Missed period with suspected pregnancy

A missed period with suspected pregnancy is a woman of reproductive age whose expected menstruation has not occurred and whose symptoms or circumstances suggest pregnancy.

The main clinical points are:

• Confirm pregnancy with a test.
• Establish that it is intrauterine and viable, and date it.
• Identify early the women at risk of ectopic pregnancy, miscarriage or maternal complications.
• Counsel on options and start care.

If the test is negative, the cause of the missed period is sought separately.

Clinical relevance. Accurate dating drives screening tests, timing of delivery and management of complications. Early recognition of pregnancy allows folic acid, review of teratogenic drugs and prevention of complications. Missed ectopic pregnancy remains a cause of maternal death.

Physiology. After implantation (6 to 12 days after ovulation), the trophoblast produces human chorionic gonadotropin, which doubles about every 48 to 72 hours in early viable pregnancy, peaks at 8 to 11 weeks, then falls. Urine tests detect hCG at about 20 to 25 IU/L.

Classification. By test: positive, negative or equivocal. By location: intrauterine, ectopic or pregnancy of unknown location. By viability: viable, failing or non viable. By symptoms: asymptomatic or with pain or bleeding.

Key distinctions. A positive test with pain or bleeding and no intrauterine pregnancy on ultrasound is ectopic pregnancy until proved otherwise. A negative urine test with a missed period and suggestive features needs a repeat test in 1 week or a serum beta hCG. A positive test without pregnancy suggests trophoblastic disease, recent pregnancy loss or another hCG source.

History

• Menstrual history: date of the last menstrual period (certain or uncertain), cycle length and regularity, previous period characteristics (a light period may be bleeding in pregnancy), use of hormonal contraception and the time since stopping, breastfeeding.
• Pregnancy symptoms: breast tenderness, nausea, vomiting, fatigue, frequent urination, food aversions.
• Symptoms of complication: lower abdominal pain, shoulder tip pain, vaginal bleeding (amount and clots), passage of tissue, dizziness or syncope, severe vomiting, fever.
• Risk factors for ectopic pregnancy: previous ectopic pregnancy, tubal surgery or sterilisation, pelvic inflammatory disease, current intrauterine device or progestogen only contraception, assisted conception, smoking, endometriosis, previous pelvic surgery.
• Contraception: failure, emergency contraception use, missed pills, vomiting, drug interactions (enzyme inducers).
• Obstetric history: gravidity, parity, previous miscarriage, termination, stillbirth, preterm birth, pre eclampsia, gestational diabetes, caesarean section, congenital anomalies.
• Medical history: hypertension, diabetes, epilepsy, thyroid disease, asthma, renal disease, heart disease, thrombophilia, venous thromboembolism, sickle cell disease, HIV, tuberculosis, mental illness, eating disorders.
• Drugs: warfarin, ACE inhibitors, angiotensin receptor blockers, statins, valproate, carbamazepine, phenytoin, isotretinoin, methotrexate, mycophenolate, tetracyclines, lithium, ribavirin, efavirenz, recreational drugs, alcohol.
• Family history: congenital anomalies, genetic disorders, twins, diabetes, hypertension.
• Social: age (child protection under 16 years), relationship safety and domestic abuse, sexual violence, housing, support, intention to continue the pregnancy.
• Region specific: malaria exposure, HIV prevalence, rubella and syphilis screening access, female genital cutting.

Examination

• Vital signs, weight, height, BMI, blood pressure (baseline), signs of anaemia.
• Breast changes, thyroid, heart and chest, abdomen (tenderness, guarding, uterine size after 12 weeks, mass).
• Speculum examination and bimanual examination only if bleeding, pain, discharge or concern (cervical os, products, cervical motion tenderness, adnexal tenderness or mass, uterine size).
• Skin for signs of abuse and injection marks.
• Bedside tests: urine pregnancy test, urine dipstick, point of care ultrasound where trained.

Red flags

• Haemodynamic instability, syncope, shoulder tip pain or peritonism with a positive test.
• Positive test with unilateral pain or vaginal bleeding (ectopic pregnancy or miscarriage).
• Previous ectopic pregnancy, current intrauterine device or tubal surgery.
• Severe vomiting with dehydration.
• Pregnancy under 16 years, sexual violence or coercion.
• Teratogenic drugs, uncontrolled diabetes, epilepsy or hypertension.
• Positive pregnancy test with a very high hCG level or enlarged uterus for dates (trophoblastic disease).
• Fever with a positive test (septic abortion, malaria).

Special groups. Adolescents: confidentiality, consent laws, child protection and psychosocial support. Women over 40: higher risk of miscarriage, chromosomal abnormality and maternal complications. Women on contraception: ectopic pregnancy risk is relatively higher when pregnancy occurs with an intrauterine device or progestogen only pill. Women with chronic disease: preconception counselling is often missed.

Organised by the result of the test and the setting. Positive pregnancy test

• Viable intrauterine pregnancy (the commonest cause).
• Serious: ectopic pregnancy (tubal, cervical, caesarean scar, interstitial, ovarian, abdominal), heterotopic pregnancy.
• Early miscarriage (threatened, inevitable, incomplete, missed), biochemical pregnancy, pregnancy of unknown location.
• Serious: gestational trophoblastic disease (complete or partial hydatidiform mole, choriocarcinoma).
• Recent pregnancy loss or termination with residual hCG.
• Multiple pregnancy.
• hCG producing tumours (germ cell tumour, gastric, lung, bladder, liver), pituitary hCG in perimenopause, exogenous hCG, heterophile antibodies (false positive).

Negative pregnancy test with a missed period

• Early pregnancy before detectable hCG (repeat test), dilute urine, or hook effect with very high hCG (serum test with dilution).
• Hormonal contraception (depot medroxyprogesterone acetate, implant, intrauterine system, pill withdrawal).
• Breastfeeding amenorrhoea.
• Polycystic ovary syndrome and anovulation.
• Hypothalamic amenorrhoea (stress, weight loss, exercise, illness).
• Hyperprolactinaemia (drugs, prolactinoma), thyroid disease.
• Premature ovarian insufficiency and menopause.
• Intrauterine adhesions (Asherman syndrome) and cervical stenosis.
• Chronic illness, endocrine tumours, Cushing syndrome, congenital adrenal hyperplasia.
• Serious: pituitary tumour, Sheehan syndrome, androgen secreting tumour.
• Drugs: antipsychotics, metoclopramide, domperidone, opioids, chemotherapy.
• Pseudocyesis (false pregnancy).

Conditions that mimic early pregnancy symptoms

• Gastroenteritis, urinary tract infection, hepatitis, peptic ulcer, pancreatitis.
• Premenstrual syndrome, perimenopause.
• Thyroid disease and anaemia.
• Pelvic mass, fibroids, ovarian cysts.

Stepwise reasoning

1. Perform a urine pregnancy test, repeating or sending serum beta hCG when the first result is negative or doubtful.
2. If positive and symptomatic, assess urgently for ectopic pregnancy and miscarriage with ultrasound and serum beta hCG.
3. If positive and asymptomatic, confirm location and viability and date the pregnancy at the first visit or at 6 to 9 weeks.
4. Start antenatal care and booking tests.
5. If negative and still amenorrhoeic, investigate the cause of amenorrhoea.

Pregnancy tests

• Urine test: most are positive on the first day of the missed period (about 14 days after ovulation); sensitivity increases with later testing. Use the first morning urine. Repeat in 3 to 7 days if negative and still amenorrhoeic.
• Serum quantitative beta hCG: detects hCG at 1 to 5 IU/L about 7 to 10 days after conception. Dilute the sample if a very high level may cause a false negative (hook effect).
• False positives: heterophile antibodies, hCG producing tumours, perimenopause, recent pregnancy, hCG injections.

Ultrasound

• Transvaginal ultrasound: gestational sac visible at about 4.5 to 5 weeks, yolk sac at about 5.5 weeks, embryo with cardiac activity at about 6 weeks (crown rump length 7 mm or more should show a heartbeat).
• Intrauterine pregnancy: eccentric gestational sac with double decidual sign, yolk sac and embryo.
• Ectopic features: no intrauterine pregnancy, adnexal mass (ring sign), free fluid.
• Pregnancy of unknown location: positive test with no pregnancy visible; repeat beta hCG at 48 hours (a rise of less than about 49 to 63% depending on starting level, or a fall of less than 50%, needs senior review) and repeat ultrasound.
• Discriminatory level: an intrauterine sac is usually visible once beta hCG exceeds about 1500 to 3500 IU/L.
• Miscarriage diagnosis: crown rump length 7 mm or more with no heartbeat, or mean sac diameter 25 mm or more with no embryo; otherwise repeat the scan after 7 to 14 days.
• Multiple pregnancy: chorionicity is best determined before 14 weeks.

Dating

• Naegele rule: add 280 days (9 months and 7 days) to the first day of the last menstrual period for a regular 28 day cycle; adjust for cycle length.
• Ultrasound dating by crown rump length (7 to 13 weeks and 6 days): redate when the difference from last menstrual period dating exceeds 5 days up to 8 weeks and 6 days, or 7 days from 9 weeks to 13 weeks and 6 days. Use head circumference from 14 weeks.
• Uncertain dates or irregular cycles: use ultrasound.

Booking and baseline tests

• Blood group, rhesus status and red cell antibodies; full blood count; haemoglobinopathy screen (sickle cell, thalassaemia) by ancestry; ferritin if anaemic.
• HIV, syphilis, hepatitis B surface antigen, hepatitis C where indicated, rubella immunity.
• Urine culture to detect asymptomatic bacteriuria; urine protein.
• Blood glucose or HbA1c with risk factors for diabetes; thyroid function with symptoms or history.
• Malaria testing in endemic regions when febrile.
• Cervical screening if due; chlamydia and gonorrhoea testing under 25 years or with risk.
• Early dating and viability scan; nuchal and anomaly screening plan.

Tests for a missed period with a negative test

• Repeat pregnancy test; thyroid stimulating hormone; prolactin; follicle stimulating hormone, luteinising hormone and oestradiol; testosterone and sex hormone binding globulin; pelvic ultrasound.
• Further evaluation of amenorrhoea directed by results.

Limitations. Urine tests can be falsely negative in early pregnancy or with dilute urine and falsely positive with hCG producing tumours or certain drugs. Ultrasound cannot exclude early ectopic pregnancy. Dates by last menstrual period are unreliable with irregular cycles, hormonal contraception or breastfeeding.

Immediate steps. Treat shock, severe pain or heavy bleeding with intravenous access, crystalloid in 250 to 500 mL aliquots, blood and urgent gynaecology review (ectopic pregnancy). For stable symptomatic women, arrange early pregnancy assessment within 24 hours. Explain the result, ask about intention and support, and give options in a non judgmental way.

Counselling and options

• Continue the pregnancy: start antenatal care.
• Termination of pregnancy where permitted by local law:
  • Medical abortion up to 10 weeks with mifepristone 200 mg orally, followed after 24 to 48 hours by misoprostol 800 microgram vaginally, buccally or sublingually.
  • Surgical abortion by vacuum aspiration.
  • Check local legal requirements and refer.
  • Give rhesus negative women anti D immunoglobulin 250 IU intramuscularly within 72 hours when abortion is surgical.
• Adoption and fostering: refer to social services.
• Miscarriage management: expectant, medical or surgical.

Prenatal supplements and risk reduction

• Folic acid 400 microgram orally daily until 12 weeks; 5 mg daily for women with BMI over 30, diabetes, previous neural tube defect, sickle cell disease, thalassaemia, epilepsy treated with antiepileptic drugs, or coeliac disease.
• Vitamin D 10 microgram daily.
• Iron: ferrous sulphate 200 mg (65 mg of elemental iron) once daily if anaemic; treat confirmed iron deficiency from first trimester.
• Aspirin 75 to 150 mg orally once daily at night from 12 weeks until 36 weeks for women at high risk of pre eclampsia (previous pre eclampsia, chronic hypertension, diabetes, renal disease, autoimmune disease; or two or more moderate risks).
• Stop if aspirin allergy or active peptic ulcer. Take with food.
• Calcium supplementation 1.5 to 2 g elemental calcium daily from 20 weeks in populations with low dietary calcium to reduce pre eclampsia (evidence limited to such settings).
• Malaria prevention in endemic regions: intermittent preventive treatment with sulphadoxine pyrimethamine (three tablets of 500 mg and 25 mg as a single dose) from 13 weeks, given at least 1 month apart, avoiding use with co-trimoxazole prophylaxis, and insecticide treated nets.
• Stop smoking, alcohol, recreational drugs. Limit caffeine to under 200 mg daily. Avoid unpasteurised dairy, raw meat, and high mercury fish.
• Vaccines: influenza, tetanus, diphtheria and pertussis in pregnancy; avoid live vaccines.
• Review and change teratogenic drugs: stop ACE inhibitors, angiotensin receptor blockers, statins.
• Warfarin (switch to enoxaparin 1 mg/kg subcutaneously twice daily or 1.5 mg/kg once daily, directed by indication).
• Valproate (switch with specialist advice), isotretinoin, methotrexate, mycophenolate and tetracyclines.
• Do not stop essential drugs for epilepsy, asthma, HIV or hypertension without alternatives.
• Optimise diabetes (HbA1c under 48 mmol/mol, 6.5%, before conception where possible), thyroid disease and mental health.

Ectopic pregnancy and pregnancy of unknown location

• Pregnancy of unknown location: clinically stable women can be managed with repeat beta hCG at 48 hours and a return plan; do not treat empirically with methotrexate.
• Stable, unruptured ectopic pregnancy with no foetal cardiac activity, mass under 35 mm and beta hCG under 5000 IU/L:
  • Methotrexate 50 mg/m2 body surface area intramuscularly as a single dose, with a second dose if beta hCG falls by less than 15% between day 4 and day 7 (up to three doses).
  • Check full blood count, renal and liver function before.
  • Avoid NSAIDs, folic acid, alcohol and live vaccines.
  • Contraindicated in breastfeeding, active infection, severe renal, hepatic or haematological disease, and haemodynamic instability.
  • Follow beta hCG weekly until undetectable.
  • Avoid conception for 3 months.
• Ruptured or unstable ectopic pregnancy: resuscitation and laparoscopic salpingectomy or laparotomy.
• Give anti D immunoglobulin 250 IU intramuscularly within 72 hours to rhesus negative women with ectopic pregnancy.

Miscarriage. Expectant management for 7 to 14 days is first line for stable women with incomplete or missed miscarriage.

Medical management: misoprostol 800 microgram vaginally (or 600 microgram orally), repeated once after 24 to 48 hours if needed. For missed miscarriage, mifepristone 200 mg orally followed after 24 to 48 hours by misoprostol 800 microgram vaginally.

Surgical evacuation for heavy bleeding, infection, instability, retained products or patient choice.

Contraindications to medical management: suspected ectopic pregnancy, sepsis, severe haemorrhage, coagulopathy and allergy.

Give anti D immunoglobulin 250 IU intramuscularly within 72 hours to rhesus negative women after surgical management.

Hyperemesis. Admit for dehydration or ketonuria: intravenous sodium chloride 0.9% with potassium chloride 20 mmol/L 1 L over 2 to 4 hours, cyclizine 50 mg intravenously three times daily, and thiamine 100 mg intravenously daily given before any dextrose.

Gestational trophoblastic disease. Suction evacuation and histology, followed by beta hCG monitoring, specialist referral and contraception for 6 to 12 months.

Women with negative tests. Repeat the test in 1 week. If still negative, investigate causes of amenorrhoea (thyroid stimulating hormone, prolactin, follicle stimulating hormone, ultrasound) and refer if indicated.

Special groups. Adolescents: confidential care, child protection assessment under 16 years or with abuse concerns, and contraception counselling. Women with HIV: start or continue antiretroviral therapy (dolutegravir with tenofovir and emtricitabine or lamivudine is widely used), viral load monitoring and plan for prevention of mother to child transmission. Women with epilepsy, diabetes or hypertension: specialist care in the first trimester. Women with previous caesarean section: scar pregnancy ultrasound early.

Monitoring. Early pregnancy assessment with ultrasound at 6 to 9 weeks when dates are uncertain, bleeding or pain occurs, or ectopic risk is high. Routine antenatal visits from booking, with dating scan 8 to 14 weeks.

Referral and escalation. Refer the same day for suspected ectopic pregnancy, heavy bleeding, hyperemesis with dehydration, trophoblastic disease, domestic violence, or severe medical disease. Refer to the early pregnancy service for pregnancy of unknown location, recurrent loss (three or more) or previous ectopic pregnancy. Refer to antenatal care for continuing pregnancies.

Admission criteria. Haemodynamic instability, suspected ruptured ectopic pregnancy, heavy bleeding, sepsis, severe vomiting with dehydration and ketonuria, and unsafe social situation. Discharge and follow up. Provide a written plan including the date of the next scan or beta hCG, the contact number, and advice to return.

Safety netting. Return the same day for worsening pain, shoulder tip pain, fainting, heavy bleeding, fever, severe vomiting, or inability to keep fluids down.