody present in high titer in 2 separate test 6 weeks apart Prolonged phospholipid dependent coagulation on screening test Exclusion of other coagulopathy Recurrent early pregnancy loss

Immunologic causes : 

Immunologic causes Recurrent pregnancy loss is associated with several autoimmune diseases 1. Antiphospholipid (APL) antibody syndrome (APS) explain 10-20% of early losses 2. Systemic lupus erythematosus 3.Antinuclear antibodies 4.Antithyroid antibodies Recurrent early pregnancy loss

Immunologic causes : 

Immunologic causes Treatment option Subcutaneous heparin Low dose aspirin Prednisone Immunoglobulins Combination of these therapies Heparin 5000U BD//S/ c + Aspirin = prednisone + Aspirin Increases fetal survival rates from 50 to 80% among woman who had at least 2 or more losses! Recurrent early pregnancy loss

Etiology : 

Etiology More than 1 etiologic factor is often present The most common causes of recurrent miscarriages are: Genetic - Aneuploidy, chromosomal inversion… Immunologic - autoimmune causes, alloimmune… Anatomic - incompetent cervix, polyps, fibroma Infectious - brucellosis, Chlamydia, HIV Environmental - smoking, alcohol, caffeine Endocrine - diabetes, luteal phase deficiency Hematologic - abnormal homocystein metabolism Recurrent early pregnancy loss Most common!

3. Anatomic causes: 

3. Anatomic causes Anatomic uterine defect are known to cause obstetric complications, including recurrent loss, preterm labor and delivery; and mal-presentation. Those complications result from impaired vascularisation and fetal growth restriction Incidence of uterine anomalies : 1 per 200-600 History of uterine abnormalities are present in 27% of women with pregnancy loss Recurrent early pregnancy loss

3. Anatomic causes: 

3. Anatomic causes Recurrent early pregnancy loss

3. Anatomic causes: 

3. Anatomic causes Accurate diagnosis of mullerian anomalies is essential Hysteroscopy, hysterosalpingography, vaginal ultrasound Confirmation : MRI Management Prophylactic cervical cerclage Resection of the uterine septum Recurrent early pregnancy loss

4. infectious causes: 

4. infectious causes Infection is view as rare cause of recurrent miscarriage But a proper work up must be done TORCH, RPR, CRP, ESR Cervical swab + culture Empiric long course antibiotic treatment with 3 agents Recurrent early pregnancy loss

Slide 22: 

Recurrent early pregnancy loss

5. Environmental causes: 

5 . Environmental causes Isotetrinoin ( Accutane ): used to treat acne Anesthetic gases: Occupational exposure to trace concentration of waste anesthetic gases in operating room increase the incidence (RR:1,9) Tobacco Alcohol Coffee consumption Recurrent early pregnancy loss

Slide 24: 

Recurrent early pregnancy loss

Etiology : 

Etiology More than 1 etiologic factor is often present The most common causes of recurrent miscarriages are: Genetic - Aneuploidy, chromosomal inversion… Immunologic - autoimmune causes, alloimmune… Anatomic - incompetent cervix, polyps, fibroma Infectious - brucellosis, Chlamydia, HIV Environmental - smoking, alcohol, caffeine Endocrine - diabetes, luteal phase deficiency Hematologic - abnormal homocystein metabolism Recurrent early pregnancy loss Most common!

6. Endocrine causes: 

6. Endocrine causes Ovulation, implantation and early stage of pregnancy depend on an intact maternal endocrine regulatory system Luteal phase abnormalities, progesterone level… Low progesterone Progesterone is the principal factor responsible for the differentiation of proliferative endometrium to secretory . Recurrent early pregnancy loss

6. Endocrine causes: 

6. Endocrine causes Low progesterone Progesterone is the principal factor responsible for the differentiation of proliferative endometrium to secretory . Luteal support remain critical until approximately 7 weeks’ gestation Luteal phase defect LPD (Jones :1943): inadequate endometrium maturation resulting from a qualitative or quantitative disorder in corpus luteal function Recurrent early pregnancy loss

Slide 28: 

Recurrent early pregnancy loss

6. Endocrine causes: 

6. Endocrine causes Low progesterone Progesterone is the principal factor responsible for the differentiation of proliferative endometrium to secretory . Luteal support remain critical until approximately 7 weeks’ gestation Endocrine modulation of decidual immunity Progesterone Luteal phase defect LPD (Jones :1943): inadequate endometrium maturation resulting from a qualitative or quantitative disorder in corpus luteal function Dx histology/endometrial biopsy Recurrent early pregnancy loss

6. Hematologic causes: 

6. Hematologic causes Many recurrent miscariages are characterised by defective placentation and micrithrombi in the placenta vasculature Various components of coagulation and fibrinolytic pathway are important in embryonic implantation, trophoblast invasion and placentation Normal pregnancy – Associated hypercoagulable state Increased procoagulant factors not balanced by anticoag , factors Platelets activation and increased production of Thromboxane This condition is worse in abnormal pregnancy Cytokines action on endothelium Abnormal fibrin distribution Deficit in thrombin- thrombomodulin anticoagulant pathway Shift in thromboxane-to-prostacyclin ratio Recurrent early pregnancy loss

6. Hematologic causes: 

6. Hematologic causes Others hematologic causes include Deficit of Hageman factor associated with systemic and placental thrombosis, leading to recurrent miscarriage Abnormal Homocystein metabolism hyperhomocysteinuria is risk factor of premature CV events and thrombosis 21% of woman in one study with SABs Congenital (autosomal recessive), acquired (deficiency in folate) Treatment Aspirin Heparin Folic acid Recurrent early pregnancy loss

Slide 32: 

Recurrent early pregnancy loss

Etiology : 

Etiology More than 1 etiologic factor is often present The most common causes of recurrent miscarriages are: Genetic - Aneuploidy, chromosomal inversion… Immunologic - autoimmune causes, alloimmune… Anatomic - incompetent cervix, polyps, fibroma Infectious - brucellosis, Chlamydia, HIV Environmental - smoking, alcohol, caffeine Endocrine - diabetes, luteal phase deficiency Hematologic - abnormal homocystein metabolism Recurrent early pregnancy loss Most common!

Summary : 

Summary Screening History taking : ? Cx incompetence, life style, pre-eclampsia , stillborn Anatomy: Sonar ( shape, fibroma, cervix length), hysterography Blood TORCH, Antiphospholipid Ab. ( aCL , LAC, Beta2 glycoprotein, ANA, ANCA…) Hormones: Progesterone level, triple test (15-18 weeks) OGTT after 14 weeks, Thyroid test Prophylactic Rx Life style : alcohol, tobacco Aspirin 150, Calcium Clexane 40mg od ; s/c ; Folate 5 mg dly, Progesterone ASA pregnant! Cyclogest 200mg PV nocte Cerclage after 14 weeks Recurrent early pregnancy loss