Recurrent Pregnancy Loss

Recurrent pregnancy loss (RPL), also known as recurrent miscarriage, is defined as the loss of two or more pregnancies before 20 weeks [1]. Although it is not often spoken about openly, it affects about 1 in 100 couples trying to conceive [2]. 

No one is ever prepared for a miscarriage, no matter how often it reoccurs, and RPL requires more than a sympathetic ear or a standard consultation. It demands a structured, evidence-based approach — one that looks beyond surface-level assessments and looks into genetic, anatomical, hormonal, immunological, and lifestyle-related factors. It also calls for empathy, and continuity of care. 

What Causes Recurrent Pregnancy Loss? 

Recurrent pregnancy loss (RPL) is rarely due to a single cause. Instead, it often results from a combination of underlying factors. It is a complex condition with multiple contributing factors and hence can be difficult to understand.

An easier way to understand miscarriage and RPL  is imagining sowing a seed in soil and the seed sprouting but not becoming a plant. The reasons for this would be related to either the seed or the soil or the environment.

The factors that can contribute to RPL, include:

• Genetic Factors (SEED): Chromosomal abnormalities in either partner can increase the risk of miscarriages. These account for 70-80% RPL.
• Uterine Factors (SOIL): Anomalies in the uterus eg septum or submucosal fibroids or cervical incompetence can make it difficult to maintain a pregnancy. These account for ~10% RPL. 
• Maternal factors (ENVIRONMENT) These account for ~10-20% RPL
  • Hormonal Imbalances: Certain hormonal imbalances, such as thyroid disorders, uncontrolled diabetes or polycystic ovary syndrome (PCOS), can increase the risk of miscarriage.
  • Immunological Factors: Some immune system disorders like  Antiphospholipid Syndrome (APS)—an autoimmune condition where the body produces antibodies that increase the risk of blood clots and interfere with placental development  or systemic lupus erythematosus (SLE),can affect pregnancy success.
    Blood Clotting Disorders: Certain disorders that affect blood clotting can lead to recurrent pregnancy loss.
  • Lifestyle Factors: Smoking, excessive alcohol consumption, drug use, and obesity may contribute to RPL.

Genetic Factors

• Genetic predisposition — One of the most commonly identified causes of RPL lies in our genetic blueprint. Approximately 2–5% of couples experiencing recurrent miscarriages are found to have a structural chromosomal abnormality, most often a balanced translocation, in which parts of chromosomes are rearranged but no genetic material is lost or gained [3]. While carriers are usually healthy, their embryos may inherit an unbalanced form, leading to early miscarriage.

• Genetic conditions — Embryonic aneuploidy, where the embryo has an abnormal number of chromosomes, is another major contributor, especially in women of advanced maternal age [4]. Though many chromosomal abnormalities occur sporadically, some may be recurrent and benefit from preimplantation genetic testing (PGT) if assisted reproductive techniques are being considered.

Anatomical Factors

• Uterine structure — The shape and structure of the uterus play a critical role in maintaining pregnancy. Congenital anomalies such as a septate uterus (a fibrous band dividing the uterine cavity) [5] or acquired issues like submucosal fibroids [6] or intrauterine adhesions can interfere with embryo implantation and growth [7]. 

• Cervical insufficiency — Another structural concern is cervical insufficiency, where the cervix begins to dilate prematurely during the second trimester, often without pain or contractions [8]. While not always easy to diagnose, it becomes more apparent when pregnancy losses follow a consistent late pattern.

Endocrine Factors

Hormonal imbalances can subtly, yet significantly, affect pregnancy maintenance. 

• Thyroid dysfunction — Thyroid dysfunction, including both overt and subclinical hypothyroidism, has been associated with increased miscarriage risk [9]. Routine screening of thyroid-stimulating hormone (TSH) levels is often recommended in women with RPL.

• Diabetes — Uncontrolled diabetes mellitus can lead to poor glycaemic control during early pregnancy, increasing the risk of miscarriage [10]. Preconception and first-trimester blood sugar management are therefore crucial in diabetic patients.

• PCOS — Polycystic ovary syndrome (PCOS), which is relatively common among women of reproductive age in Singapore, may also contribute to RPL due to insulin resistance, hyperandrogenism, and altered endometrial receptivity [11].

Immunological Factors

In some cases, the maternal immune system may fail to properly accommodate the developing embryo. The most well-established immunological cause of RPL is Antiphospholipid Syndrome (APS)—an autoimmune condition where the body produces antibodies that increase the risk of blood clots and interfere with placental development [12]. 

Other autoimmune diseases, such as systemic lupus erythematosus (SLE), may also increase the risk of pregnancy loss, even in the absence of APS, due to inflammation and impaired placental function [13].

Thrombophilic Disorders

Thrombophilia refers to a predisposition to form abnormal blood clots. Inherited thrombophilias, such as Factor V Leiden mutation or prothrombin gene mutation, may lead to placental thrombosis, compromising fetal blood supply [14]. 

Infectious Factors

• Chronic infections — Chronic, low-grade infections can disrupt the uterine environment. Chronic endometritis, often caused by bacteria such as Mycoplasma or Ureaplasma, may go undetected in standard screenings. Diagnosis typically requires endometrial biopsy or hysteroscopy with targeted sampling. 

• Acute infections — While acute infections like rubella or cytomegalovirus are known miscarriage risks, they are less commonly linked to recurrent losses, especially in countries like Singapore where vaccination and prenatal screening are routine.

Lifestyle and Environmental Factors

• Lifestyle choices — Everyday choices and exposures can also impact pregnancy health. Smoking, excessive alcohol intake, and obesity have all been independently associated with higher miscarriage rates [15]. These factors may affect hormonal balance, egg quality, or uterine receptivity, and addressing them is an essential part of preconception care.

• Environmental factors — Exposure to environmental toxins, such as pesticides or endocrine-disrupting chemicals, may also play a role in affecting chances of pregnancy. 

How is Recurrent Pregnancy Loss Diagnosed?

For couples navigating the emotional and physical burden of recurrent pregnancy loss (RPL), clarity begins with thorough investigation. While the cause of RPL remains unexplained in up to 50% of cases, advances in reproductive medicine have made it possible to identify underlying issues in many others — paving the way for targeted treatment and a more hopeful path forward.

In Singapore, with access to advanced diagnostic facilities and subspecialist care, couples can benefit from a full spectrum of tests that investigate genetic, anatomical, hormonal, immune, and infectious contributors to pregnancy loss.

Here is what a comprehensive evaluation typically involves:

Clinical Evaluation

The foundation of any good investigation begins with listening and understanding. A detailed clinical consultation helps identify subtle patterns or overlooked risk factors.

• Medical, Obstetric, and Family History — Your doctor will ask about previous pregnancies (including gestational age at loss, symptoms, and any complications), menstrual cycles, medical conditions (e.g., thyroid disease, diabetes), family history of miscarriage or genetic disorders, and use of medications or supplements.

• Lifestyle Assessment — Factors such as smoking, alcohol consumption, caffeine intake, weight, occupational exposures, and emotional stress are also taken into account. While these might seem minor, they can impact both fertility and pregnancy outcomes.

Genetic Testing

Chromosomal abnormalities are a leading cause of early miscarriage, particularly in the first trimester.

• Karyotyping of Both Partners — A blood test can detect whether either partner carries a balanced chromosomal rearrangement (such as a translocation or inversion) that could lead to the formation of abnormal embryos [16].

• Genetic Analysis of Miscarriage Tissue — If tissue from a prior pregnancy loss is available, testing it for embryonic aneuploidy (abnormal chromosome number) can be especially helpful. In Singapore, chromosomal microarray analysis is becoming increasingly common in specialist centres for this purpose [17].

Anatomical Assessment

Structural problems in the uterus can interfere with implantation or fetal development, especially in second-trimester losses.

• Transvaginal 3D Ultrasonography — Often the first-line tool, it provides detailed images of the uterus and endometrial lining and can detect fibroids, polyps, or congenital anomalies.

• Hysterosalpingography (HSG) — This X-ray test uses contrast dye to examine the shape of the uterine cavity and fallopian tubes, which helps identify issues like uterine septa or adhesions [18].

• Magnetic Resonance Imaging (MRI) — Used selectively, MRI can offer high-resolution imaging of the uterus in more complex or unclear cases, especially when congenital anomalies are suspected.

Endocrine Evaluation

Hormonal imbalances can disrupt early embryonic development and implantation.

• Thyroid Function Tests — TSH (thyroid-stimulating hormone) is commonly tested, along with free T4 and thyroid antibodies if needed. Even mild hypothyroidism can increase the risk of miscarriage.

• Glycaemic Control Assessment — A fasting glucose level and HbA1c test help screen for diabetes and insulin resistance, which is important in women with or without a formal diagnosis of diabetes or PCOS.

• PCOS Evaluation — In women with irregular cycles or signs of hyperandrogenism (e.g., acne, excess hair), further hormonal testing and ultrasound can assess for polycystic ovary syndrome, which has been linked to miscarriage risk due to poor endometrial receptivity and metabolic dysfunction.

Immunological Testing

The immune system plays a delicate role in pregnancy, requiring it to tolerate the embryo while still protecting the mother.

• Antiphospholipid Antibody Testing — Blood tests for lupus anticoagulant, anticardiolipin antibodies, and beta-2 glycoprotein I antibodies are crucial in diagnosing antiphospholipid syndrome (APS), a treatable condition known to cause RPL, particularly in the second trimester.

• Screening for Other Autoimmune Conditions — Depending on clinical symptoms (such as joint pain, skin rashes, or fatigue), additional autoimmune markers may be tested, including antinuclear antibodies (ANA) or thyroid autoantibodies.

Thrombophilia Screening

In women with a history of late pregnancy loss, placental insufficiency, or stillbirth, screening for blood clotting disorders may be considered.

• Inherited Thrombophilias — These include Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in proteins C, S, or antithrombin.

• Acquired Thrombophilias — Often overlapping with APS, these conditions are evaluated through antibody testing and coagulation studies.

Infectious Disease Screening

Chronic uterine infections are a less commonly recognised but important contributor to RPL.

• Tests for Chronic Endometritis — Diagnosis usually requires an endometrial biopsy or hysteroscopy, where the uterine lining is visually assessed and sampled. Chronic inflammation can impair embryo implantation, and targeted antibiotic treatment has been shown to improve live birth rates in affected women.

How is Recurrent Pregnancy Loss Treated?

It is important to have a treatment plan supported by strong clinical evidence and tailored to the individual needs of each couple. With the right diagnosis, many causes of RPL are treatable, and the chances of achieving a healthy pregnancy can be significantly improved.

Genetic Interventions

• Preimplantation Genetic Testing (PGT): For couples undergoing in-vitro fertilisation (IVF), PGT allows the selection of chromosomally normal embryos before implantation [19]. This is particularly helpful for those with recurrent miscarriages linked to embryonic aneuploidy. 

Surgical Treatments

When anatomical abnormalities are identified, surgical correction can restore normal uterine function and significantly improve pregnancy outcomes.

• Correction of Uterine Anomalies: Procedures like hysteroscopic septum resection (removal of a fibrous band dividing the uterus) have been shown to reduce miscarriage rates and support full-term pregnancies [20].

• Removal of Submucosal Fibroids: Submucosal or intracavitary fibroids—those that distort the uterine cavity — can interfere with implantation or lead to early miscarriage. Surgical removal via hysteroscopy or laparoscopy is typically recommended, especially if other causes of RPL have been ruled out.

Both procedures are routinely performed in Singapore and are often done as day surgeries, with minimal recovery time.

Medical Management

The role of medical therapy in RPL is well established for certain endocrine, immunological, and infectious conditions.

Endocrine Disorders

• Thyroid Hormone Replacement: For women with hypothyroidism or subclinical thyroid dysfunction, levothyroxine is prescribed to maintain TSH levels in the optimal range [21] (usually below 2.5 mIU/L during preconception and early pregnancy).

• Metformin for PCOS: Although the data is mixed, metformin may be considered in women with PCOS who exhibit insulin resistance or glucose intolerance. It has been shown to reduce the risk of miscarriages.

Immunological Conditions

• Low-Dose Aspirin and Heparin for APS: Women diagnosed with antiphospholipid syndrome benefit from a combination of low-dose aspirin and prophylactic low-molecular-weight heparin throughout pregnancy [22]. This regimen significantly improves live birth rates by preventing placental thrombosis and supporting healthy implantation.
• Intralipid - an Intravenous lipid emulsion is used in selected cases to help improve pregnancy outcome by regulating immune responses and reducing the activity of Natural killer cells.

Thrombophilic Conditions

• Anticoagulation Therapy: For women with confirmed inherited thrombophilias and a relevant obstetric history (such as late pregnancy loss or placental insufficiency), anticoagulant therapy—usually in the form of heparin—is considered [23]. Routine use is not recommended in women with isolated early pregnancy loss unless additional risk factors are present.

Infections

• Antibiotic Therapy for Chronic Endometritis: If chronic endometritis is diagnosed through biopsy or hysteroscopy, a course of targeted antibiotics (often doxycycline or metronidazole) is prescribed. 

Lifestyle Modifications

While often underestimated, lifestyle changes can play a vital supportive role in RPL management. They are non-invasive, cost-effective, and within the couple’s control.

• Smoking Cessation: Smoking is linked to reduced fertility, poor egg quality, and increased miscarriage risk [24]. Quitting smoking, ideally before conception, can significantly improve pregnancy outcomes.

• Weight Management: Both obesity and being underweight can negatively impact hormone regulation and pregnancy health. In Singapore, where metabolic conditions like diabetes and PCOS are prevalent, maintaining a healthy BMI through diet and exercise is a key focus in preconception counselling.

• Nutritional Counselling: Ensuring sufficient intake of folic acid, iron, and vitamin D, along with a balanced diet, supports both general health and early foetal development.

• Stress Reduction Techniques: While stress itself doesn’t directly cause miscarriage, high levels of chronic stress can interfere with hormone balance and emotional wellbeing. Mind-body approaches such as meditation or acupuncture, may be helpful complementary therapies, especially during fertility treatment or after loss.

A Personalised, Evidence-Based Path Forward

It is important to understand that the treatment of recurrent pregnancy loss is not a one-size-fits-all approach. It requires thorough evaluation, multidisciplinary care, and most importantly, compassion. 

In Singapore, with access to comprehensive diagnostic tools and specialist-led fertility care, couples experiencing RPL have a wide range of evidence-based treatment options available to them. When addressed methodically, many go on to achieve successful and healthy pregnancies.

The Role of Assisted Reproductive Technologies (ART) in Recurrent Pregnancy Loss

Assisted reproductive technologies (ART) offer alternative paths to parenthood that are supported by both clinical evidence and growing success rates. While ART is not the first line of treatment for every couple with RPL, it plays a valuable role for selected cases — particularly when there are significant genetic or age-related concerns. 

In Vitro Fertilisation (IVF)

IVF is one of the most common ART options and may be recommended in the context of RPL when:

• Genetic abnormalities have been identified, and preimplantation genetic testing (PGT) is necessary to select chromosomally normal embryos.

• Advanced maternal age is contributing to a higher rate of embryonic aneuploidy.

• There are coexisting fertility issues, such as tubal blockage, low ovarian reserve, or male factor infertility.

With IVF, eggs are retrieved from the ovaries and fertilised with sperm in a laboratory. The resulting embryos are cultured and assessed for viability before one or more are transferred into the uterus. When combined with PGT-A (preimplantation genetic testing for aneuploidy), IVF can reduce the risk of miscarriage by allowing only genetically normal embryos to be transferred, particularly beneficial for older women or those with prior chromosomal pregnancy losses [25].

However, it’s important to note that IVF is not a guaranteed solution to RPL. It does not address all causes, such as uterine anomalies, autoimmune issues, or thrombophilias. A thorough workup should always be completed before proceeding with IVF as a treatment for RPL.

Use of Donor Gametes

In cases where one partner carries a significant genetic condition that is likely to be passed on, or where egg or sperm quality is contributing to recurrent losses, the use of donor eggs or donor sperm may be considered [26].

• Donor eggs are often recommended for women with significantly diminished ovarian reserve or poor egg quality due to age or medical conditions.

• Donor sperm may be an option if severe male factor infertility or chromosomal issues are identified.

While using donor gametes is a deeply personal decision, it can provide a viable solution for couples who have experienced repeated losses due to genetic incompatibility or gamete-related issues. In Singapore, the use of donor gametes is permitted, however permission from the ministry of health may be needed. However, single women are not permitted to use donor sperm for conception. 

Prognosis and Future Pregnancy Planning After Recurrent Pregnancy Loss

One of the most important messages for couples facing recurrent pregnancy loss (RPL) is this: a successful pregnancy is still very possible. With the right investigations and evidence-based treatment, many couples go on to have healthy, full-term pregnancies. 

Success Rates After Treatment

While the emotional toll of recurrent miscarriage can feel defeating, the long-term prognosis is often far more hopeful than expected. According to the American Society for Reproductive Medicine (ASRM), over 60–70% of couples with RPL eventually achieve a successful live birth, even if the underlying cause remains unexplained [28].

For couples with identified and treatable causes, outcomes are often even better. Studies published show that:

• Women with antiphospholipid syndrome who receive low-dose aspirin and heparin have live birth rates exceeding 70–80% [29].

• Surgical correction of uterine anomalies, such as septate uterus, can result in dramatically improved pregnancy outcomes, with some studies showing success rates of over 80% following hysteroscopic septum resection [30].

• Couples undergoing IVF with preimplantation genetic testing (PGT), particularly when chromosomal issues or maternal age are concerns, see higher implantation and reduced miscarriage rates, particularly when chromosomally normal embryos are selected.

Monitoring Strategies in Subsequent Pregnancies

After recurrent losses, even a new pregnancy brings mixed emotions — relief, anxiety, and fear of another heartbreak. This is why close and continued monitoring is crucial.

In Singapore, most fertility specialists offer early pregnancy support plans for women with a history of RPL. This may include:

• Early viability scans (around 6–8 weeks) to confirm a heartbeat and monitor growth.

• Serial beta-hCG and progesterone measurements to assess hormone levels and pregnancy progression.

• Frequent check-ups during the first trimester to detect any signs of complications.

• Close monitoring of blood clotting markers or autoimmune activity in women with conditions such as APS or thrombophilias.

• Cervical length scans from 16 weeks onwards in women at risk of cervical insufficiency.