Diagnosing  Pregnancy

Pregnancy is diagnosed on clinical grounds by a missed period and symptoms and signs including:

  • ■  Nausea
  • ■  Breast tenderness
  • ■  Urinary frequency
  • ■  Clinically an enlarged uterus.

Other relevant features of a history in evaluating the state/viability of a pregnancy include:

  • ■  Fertility history
  • ■  Known tubal disease
  • ■  History of previous ectopic pregnancy
  • ■  Miscarriage and previous pregnancy outcomes.

The expected date of delivery is calculated (Naegele’s formula) as last menstrual period (last menstrual period) plus 7 days and 9 calendar months.

Pregnancy tests

Home kits give a faster and less expensive indication of pregnancy compared to radioimmunoassay.

Types of pregnancy test

(1) Slide or tube latex-particle agglutination inhibition tests are performed within 2-3 minutes. They require 300-500 mlU human chorionic gonadotrophin/ml of urine for a positive result. These levels are achieved about 4 weeks after the last menstrual period. The test is performed by taking a urine specimen and mixing it with a solution of human chorionic gonadotrophin antibody which will bind any human chorionic gonadotrophin present in the test specimen. A suspension of human chorionic gonadotrophin-coated latex heads or erythrocytes is then added. If human chorionic gonadotrophin is present in the test specimen, the binding of the human chorionic gonadotrophin-coated latex particles or erythrocytes to the antibody will be blocked and the agglutination reaction inhibited. No agglutination indicates a positive pregnancy test. Agglutination (i.e. the presence of a fine floccular precipitant) indicates a negative pregnancy test.

(2)  The enzyme-liked immunosorbent assay (ELISA) method is performed in 4-5 minutes. It can detect 50mIU human chorionic gonadotrophin/ml of urine as early as 10-12 days after ovulation.

(3)  Quantification of human chorionic gonadotrophin by radioimmunoassay. These assays are performed in 70-180 minutes and can detect as little as 1 mlU human chorionic gonadotrophin as early as 7 days after ovulation.

Ultrasound imaging of early pregnancy

The pregnancy is imaged to identify a viable intrauterine fetus, confirm the gestational age and exclude any other abnormality or normal variant, e.g. multiple pregnancy.

  • ■  The first sign of pregnancy is thickening of the endometrium but this may not be recognized for what it is.
  • ■  With vaginal scanning, a 1 mm gestational sac may be imaged at 4 weeks and 2 days from the last menstrual period of a regular cycle. Early gestational structures can usually be seen about 1 week earlier by transvaginal rather than transabdominal ultrasound.
  • ■  An intrauterine pregnancy is visible on vaginal ultrasound scan at a β-human chorionic gonadotrophin level of 1000IU/1, and at 5000IU/1 for transabdominal ultrasound scanning.
  • ■  Sac size at 6 weeks transabdominal is about 25 mm with an embryo with a heartbeat. Transvaginally, sac size is 15 mm with an embryo with a heartbeat, corresponding to an earlier gestation.
  • ■  With an embryo of 3 mm transabdominal or transvaginal, a heartbeat should be visualised with most machines, which is a gestation of about 6 weeks. However, if a heartbeat is not seen up to a crown rump length of 5 mm, rescanning 1 week later is indicated. It does not necessarily indicate fetal demise.
  • ■  In normal pregnancy the sac diameter increases by 1 mm/day. Growth of less than 1 mm/day is a poor prognostic sign. The sac diameter should be greater than 30 mm at 6-7 weeks’ gestation.
  • ■  The yolk sac is the first structure that can be accurately identified within the gestational sac (5 weeks and 5 days) – a little earlier than the embryo, and initially it is much larger than the embryo.
  • ■  Because the yolk sac is part of the embryo when seen, it means it is a gestational sac and not a fluid collection and therefore in most cases there is not an extrauterine pregnancy. The incidence of hetero-topic pregnancy is 1 per 30 000, but the risk is increased with assisted reproductive techniques.
  • ■  A diagnosis of an anembryonic pregnancy (blighted ovum) is suggested when a gestational sac is larger than 20 mm in diameter with no yolk sac, or greater than 25 mm without a fetus or the yolk sac is large (greater than 10mm in diameter).
  • ■  Fetal crown rump length should be measured.
  • ■  Fetal cardiac activity can be first identified at 41-43 days of gestation using a 2.5 MHz transabdominal sector transducer.
  • ■  Over 90 per cent of embryos with cardiac activity identified on ultrasound develop normally. The risk of miscarriage is reduced from about 40-50 per cent to between 1 and 3 per cent, depending on the gestational age when the fetal heart is first imaged and the age of the woman. If the heart rate is less than 85 beats per minute, miscarriage is likely.

Bleeding In Early Pregnancy (Threatened  Miscarriage  Or Missed  Miscarriage)

  • ■  A diagnosis of missed miscarriage should not be made if no fetal pole is seen and the gestation sac diameter is less than 20 mm.
  • ■  If the crown rump length is <6mm, the pregnancy should be rescanned in 7-10 days. A missed miscarriage can be confirmed by correlating fi-human chorionic gonadotrophin levels with the ultrasound findings.
  • ■  If crown rump length is >6 mm with no cardiac activity, the pregnancy is non-viable.
  • ■  Any intrauterine haematoma should be noted.
  • ■  Retained products of conception are shown as tissue of mixed echogenicity with no gestation sac. If the volume is <30mm (maximum diameter) with mild blood loss, and no evidence of infection, expectant management is all right. Evacuation of the uterus is indicated for women with a large volume of products of conception and/or heavy blood loss.
  • ■  The adnexa should be imaged and peritoneal fluid looked for.
  • ■  If the uterus is empty with a positive pregnancy test, the pregnancy is very early, a complete miscarriage or an ectopic pregnancy.

First Trimester Miscarriage

Second Trimester Miscarriage

Early Pregnancy: Ectopic Pregnancy

Termination of Pregnancy

Gestational Trophoblastic Disease

Gestational trophoblastic disease is identified as an abnormal proliferation histologically of trophoblastic tissue. Trophoblastic disease manifests itself clinically as irregular vaginal bleeding and typical ultrasound features of a classic ‘snowstorm’ appearance   with    an    absence   of   fetal   parts    and   heartbeat.

Table World Health Organisation (WHO) classification of trophoblastic disease.

1  Hydatidiform mole
Complete
Partial
2 Invasive hydatidiform mole
3 Choriocarcinoma
4 Placental site trophoblastic tumour
5 Trophoblastic tumour, miscellaneous
Exaggerated placental site
Placental site nodule or plaque
6 Unclassified trophoblastic lesions

Table Staging of gestational trophoblastic diseases.

FIGO stages TNM categories
I Primary tumour cannot be assessed TX
No evidence of primary tumour TO
Tumour confined to uterus T1
II Tumour extends to other genital structures: vagina, ovary, broad ligament, fallopian tube by metastasis or direct extension T2
III Metastasis to the lung(s) M1a
IV Other distant metastasis with or without lung involvement M1b

Occasionally grape-like hydropic villi may be passed vaginally.

Hydatidiform mole

  • ■  May be complete and incomplete or partial.
  • ■  Complete moles are diploid lesions with 46XX karyotype being the most common.
  • ■  Incomplete moles have chromosomes that are paternally derived.
  • ■  Characterised by hydropic swelling of the chorionic villi with diffuse trophoblastic proliferation.
  • ■  Absent embryonic or fetal tissue.
  • ■   10-30 per cent of evacuated complete moles may be followed by persistent gestational trophoblastic disease requiring therapy.
  • ■  The risk of requiring chemotherapy is 1 in 10
Partial moles
  • ■  Karyotype is triploid (69 chromosomes).
  • ■  Two paternal sets and a maternal chromosome complement.
  • ■  Varying size chorionic villi with focal hydropic changes and trophoblastic hyperplasia.
  • ■  Fetal or embryonic tissues are usually identified. They have lower frequency of progressing to choriocarcinoma.
  • ■  The risk of requiring chemotherapy after partial hydatidiform mole is about 1 in 200.
  • ■  A complete or partial hydatidiform mole may undergo malignant transformation. Even after surgical evacuation it may persist and remain confined to the uterine cavity or penetrate into the myometrium. Embolisation to the lungs or vagina may occur or it may transform to choriocarcinoma.
Follow-up
  • ■  If the serum human chorionic gonadotrophin falls to <5 IU/1 by 56 days post-evacuation, the follow-up period may be reduced to 6 months.
  • ■  If the human chorionic gonadotrophin has not fallen to <5 IU/1, follow-up should continue for 2 years.
  • ■  The risk of requiring chemotherapy after partial hydatidiform mole is about 1 in 200, compared with a risk of about 1 in 10 after a complete hydatidiform mole.
  • ■  Patients treated for a persisting trophoblastic lesion within 6 months of evacuation of a mole usually respond completely to a low-toxicity methotrexate/folinic acid regimen.
  • ■  Twenty-five per cent require additional cytotoxics.
  • ■  The overall cure rate in the post-hydatidiform mole group is more than 99 per cent.
  • ■  Etoposide, methotrexate, actinomycin D/cyclophosphamide with vincristine regimen is used to treat patients with persisting disease, which achieves eradication in 85 per cent of choriocarcinomas.
  • ■  The placental site of trophoblastic tumours should be identified because of the need for possible early hysterectomy.
  • ■  Drug resistance requires additional therapeutic agents and often surgery.
  • ■  Central nervous system metastases also require treatment, and may be eradicated in up to 70 per cent of cases.
  • ■  Fertility is not significantly impaired by chemotherapy.
  • ■  There is no increased risk of secondary tumours but therapy-induced leukaemias have occurred.
  • ■  The incidence of choriocarcinoma following hydatidiform mole is about 1 in 30; 1 in 50 000 occurs after a term pregnancy.
Treatment of a molar pregnancy

Suction evacuation of the uterine cavity is the treatment of choice. There are significant risks of perforation and haemorrhage. All tissue should be sent for histological examination.

Table Gestational trophoblastic disease prognostic score.

0 1 2 4
Age (years) <39 >39
Antecedent pregnancy Mole Miscarriage/TOP Term pregnancy
Interval (months) 4 4-6 7-12 >12
Pretreatment human chorionic gonadotrophin (log) <3 <4 <5 <5
ABO group (female x male) Ox A AxO В AB
Largest tumour (cm) 3-5 5
Site of metastasis Spleen, kidney Gl tract, liver Brain
Number of metastases identified 1-4 4-8 >8
Previous chemotherapy failed Single drug Two or more
Chemotherapy

Chemotherapy protocols are initiated to minimise the risk of progressive disease by timely intervention without subjecting more patients than necessary to cytotoxic agents. Approximately 8 per cent of patients with hydatidiform mole using these protocols require chemotherapy.

The risk of relapse at 6 months if the beta-human chorionic gonadotrophin is <5 IU/1 is less than 1 in 2000. This means that for approximately 65 per cent of patients whose beta-human chorionic gonadotrophin results fall into this normal range by the 56th day post-evacuation, they do not need to wait before trying for a further pregnancy.

The risk of a second hydatidiform mole is 1 in 76 and that of a third 1 in 6.

Choriocarcinoma

  • ■  Malignant tumour of the trophoblast.
  • ■  Generally follows an identifiable gestational event such as a molar pregnancy, abortion, ectopic or term pregnancy.
  • ■  Approximately 50 per cent of cases of choriocarcinoma are preceded by a hydatidiform mole.
  • ■  Twenty-five per cent occur after a miscarriage.
  • ■  Twenty-two per cent occur after a normal pregnancy.
  • ■  Three per cent occur after an ectopic pregnancy.
  • ■  Haemoptysis may occur due to blood-borne metastases.
  • ■  Thyrotoxicosis may occur because of the thyrotrophic effect of beta-human chorionic gonadotrophin.
Good prognostic factors for cboriocarcinoma
  • ■  Urinary human chorionic gonadotrophin <100 000 IU/1 for 24 hours.
  • ■  Serum human chorionic gonadotrophin <40 000 IU/1.
Symptoms
  • ■  Pregnant for <4 months.
  • ■  Absence of brain or liver metastases.
  • ■  No prior chemotherapy where the pregnancy was not a term delivery.

Treatment for low and high risk prognostic score of Gestational trophoblastic disease

Low risk Gestational trophoblastic disease (WHO score 4 or less)
  • ■  Commence treatment as soon as possible.
  • ■  A low risk of Gestational trophoblastic disease can be managed with single-agent chemotherapy using methotrexate with folinic acid.
  • ■  Other drugs include etoposide.
  • ■  If single-agent chemotherapy is used and is not working, a more aggressive treatment is warranted to prevent the emergence of drug resistance.
Intermediate risk Gestational trophoblastic disease (WHO score 5-7)
  • ■  Commence on regimen that includes combination chemotherapy – methotrexate and actinomycin D, as well as an alkylating agent.
  • ■  If a complete response is not achieved on this regimen the patient should be commenced on etoposide, methotrexate and actinomycin D, alternating with cyclophosphamide and vincristine (EMA-CO).
High risk Gestational trophoblastic disease (WHO score 8 or more)
  • ■  These patients require significant chemotherapy because they include those with brain metastases, liver and gastrointestinal tract metastases and they are at significant risk from massive bleeding.
  • ■  A combination of chemotherapy, either EMA-CO or methuotrex-ate and folinic acid chemotherapy is indicated.

Surgical treatment

  • ■  Surgery is indicated if profuse vaginal or intraperitoneal haemorrhage occurs and cannot be managed conservatively.
  • ■  Hysterectomy may be indicated for intramyometrial invasion.

How long should patients be followed up after evacuation of hydatidiform mole?

  • ■  Patients whose fi-human chorionic gonadotrophin became normal, i.e. <5 IU/1 by the 56th day post-evacuation (8 weeks) have little or no risk of late recurrence.
  • ■  More than half of patients will have a fall of beta-hCG to normal by the 56th day post-evacuation and they may be followed up for a period of 6 months only, after which a further pregnancy is not contraindicated.
  • ■  The risk of subsequent relapse in this group is of the order of <1 in 2000.
  • ■  The risk of a second hydatidiform mole is 1 in 76 and a third is 1 in 6.

Oral contraception following trophoblastic disease (E.S. Newlands, personal communication)

  • ■  All forms of exogenous hormones should be avoided until the human chorionic gonadotrophin is clearly normal. This is because taking exogenous hormones when the human chorionic gonadotrophin is raised means that the proportion of patients needing chemotherapy goes up from 7-8 per cent to 30 per cent (a significant increase over a very large database of over 20000 patients).
  • ■  Once the human chorionic gonadotrophin is clearly normal, there is no contraindication to patients going onto oral contraceptives or, later in life, going onto hormone replacement therapy.
  • ■  There is controversy between the data from the UK, which are from a larger database with a more conservative policy of treating patients with chemotherapy, and data from the USA. The main difference between the data from the two sides of the Atlantic is that policy in the USA is for all patients to be given chemotherapy if the human chorionic gonadotrophin is not normal by 8 weeks following evacuation of their molar pregnancy. In the USA a higher proportion of patients are treated than in the more conservative approach adopted in the UK.


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