Infertility and fetal loss Notes

NOTES NOTES INFERTILITY & FETAL LOSS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Disorders that adversely affect the function of the female reproductive system fertility SIGNS & SYMPTOMS ▪ See individual disorders DIAGNOSIS DIAGNOSTIC IMAGING ▪ Ultrasound LAB RESULTS ▪ Serum hormonal levels OTHER DIAGNOSTICS ▪ Obstetric history TREATMENT ▪ See individual disorders AMENORRHOEA osms.it/amenorrhoea PATHOLOGY & CAUSES ▪ Abnormal menstruation cessation/absence in biologically female people of reproductive age, not related to menopause/pregnancy/ lactation TYPES ▪ Primary amenorrhoea ▫ Failure to reach menarche by age 15 years ▪ Secondary amenorrhoea ▫ Previously regular menses ceases for three months or longer RISK FACTORS ▪ Hypothalamic-pituitary-gonadal axis does not induce cyclic changes in the endometrium ▫ Hypothalamic dysfunction (e.g. GnRH deficiency, traumatic injury, functional (stress, excessive exercise, eating disorders, systemic illness) ▫ Pituitary dysfunction (e.g. empty sella syndrome, pituitary tumor/infarct) ▫ Ovarian dysfunction (e.g. primary ovarian insufficiency (POI), Turner syndrome, FMR1 mutation) ▪ Psychogenic amenorrhea ▫ Pseudocyesis (false pregnancy) OSMOSIS.ORG 757

▪ Outflow tract disorders ▫ E.g. Müllerian agenesis (Mayer– Rokitansky–Kuster–Hauser syndrome), intrauterine adhesions (Asherman syndrome) ▪ Other ▫ Polycystic ovary syndrome (PCOS) ▫ Hypo/hyperthyroidism ▫ Hormone receptor abnormalities ▫ Enzyme deficiencies COMPLICATIONS ▪ Infertility ▪ Osteoporosis ▪ Psychological distress SIGNS & SYMPTOMS ▪ Menses absent ▪ Clinical presentation of causative disorder DIAGNOSIS ▪ Evaluate secondary sexual characteristics (Tanner staging) ▪ Discrepancy in Tanner stage and age may indicate constitutional puberty delay, Turner syndrome ▪ ↑ body mass index (BMI) + hyperandrogenism signs (acne, hirsutism) may indicate PCOS DIAGNOSTIC IMAGING Pelvic ultrasound/hysteroscopy ▪ Detects structural abnormalities Head MRI ▪ Identifies pituitary anomalies LAB RESULTS ▪ ↑ hGH indicates pregnancy ▪ ↑ serum prolactin indicates pituitary adenoma, prolactinoma ▪ Follicle stimulating hormone (FSH) ▫ ↑ level indicates Turner syndrome, primary ovarian insufficiency (POI) 758 OSMOSIS.ORG ▫ ↓ level indicates functional hypothalamic amenorrhea/hypothalamic-pituitary disorders ▪ ↓ luteinizing hormone level indicates functional hypothalamic amenorrhea/ hypothalamic-pituitary disorders ▪ ↓ estradiol indicates abnormal ovarian function ▪ ↑ free and total testosterone indicates PCOS, ovarian/adrenal tumor OTHER DIAGNOSTICS ▪ Progesterone challenge test ▫ Oral medroxyprogesterone administered daily for 7–10 days → withdrawal bleeding when hormone stopped indicates adequate endogenous estrogen level, rules out outflow tract abnormality ▫ If no withdrawal bleeding, administer estrogen + progestin daily for 10 days → failure to bleed indicates abnormal endometrium ▪ Karyotype ▫ E.g. Turner syndrome (45,X), Müllerian agenesis (46,XX) ▪ Genetic testing ▫ Fragile X syndrome (FMR1) associated with primary ovarian insufficiency TREATMENT MEDICATIONS ▪ Hypothalamic dysfunction ▫ Oral contraceptives if pregnancy not desired, gonadotropins if pregnancy desired ▪ Ovarian insufficiency ▫ Estrogen, progesterone replacement SURGERY ▪ Tumor: surgical resection ▪ Surgically correct anatomic abnormalities preventing outflow PSYCHOTHERAPY ▪ If functional hypothalamic dysfunction, address underlying cause (e.g. eating disorder)

Chapter 126 Infertility & Fetal Loss OTHER INTERVENTIONS ▪ Specific treatments for causative morbidities (e.g. PCOS, thyroid disorders) ▪ Treat complications (e.g. estrogen replacement therapy, calcium + vitamin D supplements) ECTOPIC PREGNANCY osms.it/ectopic-pregnancy PATHOLOGY & CAUSES TYPES ▪ Ectopic pregnancy ▫ Pregnancy in which fertilized ovum is implanted at site other than uterine endometrium ▪ Heterotopic pregnancy (rare) ▫ Concurrent ectopic pregnancy and intrauterine pregnancy CAUSES ▪ Altered anatomy/function (e.g. impaired tubal motility) ▪ Inflammatory-induced tubal damage, distorted/blocked patency → disrupted blastocyst progress to endometrial implantation site ▪ Ectopic sites ▫ Fallopian tube (most common site, especially ampullary region) ▫ Cervical ▫ Abdominal ▫ Ovarian ▫ Interstitial/cornual (implantation where fallopian tube passes through myometrium) ▫ Uterine cesarean scar OSMOSIS.ORG 759

RISK FACTORS ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Previous tubal pregnancy Cesarean section history Endometriosis Infection, pelvic inflammatory disease (e.g. salpingitis) ▫ Chlamydia: damages cilia lining fallopian tube ▫ Gonorrhea: causes clubbed fimbriae, blocked/tortuous tube Previous pelvic surgery Congenital anomalies Tumors Smoking (dose-dependant) Vaginal douching Risk increases with age Intrauterine device (IUD) use (past and present) Use of assisted reproductive technologies (ART) In utero diethylstilbestrol (DES) exposure COMPLICATIONS ▪ Rupture of fallopian tube or other structures, leading to profound bleeding ▫ May be life-threatening ▪ Pregnancy loss ▪ Infertility ▪ A significant cause of pregnancy-related maternal mortality in first trimester SIGNS & SYMPTOMS ▪ May be asymptomatic before rupture ▪ Common triad of symptoms ▫ Variable bleeding (spotting/intermittent/ hemorrhage) ▫ Lower abdominal pain/tenderness (abrupt/slow, continuous/intermittent) ▫ Menses absent ▪ Other symptoms ▫ Normal early pregnancy discomforts (e.g. nausea, breast tenderness) ▪ Symptoms of rupture (surgical emergency) ▫ Severe abdominal pain (may refer to shoulder with phrenic nerve irritation; rebound tenderness, guarding indicates peritoneal irritation) ▫ Hemodynamic instability (feeling faint, syncope; tachycardia; hypotension; diaphoresis) DIAGNOSIS ▪ Pelvic examination ▫ Can identify source of bleeding ▪ Gentle adnexal palpation (light pressure to avoid rupture) ▫ Palpable mass, cervical motion, adnexal, abdominal tenderness DIAGNOSTIC IMAGING Figure 126.1 A ruptured cornual ectopic pregnancy following surgical removal. The fallopian tube (left) is distended at the junction with the cornu. The fetus is present on the right with an intact embryonic sac. 760 OSMOSIS.ORG Ultrasound ▪ Combination of empty uterus on ultrasound with a positive pregnancy test can confirm diagnosis ▪ If hemodynamically unstable ▫ Abdominal Focused Assessment with Sonography for Trauma (FAST): detects peritoneal bleeding, indicates rupture ▪ If stable ▫ Transvaginal ultrasound (TVUS): locates anatomical pregnancy site LAB RESULTS ▪ ↑ serum human chorionic gonadotropin indicates pregnancy

Chapter 126 Infertility & Fetal Loss TREATMENT MEDICATIONS ▪ If unruptured ▫ Methotrexate: folic acid antagonist inhibits DNA synthesis, cellular replication SURGERY Figure 126.2 A Doppler ultrastound scan of the pelvis demonstrating the ring of fire sign in an individual with a tubal ectopic pregnancy. ▪ If ruptured, laparoscopic surgery ▫ Salpingectomy: fallopian tube removal (standard practice) ▫ Salpingostomy: tubal incision to remove tubal gestation only OTHER INTERVENTIONS ▪ Stabilization measures if hemodynamic compromise is evident MISCARRIAGE osms.it/miscarriage PATHOLOGY & CAUSES ▪ Loss of pregnancy < 20 gestation weeks ▫ AKA spontaneous abortion TYPES ▪ Complete ▫ Spontaneous passage of all products of conception ▪ Incomplete (inevitable) ▫ Bleeding, partially dilated cervix, ruptured membranes, products of conception remain in utero ▪ Threatened ▫ Embryo/fetus jeopardized by bleeding, viable pregnancy, closed cervix ▪ Missed ▫ Intrauterine fetal death that is not expelled ▪ Recurrent ▫ History of ≥ three spontaneous pregnancy losses RISK FACTORS Prior miscarriage Multiparity Advanced maternal age Smoking, substance abuse (e.g. cocaine) Chromosomal abnormalities (e.g. aneuploidies) ▪ Structural uterine anomalies (e.g. cervical insufficiency, fibroids) ▪ Maternal infections ▫ Bacterial vaginosis ▫ Toxoplasmosis ▫ Coxsackie virus infection ▫ Paramyxovirus infection (measles, mumps) ▪ Maternal comorbidities ▫ Thrombophilia: ↑ decidual thrombosis risk ▫ Hypothyroidism: thyroid peroxidase autoantibodies → may impair thyroid function during pregnancy ▫ Diabetes mellitus: poor glycemic control ▪ ▪ ▪ ▪ ▪ OSMOSIS.ORG 761

(teratogenic effects of hyperglycemia; maternal vascular disease → uteroplacental insufficiency) ▫ Systemic lupus erythematosus: uteroplacental insufficiency, antiphospholipid antibodies, lupus anticoagulant ▫ Obesity: may be related to insulin resistance ▪ Trauma ▫ Iatrogenic: invasive intrauterine procedures (e.g. chorionic villus sampling, amniocentesis) ▫ Other injuries ▪ Idiopathic 762 OSMOSIS.ORG COMPLICATIONS ▪ Vaginal blood/clots/fetal tissue passage ▪ Infection (e.g. septic abortion related to infection and retained products of conception) ▪ Disseminated intravascular coagulation (DIC) ▫ Missed abortion → retained products release chemical mediators → coagulopathy

Chapter 126 Infertility & Fetal Loss SIGNS & SYMPTOMS ▪ Vaginal bleeding ▪ Cramping abdominal/suprapubic pain DIAGNOSIS ▪ Internal digital examination ▫ Evaluates cervical dilation ▪ Vaginal speculum exam ▫ Determines cervical dilation, characteristics of blood or tissue DIAGNOSTIC IMAGING Ultrasound ▪ TVUS ▫ < nine gestation weeks ▪ Transabdominal ▫ ≥ nine gestation weeks LAB RESULTS ▪ Urine ▫ ↑ hCG confirms pregnancy ▪ Complete blood count ▫ Evaluates blood loss degree ▪ Blood type and Rh(D) testing ▫ Determines risk for isoimmunization TREATMENT MEDICATIONS ▪ Inevitable/incomplete/missed abortion (nonviable pregnancy) ▫ If medically stable: medical evacuation (prostaglandin E1 analog, antiprogesterone); expectant management (allow for natural passage) ▪ Prophylaxis with Rho(D) immunoglobulin as indicated SURGERY ▪ Inevitable/incomplete/missed abortion (nonviable pregnancy) ▫ If medically unstable: surgical evacuation (dilation and curettage/ vacuum extraction) OTHER INTERVENTIONS ▪ Complete abortion ▫ No medical intervention ▪ Recurrent abortion ▫ Screening for possible causes ▪ Threatened abortion (viable pregnancy) ▫ Expectant management MOLAR PREGNANCY osms.it/molar-pregnancy PATHOLOGY & CAUSES ▪ Benign abnormal trophoblastic growth, included in disease group called gestational trophoblastic disease (GTD) ▫ AKA hydatidiform mole (HM) ▪ Premalignant disease with potential to develop into gestational trophoblastic neoplasia (GTN), which includes invasive mole, choriocarcinoma, placental site trophoblastic tumor, epithelioid trophoblastic tumor TYPES ▪ Classifications based on histopathology, karyotype Complete hydatidiform mole ▪ Single sperm fertilizes enucleated egg → paternal DNA duplication ▪ Usually diploid 46,XX/46,XY ▪ Contains paternal genetic material only OSMOSIS.ORG 763

▪ No fetal cells present ▪ Potential to become invasive → malignant gestational trophoblastic disease (GTD) Partial hydatidiform mole ▪ One (normal) egg fertilized by two sperm ▪ Usually triploid 69,XXX/69,XXY/69XYY ▪ Contains maternal and extra paternal genetic material ▪ Some fetal cells evident (e.g. amnion, RBCs) ▪ Not usually associated with choriocarcinoma (< 5%) CAUSES ▪ When nonviable fertilized ovum implants in uterus → paternal gene overexpression → trophoblastic proliferation, vesicular placental villi swelling → nonviable pregnancy RISK FACTORS ▪ Obstetric history ▫ Previous molar pregnancy ▫ Spontaneous abortion ▫ Infertility ▪ Maternal age extremes (≤ 15 and > 35 years old) ▪ Low dietary carotene (vitamin A precursor) and animal fat is associated with partial mole Figure 126.3 A transvaginal ultrasound scan demonstrating a mass within the uterus. The “bunch of grapes” sign is characteristic of a complete molar preganncy. ▪ ▪ ▪ ▪ COMPLICATIONS ▪ Potential for malignancy and metastasis (pulmonary, CNS) ▪ Trophoblastic pulmonary emboli ▪ Complete mole (if diagnosed in second trimester) ▫ ↑ ↑ hCG levels → theca lutein cysts (multiloculated cysts due to ovarian hyperstimulation), hyperthyroidism, preeclampsia ▫ Anemia may also be present SIGNS & SYMPTOMS ▪ Missed menses ▪ Enlarging uterus, feeling of pelvic pressure ▫ Partial mole: small or normal for gestational age 764 OSMOSIS.ORG ▪ ▫ Complete mole: large for gestational age Hyperemesis gravidarum ▫ Associated with ↑ ↑ hCG First trimester uterine bleeding ▫ Evident when molar villi separate from underlying decidua ▫ Complete mole: dark, “prune juice”colored discharge (accumulated, oxidized blood) Spontaneous passage of “grape-like” molar vesicles (hydropic villi) Hyperthyroidism ▫ Tachycardia, warm skin, tremor, heat intolerance Preeclampsia ▫ ↑ blood pressure DIAGNOSIS ▪ Bimanual examination ▫ Assess uterine size DIAGNOSTIC IMAGING Transvaginal ultrasound ▪ Complete mole ▫ No embryo, fetus, or gestational sac visualized; absent fetal heartbeat ▫ Absence of amniotic fluid ▫ Numerous anechoic spaces contained

Chapter 126 Infertility & Fetal Loss in a central heterogeneous mass: snowstorm, bunch of grapes, or swiss cheese pattern ▫ Theca lutein cysts ▪ Incomplete mole ▫ A fetus may be identified ▫ Amniotic fluid is present ▫ Chorionic villi echogenicity ▫ Usually no theca lutein cysts Chest X-ray ▪ Screen for metastasis LAB RESULTS ▪ ↑ ↑ serum hCG ▪ Blood type and Rh(D) testing ▫ Determines risk for isoimmunization ▪ Histopathologic analysis of evacuated material (definitive diagnosis) ▫ Hydropic swelling of chorionic villi (cluster of grapes tissue) OTHER DIAGNOSTICS ▪ Monitoring hCG levels to assess malignant transformation Figure 126.4 The histological appearance of a complete mole. The chorionic villi are expanded by loose fibrillar material (hydropic) and the overlying trophoblasts demonstrate marked atypical hyperplasia. MEDICATIONS ▪ Actinomycin D ▫ Chemoprophylaxis for complete mole ▪ Rh(D) immune globulin if indicated SURGERY ▪ Hysterectomy ▫ If ≥ 40 years old and/or do not wish further pregnancies OTHER INTERVENTIONS ▪ Periodic (usually weekly) monitoring of hCG levels at regular intervals + reliable contraception until hCG is undetectable ▫ Persistent elevation indicates postmolar gestational trophoblastic neoplasia Figure 126.5 A CT scan of the pelvis in the axial plane demonstrating a molar pregnancy. The uterine corpus is distended by heterogenously enhancing mass. There is no evidence of a fetus. TREATMENT ▪ Uterine evacuation: suction and curettage Figure 126.6 The histological appearance of a partial mole. In contrast to a complete mole, there will be both normal villi (right of image) and hydropic villi (left of image). Trophoblastic proliferation is minimal. OSMOSIS.ORG 765