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Fertilization, Early Pregnancy and Its Disorders

Harry H. Hatasaka, M.D.
Assistant Professor
Department of OB/GYN
U of U College of Medicine

Objectives

Definitions

Outline

Take Home Points






Objectives

The student should be able to:

  1. Understand the process of ovulation, fertilization and implantation.

  2. List the presumptive, probable and positive signs of pregnancy.

  3. Understand the basis of pregnancy tests and their limitations.

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Definitions

(See Text for Definitions)

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Outline

  1. Ovulation

  2. Fertilization

  3. Implantation

  4. Diagnosis of Pregnancy

  5. Pregnancy Tests

  6. Differential Diagnosis

  7. Spontaneous Abortion

  8. Causes of Abortion

  9. Complications of Abortion

  10. Therapy

  11. Ectopic Pregnancy

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Outline

  1. Ovulation

    The ovulation process is important if subsequent fertilization is to take place. This is an exquisitely timed phenomenon dependent on a host of hormonal interactions involving a variety of endocrine glands. Tubal function must also be adequate or the ovum will not be picked up by the fallopian tube to be fertilized within the ampulla.

  2. Fertilization

    Following ovulation, the ovum with its cumulus oophorus cells are picked up by the fimbria of the fallopian tube. The ovum has now formed the first polar body. It remains in the ampulla portion of the tube and is viable for about 18 to 24 hours. If fertilization does not occur, the ovum disintegrates and is destroyed by the tube. Sperm will remain viable in the female reproductive tract for about 48 hours, although this can be quite variable. Sperm present in the ampulla meet the cumulus oophorus mass and penetrate by chemical and mechanical means to reach the zona pellucida. One sperm penetrates the zona pellucida, the second polar body is formed, and the nuclear material of the sperm enters the vitelline membrane. The diploid chromosome number is re-established, and mitotic cell division can now occur.

  3. Implantation

    After fertilization occurs, the ovum remains in the fallopian tube for about 72 hours. During this time there are several cellular division, but the size of the fertilized ovum does not increase. Around 72 hours the zona pellucida fragments and falls away. The ovum enters the uterine cavity for 60 to 72 more hours, and the central cavity begins to form. A definite cell mass is formed on one side of the blastocyst by the time implantation occurs. The trophoblast cells burrow into the endometrial stroma to form syncytiotrophoblast. Primitive amniotic and chorionic cavities begin to form, and a germ disk is recognizable soon after implantation.

  4. Diagnosis of Pregnancy

    Most women suspect pregnancy before seeking confirmation. However, it is sometimes necessary to differentiate pregnancy from other causes of uterine enlargement and/or amenorrhea. The signs and symptoms are as follows:

    1. Presumptive

      a. Cessation of menses (amenorrhea).
      b. Breast changes.
      c. Vaginal discoloration.
      d. Skin pigmentation.
      e. Morning sickness.
      f. Perception of fetal movements (quickening).
      g. Urinary frequency.
      h. Fatigue.

    2. Probable

      a. Abdominal enlargement.
      b. Uterine and cervical changes (shape, size, consistency).
      c. Intermittent uterine contractions.
      d. Ballottement of fetus.
      e. Palpation of fetal parts.
      f. Positive hormonal (hCG) tests.

    3. Positive

      a. Fetal heart tones heard or recorded.
      b. Fetal movements perceived by examiner.
      c. Fetus identified ultrasonically or radiologically.

    The diagnosis is substantiated by the appearance of softening of the cervix on pelvic examination (Goodell,s sign), a purple hue of the vagina and cervix (Chadwick,s sign) and compressibility and softening of the isthmus (Hegar,s sign) by six to eight weeks, gestation. Abdominal signs of pregnancy appear somewhat later. From 14 weeks, enlargement of the uterus is palpable abdominally. Fetal movement is felt by 18 to 20 weeks (quickening), and fetal heart tones are heard with the fetoscope slightly later. With the doppler, fetal life can be confirmed much earlier (9 to 12 weeks) than with conventional auscultation methods.

  5. Pregnancy Tests

    The biochemical test for pregnancy has evolved from dependence on laboratory animals to rapid accurate assays of human chorionic gonadotropin (hCG) produced by the syncytiotrophoblast. Pregnancy tests generally available currently are enzyme immunoassays (E.I.A.) utilizing monoclonal antibodies specific for hCG, thus avoiding false positive reactions with luteinizing hormone. Serum or urine may be tested, and both cost about the same and can be run in about ten minutes. It is sensitive to about 25 mIU/mL, making it reliable soon after implantation which occurs seven or eight days after ovulation. At approximately the time a woman expects her menses to begin, her hCG concentration will be about 100 mIU/mL if she is pregnant. Therefore commercial urine home pregnancy tests are generally positive by that time. Home pregnancy tests are considered qualitative (yes or no) tests as opposed to quantitative tests.

    Serum radioimmunoassay beta subunit (RIA-hCG-b) testing measures only beta subunit hCG. It is sensitive to approximately 5 mIU/mL and is particularly useful for diagnosing pregnancy very early. Serial quantitative RIA-hCG-b analyses are helpful in diagnosing ectopic pregnancies, distinguishing viable pregnancies from non-viable ones and for monitoring trophoblastic diseases (such as hydatidiform mole).

  6. Differential Diagnosis

    Errors may be caused by uterine fibroids and ovarian cysts which may be confusing by their size. Other sources of diagnostic error are premature menopause, obesity, and other endocrine causes of amenorrhea. Pseudocyesis (a psychiatric condition where a woman feels and fully believes she is pregnant when she is not) may be accompanied by many of the subjective symptoms and signs of true pregnancy, but the pelvic signs of pregnancy are absent and the laboratory tests are negative. Lastly, ectopic or tubal pregnancy should always be kept in mind in any woman of reproductive age who develops menstrual abnormalities and pelvic pain along with symptoms of pregnancy.

  7. Spontaneous Abortion

    Definition: The natural termination of pregnancy prior to the 20th week of gestation or with fetal weight less than 500 gm.

    Clinical Classification:

    1. Threatened Abortion: Uterine bleeding in early pregnancy, with or without cramping.

    2. Inevitable Abortion: Symptoms of threatened abortion plus the physical finding of dilatation of the internal os of the cervix.

    3. Incomplete Abortion: Passage of a portion of the products of conception from the uterus.

    4. Complete Abortion: Passage (grossly) of all of the products of conception from the uterus.

    5. Missed Abortion: Retention of the conceptus in the uterus for a clinically appreciable time after death of the embryo or fetus.

    6. Habitual Abortion: The usual criterion is three or more consecutive abortions.

      Incidence: Clinically recognizable spontaneous abortion occurs in 15% to 20% of pregnancies, the majority occurring in the first three months. It is probable that at least as many abortions occur very early in pregnancy without recognition of the event.

  8. Causes of Abortion:

    A. Fetal factors (most common).

    1. Developmental anomalies in more than 60% of cases (Hertig).

    2. Chromosome abnormalities (22% in Carr,s study).

    B. Maternal factors (less common, but more often treatable).

    1. Systemic diseases.

      a. Infections transmitted to the fetus (viral, bacterial, protozoal).
      b. Febrile illness without fetal infection.
      c. Peritonitis secondary to infection or surgery.
      d. Hypertensive vascular disease.
      e. Severe metabolic disorders (diabetes, thyroid dysfunction).
      f. Chronic debilitating disease states.

    2. Inadequate progesterone production (corpus luteum or placenta) is a definite but probably infrequent cause.

    3. Immunologic Factors - Women expressing serum Lupus anticoagulant and anticardiolipin antibodies in high titers are at increased risk of abortion (antiphospholipid syndrome).

    4. Trauma - a rare factor.

    5. Psychosomatic - suspected but unproven factor.

    6. Uterine abnormalities.

      a. Malformation, especially septate uterus.
      b. Myoma (submucous).
      c. Intrauterine synechiae (bands).
      d. Incompetent cervix.

      A uterine abnormality is particularly suspect with repeated late abortion (second trimester).

  9. Complications of Abortion

    1. Hemorrhage - More common with late abortions. Continued heavy bleeding indicates retained tissue (incomplete abortion).

    2. Infection (septic abortion) seen most commonly with criminally-induced abortion but may ensue in spontaneous or therapeutic abortion. Septic shock may occur in severe instances.

    3. If a missed abortion is retained beyond one month, thromboplastin passage into the maternal circulation may result in a clotting disorder (DIC). This risk is greater in late abortion.

  10. Therapy

    1. Threatened Abortion - no specific therapy is rational since the majority of abortions result from failure of normal fetal development and the fetus usually is dead by the time of onset of bleeding. Management is directed toward avoiding the complications of infection or excessive blood loss.

      Of all women who present uterine bleeding in early pregnancy, fewer than half proceed to abortion.

    2. Inevitable and incomplete abortion - the aim of therapy is prompt evacuation of the uterus to prevent hemorrhage or infection.

      1. Intravenous oxytocin infusion.

      2. Removal of tissue with sponge forceps and uterine curettage (suction or instrumental).

      3. An exception in the management of "inevitableo/oo abortion is that of cervical incompetence. In this condition painless dilatation of the cervix has occurred (without bleeding) in the mid trimester. In this circumstance, a purse-string suture of the cervix (cerclage) may succeed in retaining the pregnancy.

    3. Complete Abortion: No further therapy is required, but the patient must be observed closely for continued bleeding or evidence of infection. These complications most often indicate that not all of the tissue has been passed.

    4. Missed Abortion: Most missed abortions will evacuate spontaneously and should then be evaluated for completion of the process. If uterine evacuation is delayed beyond four weeks, intervention to empty the uterus should be considered to prevent a coagulation disorder.

  11. Ectopic Pregnancy
    See chart

    1. Defined: Ectopic pregnancy refers to implantation of the zygote outside the uterus or in an abnormal location within the uterus.

    2. Incidence.

      1. Varies widely from study to study.

      2. Probably dependent on population base (Jamaica 1:28).

      3. From 1:64 to 1:350, but generally accepted at 1:130.

      4. Recently has shown increasing frequency.

    3. Mortality.

      1. Felt to be responsible for 10% of maternal deaths.

      2. Approximate maternal mortality: 1-2/1,000.

    4. Etiology.

      1. Chronic PID.

      2. Tubal damage (previous surgery, endometriosis).

      3. Hormonal factors slowing ovum transport.

      4. Menstrual bleeding (unsuppressed).

      5. Tubal atony or spasm.

      6. Blighted conceptus - features of blighted ovum are seen twice as often in tubal pregnancies.

      7. Developmental abnormalities of the tube.

      8. Extrinsic obstruction.

      9. IUD usage.

    5. Pathology: "Normalo/oo conceptus but with pathologic site.

      1. Uterine changes.

        1. In first two months uterus growth may be comparable to normal pregnancy due to the circulating hormonal changes of early pregnancy.
        2. Decidual changes.
        3. Arias-Stella ("Sturgis-Arias-Stellao/oo): Secondary to hyperstimulation by progesterone and estrogen (occurs in 60%), suggestive of tubal ectopic pregnancy.

      2. Pathologic distribution of nidation.

        1. Uterine.

          (1) Cervical - 1.5%
          (2) Diverticular - rare.
          (3) Uterine sacculation - more rare.
          (4) Intramural.
          (5) Angular.
          (6) Cornual - 2%.
          (7) Rudimentary horn.

        2. Tubal - 95%.

          (1) Interstitial.
          (2) Isthmic.
          (3) Ampullar (most common).
          (4) Infundibular.
          (5) Fimbrial.

        3. Interligamentous.

        4. Ovarian - 1:9,000 to 1:60,000.

        5. Abdominal - 1:15,000 live births.

    6. Diagnosis.

      1. Clinical history will give greatest amount of useful information.

        1. Clinical history - negative history of amenorrhea in 25%.
        2. Pain - most common symptom - more than 90%.
        3. Syncope - 33%.

      2. Physical exam.

        1. Signs of hypovolemia - 33% heart rate - blood pressure.
        2. Pelvic mass - 50%.
        3. Pelvic pain - especially with movement of cervix.
        4. Temperature.
          (1) May be subnormal with acute blood loss.
          (2) May be elevated when patient stable (2%).
        5. Diaphragmatic irritation - 10%.

      3. Lab data.

        1. CBC with differential.
          (1) Hct - Hbg: almost always low.
          (2) Leukocytosis: 50% greater than 15,000/cu mm.
        2. Pregnancy testing: almost always positive with RIA or EIA tests.
        3. Ultrasonography: A gestational sac should be seen using a transvaginal ultrasound probe when the serum quantitative bhCG exceeds 2,500 mIU/mL (even 1,000 at some centers) in a normal intrauterine gestation. The inability to detect an ectopic pregnancy ultrasonographically DOES NOT rule out the possibility of ectopic pregnancy.

      4. Surgical Diagnostic Options.

        1. Culdocentesis: quick and simple with extremely high correlation in ruptured ectopics (90% to 95%).
        2. D & C.
          (1) Only 20% will show decidual response.
          (2) Questionable value.
        3. Laparoscopy: especially if diagnosis is only a suspicion.

    7. Differential diagnosis.

      1. Ectopic pregnancy

      2. Pelvic inflammatory disease.

      3. Abortion: threatened or incomplete.

      4. Ovarian pathology: torsion, cyst.

      5. Acute appendicitis.

    8. Treatment.

      1. Lab: CBC, ABO-Rh, cross match, electrolytes, UA.

      2. Stabilize patient.

      3. Salpingectomy.

      4. Ipsilateral oophorectomy with ovarian involvement.

      5. Conservative approach.

        1. Resection.
        2. Expression.
        3. Evacuation.
        4. Linear salpingostomy.

      6. Contralateral tube.

      7. Hysterectomy: criteria.

      8. The Rh negative patient.

      9. Medical treatment: single dose IM methotrexate, hyperosmolar glucose.

    9. Prognosis.

      1. Tubal pregnancy interferes with future reproductive ability in 50% to 60%.

      2. Recurrent tubal pregnancy ranges from 7.7% to 20%.


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Take Home Points

  1. The number one reason for amenorrhea in a woman of reproductive age is pregnancy.

  2. The diagnosis of early pregnancy is not always straightforward; clinicians from all disciplines must become expert in the methods of diagnosing pregnancy.

  3. The most common disorder of early pregnancy is abortion in all its varied presentations.

  4. The most life-threatening disorder of early pregnancy is ectopic pregnancy. High suspicion for ectopic pregnancy should always be maintained for gynecologic patients, and prompt diagnosis and therapy should be reflexive.

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