Human Chorionic Gonadotropin

Human chorionic gonadotropin (hCG) is a glycoprotein of alpha and beta subunits made by syncytiotrophoblast cells. It maintains the corpus luteum in early pregnancy. The beta subunit is specific, and the alpha subunit is shared with LH, FSH and TSH. Total beta-hCG (intact hCG, free beta subunit and nicked forms) is measured by immunoassay in serum or urine. Qualitative urine tests detect hCG from about 25 mIU/mL and give a result in minutes. Quantitative serum results are reported in IU/L.

The test confirms pregnancy, assesses early pregnancy viability and location, and screens for gestational trophoblastic disease. It also acts as a tumour marker for germ cell tumours and trophoblastic neoplasia.

About 1 in 4 to 1 in 3 clinical pregnancies end in miscarriage, and ectopic pregnancy affects 1 to 2% of pregnancies and remains a leading cause of first trimester maternal death. Gestational trophoblastic disease affects 1 in 500 to 1000 pregnancies in Europe and North America and more often in parts of Asia.

Indications. Missed menstruation, any woman of reproductive age before drugs, imaging with radiation or surgery, abdominal pain or vaginal bleeding in early pregnancy, hyperemesis, suspected molar pregnancy, after miscarriage or ectopic pregnancy, testicular or ovarian mass, mediastinal or retroperitoneal midline mass in a young adult, and monitoring of trophoblastic disease.

Specimen. Serum for quantitative beta-hCG, or a first morning urine for a qualitative test. Serial values are measured on the same assay. Record gestation by last menstrual period and any fertility treatment, including recent hCG injections.

Reference values. Non-pregnant women, men: under 5 IU/L. A value over 25 IU/L supports pregnancy, and 5 to 25 IU/L is indeterminate and repeated in 48 hours. Postmenopausal women may have values up to 14 IU/L from pituitary hCG.

Normal pregnancy kinetics.

• hCG becomes detectable about 8 to 11 days after ovulation.
• Doubling time is about 1.4 to 2 days in the first 4 weeks (about 48 hours until 1500 IU/L, slower at higher levels).
• A rise of at least 49% in 48 hours is expected in a viable intrauterine pregnancy when the starting level is under 1500 IU/L, 40% at 1500 to 3000 IU/L, and 33% over 3000 IU/L.
• Peak at 8 to 11 weeks (about 25 000 to 300 000 IU/L), then falls to a plateau.

Discriminatory zone. A normal intrauterine pregnancy should be seen as a gestational sac on transvaginal ultrasound once hCG exceeds about 1500 to 3500 IU/L. A non-visualised pregnancy over this level is a pregnancy of unknown location with a high risk of ectopic pregnancy, and the conservative cut off is chosen at 3500 IU/L to avoid disturbing a viable pregnancy.

Abnormal patterns.

• Ectopic pregnancy: slow rise (under the expected minimum), plateau, or fall, with no intrauterine sac. Up to 20% of ectopic pregnancies show a normal rise, and so a normal hCG does not exclude it. Very low values are possible.
• Miscarriage: falling hCG (a fall of 21 to 35% in 2 days if under 1500 IU/L, and over 50% in 7 days after complete miscarriage), with return to non-pregnant levels in 2 to 6 weeks.
• Molar pregnancy: very high hCG (over 100 000 IU/L) for gestational age, with exaggerated symptoms (hyperemesis, early pre-eclampsia, thyrotoxicosis), and ultrasound showing a snowstorm pattern.
• Persistent trophoblastic disease: a plateau of 4 values over 3 weeks, a rise over 10% in 3 values over 2 weeks, or a persistent value 6 months after evacuation. This indicates gestational trophoblastic neoplasia.
• Multiple pregnancy and Down syndrome: higher values. Low values are seen with trisomy 18 and in failing pregnancies.

Tumour marker.

• Germ cell tumours: raised in choriocarcinoma, embryonal carcinoma, seminomas (low levels in about 15%) and mixed tumours. Used with AFP and LDH for staging, prognosis and monitoring after treatment.
• Gestational trophoblastic neoplasia: monitored weekly until normal and then monthly.
• Other tumours: bladder, lung, liver and pancreatic cancers, and neuroendocrine tumours may secrete hCG.

Other uses. hCG is used in screening for Down syndrome (with AFP, oestriol and inhibin A), and in fertility treatment to trigger ovulation.

Critical values and findings needing immediate action.

• Positive hCG with abdominal pain, shoulder tip pain, haemodynamic instability or vaginal bleeding: ruptured ectopic pregnancy until proven otherwise.
• Positive hCG in a woman with an intrauterine contraceptive device in place.
• hCG over 100 000 IU/L with vaginal bleeding, hyperemesis or thyrotoxic features.
• Persistently raised or rising hCG after molar evacuation, or after treatment for germ cell tumour.
• Positive hCG before surgery, radiotherapy or teratogenic drugs.

Interferences and pitfalls.

• A false negative qualitative test can occur with very early testing, dilute urine, or very high hCG saturating the test (hook effect), and a repeat on diluted serum corrects this.
• False positive results arise from heterophile antibodies, hCG injections (trigger shots clear in 10 to 14 days), pituitary hCG in perimenopausal women, certain tumours, and assay cross-reaction with LH in very high LH states.
• Phantom hCG is a persistent low level false positive from heterophile antibodies, and urine hCG is negative.
• Different assays measure different hCG forms, so serial values should come from the same method.
• Biotin can interfere with some immunoassays.
• A single value does not determine pregnancy viability or location, and serial values and ultrasound are used together.
• Quantitative hCG falls slowly after delivery, miscarriage and termination, so a positive test in the following weeks is expected.

Special groups.

• Adolescents: pregnancy must be considered in any amenorrhoea, and consent and confidentiality apply.
• Pregnancy after fertility treatment: high values and multiple pregnancy, with higher risk of ectopic and heterotopic pregnancy.
• Postmenopausal women: low level hCG alone is rarely a tumour.
• Men: raised hCG with a testicular mass or a mediastinal mass indicates a germ cell tumour.
• Regions: molar pregnancy is more frequent in parts of East and South-East Asia.

Follow up tests. Repeat quantitative hCG at 48 hours, transvaginal ultrasound, progesterone, blood group and antibody screen (anti-D prophylaxis if Rhesus negative), full blood count, thyroid function tests, AFP and LDH, chest imaging for trophoblastic disease, pelvic and testicular imaging, and histology of tissue.