When “Try Again” Stops Being a Plan

Two women may each have experienced three pregnancy losses. They may not need the same investigations.

The stage at which each pregnancy ended changes the clinical questions that should be asked.

A very early loss should not automatically be attributed to low progesterone, immunity, blood clotting or poor egg quality.

The timing of the positive test, hCG pattern, symptoms, menstrual history, method of conception and confirmation of complete resolution all matter.

A biochemical pregnancy is part of the history. It is not, by itself, a diagnosis.

Chromosomal abnormalities are a common explanation for early pregnancy loss. The probability is influenced strongly by maternal age.

However, chromosome error is not the only possibility. The complete history determines whether uterine, endocrine, autoimmune, genetic or other factors require investigation.

The gestational age, fetal measurements, ultrasound progression and any available pregnancy-tissue results become especially important.

A pregnancy that stops after documented heart activity may deserve a different emphasis from a pregnancy that ends shortly after implantation.

The timing guides the investigation. It does not prove the cause.

A later loss requires its own pathway.

The review may need to consider cervical insufficiency, uterine structure, fetal abnormalities, placental disease, infection in selected circumstances, and antiphospholipid syndrome.

It should not simply be placed into the same category as repeated very early losses.

The first consultation is not a hunt for rare diagnoses. It is a reconstruction.

For each pregnancy, I review:

A chronological record is often more valuable than a thick folder of unorganised reports.

Please bring, wherever available:

A test should earn its place.

It should do at least one of three things:

Testing without a clear purpose can create incidental findings, unnecessary treatment and more anxiety.

The aim is not to produce the longest report. The aim is to find an answer without manufacturing one.

When pregnancy tissue is available, chromosome testing can identify whether the loss involved an abnormal number or arrangement of chromosomes.

This can be particularly valuable after a second miscarriage.

A result showing a sporadic chromosome error may explain the loss and prevent the mother from being incorrectly labelled with an immune, hormonal or clotting disorder.

Array-based chromosome testing is generally preferred over traditional tissue karyotyping because it does not require cell culture and is less vulnerable to culture failure.

However, every testing method has limitations.

Maternal-cell contamination can affect interpretation. No single platform identifies every possible genetic abnormality.

A normal result does not exclude every genetic cause.

The result must always be interpreted alongside maternal age, ultrasound findings and the previous pregnancy history.^[1,3]

An abnormal chromosome number may support counselling about age-related or sporadic embryo aneuploidy.

An unbalanced structural chromosome rearrangement may lead to parental chromosome testing and genetic counselling.

A chromosomally normal loss shifts attention towards other possible maternal, paternal or placental factors.

Pregnancy-tissue testing is an investigation. It is not a judgement on the pregnancy or on either parent.

The uterus must be assessed in women with otherwise unexplained RPL.

The assessment should look beyond its general appearance.

It should examine:

A three-dimensional transvaginal ultrasound is often the most informative first examination when available.

Saline-infusion sonography can provide additional detail about the uterine cavity.

Hysteroscopy allows direct inspection and may permit treatment during the same procedure.

MRI is generally reserved for complex anatomy that remains unclear after ultrasound.^[1,3]

A uterine finding must be clinically relevant.

A small intramural fibroid that does not distort the cavity is different from a submucosal fibroid occupying the implantation space.

A minor anatomical variation is different from a significant uterine septum.

Surgery should be considered only when the likely benefit outweighs the risks of bleeding, perforation, infection or new scar formation.

A septate uterus is associated with miscarriage.

The more difficult question is whether removing the septum will improve the chance of live birth for a particular woman.

Observational studies have suggested benefit.

A small randomised trial did not demonstrate a clear improvement in live birth after septum resection. It also included women with different reproductive histories and was not large enough to settle every clinical question.

For that reason, hysteroscopic septum resection should be discussed through shared decision-making.

The discussion should include:

Antiphospholipid syndrome, or APS, is an acquired autoimmune condition.

It is different from inherited thrombophilia.

APS can be associated with pregnancy loss, thrombosis, fetal death, placental insufficiency and severe early pre-eclampsia.

The principal laboratory tests are:

A single positive test does not establish APS.

The antibodies must usually remain positive when repeated at least 12 weeks later.

The antibody type, level, persistence and clinical history all matter.

Testing and diagnosis are not the same thing.

Guidelines differ slightly regarding when testing should begin. The decision should consider the number and timing of losses, previous thrombosis and previous placental complications.^[1,3,4]

Low-dose aspirin combined with prophylactic heparin has an established role in appropriately diagnosed obstetric APS.

The exact starting point, dose and duration should be individualised.

Women with persistent moderate or high antibody levels, lupus anticoagulant or previous thrombosis may also require input from a haematologist or rheumatologist.

Aspirin and heparin should not be self-started simply because a pregnancy test becomes positive.^[1]

Factor V Leiden, the prothrombin gene variant, protein C deficiency, protein S deficiency and antithrombin deficiency are inherited thrombophilias.

Routine testing for these conditions is not recommended solely because a woman has experienced recurrent early pregnancy loss.

Testing may still be appropriate when there is:

MTHFR testing should not form part of a routine RPL investigation.

An MTHFR result does not identify a proven cause of recurrent miscarriage and does not determine whether heparin is required.^[1,3,4]

Low-molecular-weight heparin does not improve live-birth rates when prescribed routinely for unexplained RPL.

It also does not improve live-birth rates when used solely because inherited thrombophilia is present.

In the ALIFE2 randomised trial, live-birth rates were almost identical with and without low-molecular-weight heparin: 72% versus 71%.^[6]

A blood-thinning injection is not a general treatment for pregnancy loss.

Thyroid function should be assessed according to the pregnancy history, previous tissue results, symptoms and clinical risk factors.

TSH is the principal screening test.

Free T4 is added when the TSH result is abnormal.

Overt hypothyroidism should be treated before conception.

Subclinical hypothyroidism requires interpretation against the laboratory reference range, pregnancy plans and the wider clinical picture.

Current guidelines differ on whether thyroid-peroxidase antibodies should be tested routinely in every woman with RPL.

There is stronger agreement on treatment:

Levothyroxine should not be prescribed solely to prevent miscarriage when thyroid function is normal and only thyroid antibodies are positive.

The TABLET and T4LIFE randomised trials did not show an improvement in live birth from levothyroxine in euthyroid women with thyroid antibodies.^[1,9,10]

Uncontrolled diabetes increases pregnancy risk.

Well-controlled diabetes is different.

HbA1c should be considered when there is:

PCOS should not automatically be named as the cause of RPL.

The relevant issues may include insulin resistance, obesity, ovulatory dysfunction and wider metabolic health.

Metformin may be appropriate for diabetes, prediabetes or selected women with PCOS and metabolic dysfunction.

It should not be prescribed to every woman with RPL as a universal miscarriage-prevention medicine.

Evidence that metformin independently prevents recurrent miscarriage remains incomplete.^[1]

Prolactin testing is useful when there is:

Routine prolactin testing is not necessary when these features are absent.

A raised result must also be interpreted carefully because stress, medicines and the circumstances of blood collection can affect prolactin levels.^[1]

Recurrent pregnancy loss should not be investigated as though reproduction were exclusively female.

The male review may include:

Standard semen analysis remains appropriate when infertility is also present.

However, ordinary semen parameters alone do not explain most cases of RPL.

Higher sperm DNA fragmentation has been associated with miscarriage and RPL.

Testing may be considered when:

Evidence that treating an abnormal fragmentation result prevents another miscarriage remains uncertain.

It should therefore be a selected investigation, not a compulsory test for every couple.^[1]

Chronic endometritis is a persistent inflammatory condition of the endometrium.

Diagnosis usually relies on an endometrial biopsy with identification of plasma cells, often using CD138 staining.

However:

Testing may be considered in selected women with otherwise unexplained RPL, associated infertility, repeated uterine procedures or suspected cavity pathology.

It should not be routine for every patient.

Earlier observational studies suggested that antibiotics might improve outcomes after chronic endometritis resolved.

More recent randomised evidence has not shown that routine doxycycline improves miscarriage or live-birth rates.

Empirical antibiotics should therefore not be prescribed to every woman with unexplained RPL.^[1]

The following are not recommended as routine investigations for every woman with RPL:

A test may become appropriate because of an individual history.

That is different from offering the same commercial panel to every patient.^[1,3,4]

For clarity, treatments can be placed into three groups:

These include:

The treatment is established because the diagnosis is established.

It is not prescribed merely because losses remain unexplained.^[1]

When one partner carries a balanced chromosome rearrangement, options may include:

Natural conception can still result in a healthy live birth.

PGT-SR may reduce the chance of transferring an embryo with a specific unbalanced rearrangement.

It has not been proved superior to continued natural conception for every carrier.

Genetic counselling should explain the probability of obtaining transferable embryos, the possibility of repeated IVF cycles, cost, time and the limitations of testing.^[1]

Progesterone is not required by every woman with RPL.

The PROMISE trial did not show a significant live-birth benefit when vaginal progesterone was routinely started after a positive pregnancy test in women with unexplained recurrent miscarriage.^[7]

The clearest current indication is different.

NICE recommends vaginal micronised progesterone 400 mg twice daily when:

When fetal heart activity is confirmed, NICE advises continuing treatment until 16 completed weeks.^[5]

The PRISM trial found that the overall difference was not statistically significant, but benefit was seen in the subgroup with early bleeding and previous miscarriage, with the greatest apparent benefit among women with several previous losses.^[8]

Empirical progesterone without bleeding remains an area for individual discussion.

A low serum progesterone result in an unassisted pregnancy should not automatically trigger supplementation.^[1]

IVF is a fertility treatment.

It is not automatically a treatment for RPL.

PGT-A tests embryos for chromosome-number abnormalities before transfer.

It may reduce the chance of transferring an aneuploid embryo in selected IVF patients.

However, in RPL it has not been shown to improve cumulative live birth or shorten the time to successful pregnancy compared with continued natural conception.

Some women may complete an IVF cycle without obtaining a transferable embryo.

Miscarriage can still occur after transfer of a tested embryo.

Discussion may be reasonable when there is:

The decision should be based on the couple’s complete reproductive situation, not on fear after the most recent loss.^[1]

The following should not be offered as standard treatment for unexplained RPL:

These treatments may feel active.

Activity is not the same as effectiveness.

When evidence does not support a treatment, restraint is also medical care.^{[1,3,4,6,9,10]}

A next-pregnancy plan should be prepared before conception wherever possible.

The plan is not the same for every woman.

It should be based on:

The purpose is to decide in advance what should happen before conception, after the first positive test and if bleeding or pain occurs.

This avoids hurried decisions during an already anxious pregnancy.

Preconception care may include:

Lifestyle optimisation supports general pregnancy health.

It cannot guarantee that another miscarriage will not occur.

A woman should not be made to believe that an imperfect meal, missed exercise session or stressful day caused her previous losses.^[1,4,12]

There is no universal rule requiring every couple to wait a fixed number of menstrual cycles after an uncomplicated early miscarriage.

Trying again may be reasonable when:

Timing requires separate advice after:

Readiness is personal.

There is no medically superior emotional timetable.^[13,14]

After a positive pregnancy test, the first step is early communication with the treating team.

The individual plan may include:

Aspirin, heparin, progesterone, steroids or other medicines should not be self-started simply because the pregnancy test is positive.

The previous loss determines what deserves attention.

It does not mean that every previous treatment should automatically be repeated.

Serial hCG measurements are not required in every pregnancy after recurrent loss.

They may be useful when:

An hCG value should not be interpreted in isolation.

A single number cannot confirm normal development, diagnose miscarriage or exclude ectopic pregnancy.

Trends, symptoms and ultrasound findings must be considered together.

An ultrasound performed too early may create uncertainty rather than reassurance.

The first scan should be timed according to:

The first purpose is to establish the location of the pregnancy.

The next is to assess development using accepted ultrasound criteria.

When findings are uncertain, a repeat scan after an appropriate interval is safer than reaching a conclusion too early.

Repeated ultrasound examinations do not prevent chromosomal miscarriage.

Their value lies in accurate assessment, prompt access to care and support during a pregnancy that may feel difficult to trust.^[4]

Bleeding in early pregnancy does not always mean miscarriage.

The priorities are to assess:

For a woman with previous miscarriage who develops early-pregnancy bleeding, NICE recommends vaginal micronised progesterone 400 mg twice daily after an intrauterine pregnancy has been confirmed by ultrasound.

If fetal heart activity is subsequently confirmed, NICE advises continuing treatment until 16 completed weeks.

Progesterone should not replace assessment of bleeding or delay investigation for ectopic pregnancy.^[5]

A previous second-trimester loss should not be managed as though it were simply a later version of an early miscarriage.

The next-pregnancy plan may require:

The pathway should reflect the suspected mechanism of the previous loss.

A pregnancy after recurrent loss can remain frightening even when every result is reassuring.

Supportive care may include:

Psychological support is recommended because recurrent loss can be traumatic.

It is not offered because anxiety or grief caused the miscarriages. ASRM and RCOG both place supportive care within appropriate RPL management.^[1,4]

Support should not depend on whether medicine has found an explanation.

Prognosis cannot be expressed accurately through one percentage placed beside the diagnosis.

ESHRE recommends basing prognosis on the woman’s age and her complete pregnancy history, including previous losses, live births and their sequence.

Other relevant factors include:

ASRM reports that approximately 50% to 80% of patients with RPL may have a successful subsequent pregnancy attempt without a specific intervention.

That is a broad population range.

It is not a personalised guarantee and should not be applied without considering age and the complete pregnancy history.^[1,3]

A normal evaluation does not mean that the losses were imaginary.

It does not mean that nothing happened.

It means that current medicine has not identified a reliable explanation that can be measured and treated.

This is described as unexplained recurrent pregnancy loss.

The appropriate response is not to fill uncertainty with every available injection, infusion or tablet.

The plan should instead include:

Unexplained is a statement about the present limits of medical knowledge.

It is not a prediction that the next pregnancy will fail.