7 Pregnancy Complications Doctors Detect Using Biomarkers

In recent years, the understanding and management of pregnancy complications have been transformed by the study of biomarkers—biological molecules found in blood, urine, or other tissues that signal normal or abnormal processes. For expectant parents and healthcare providers, these molecular clues offer a window into the health of the placenta and the fetus, often long before symptoms appear . This article explores seven significant pregnancy complications that doctors can now detect earlier and manage more effectively using biomarkers.

1. Preeclampsia: The Angiogenic Imbalance

Preeclampsia is a multisystem disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. It remains a leading cause of maternal and perinatal morbidity and mortality worldwide . The condition is now understood to be fundamentally a disease of placental dysfunction, driven by an imbalance in angiogenic factors.

Key Biomarkers: sFlt-1, PlGF, and the sFlt-1/PlGF Ratio

The most clinically impactful biomarkers for preeclampsia are soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) . sFlt-1 is an anti-angiogenic protein secreted by the placenta that acts as a “sponge,” binding to and neutralizing pro-angiogenic factors like PlGF and vascular endothelial growth factor (VEGF). In a healthy pregnancy, PlGF levels rise steadily. In preeclampsia, however, the stressed placenta releases excessive sFlt-1, leading to a dramatic drop in free PlGF .

Clinical Applications

This understanding has led to the development of the sFlt-1/PlGF ratio, a powerful tool for both prediction and diagnosis. A study published in late 2025 confirmed that serum PlGF concentrations are markedly reduced in women with preeclampsia (mean 5.18 pg/mL) compared to controls (14.38 pg/mL), while sFlt-1 levels are significantly elevated (6.84 vs. 3.74 ng/mL) . The resulting sFlt-1/PlGF ratio is a robust predictor.

• Predicting Adverse Outcomes: The ratio has shown an area under the curve (AUC) of 0.92 for predicting adverse outcomes in preeclampsia, demonstrating excellent diagnostic accuracy .
• Rule-Out Tool: A low sFlt-1/PlGF ratio has a high negative predictive value, meaning it can reliably rule out the development of preeclampsia in the near future (typically within one week), helping to avoid unnecessary hospital admissions .
• First-Trimester Screening: When combined with maternal characteristics, blood pressure, and uterine artery Doppler, PlGF and PAPP-A are now part of the most accurate screening method for predicting preterm preeclampsia, allowing for early intervention with aspirin prophylaxis .

2. Fetal Growth Restriction (FGR): Stratifying Risk

Fetal growth restriction (FGR) refers to a fetus’s failure to achieve its genetically determined growth potential, often due to placental insufficiency. Differentiating between a constitutionally small but healthy fetus and one at risk of adverse outcomes due to placental dysfunction is a key clinical challenge.

Key Biomarkers: sFlt-1/PlGF and PlGF

The same angiogenic biomarkers used in preeclampsia have proven valuable in suspected FGR, as the two conditions share a common pathophysiology of placental dysfunction. A blinded cohort study published in 2025 investigated the value of measuring sFlt-1/PlGF in pregnancies with suspected FGR but without signs of preeclampsia .

Clinical Applications

The study’s findings highlight the power of biomarkers for risk stratification in FGR.

• Enhanced Risk Prediction: In cases of suspected FGR presenting before 32 weeks, a positive angiogenic biomarker test (defined as sFlt-1/PlGF > 38 or PlGF < 100 pg/mL) was associated with a significantly increased risk of preterm birth (Relative Risk 5.32) and birthweight below the 3rd centile (Relative Risk 2.11). Traditional New Zealand FGR criteria alone did not achieve statistical significance for these outcomes .
• Guiding Management: These results suggest that angiogenic biomarkers can help identify which FGR cases are truly driven by severe placental insufficiency and thus require closer monitoring and potential early intervention .

3. Preterm Birth: Ruling Out Imminent Risk

Preterm birth, defined as delivery before 37 weeks of gestation, affects approximately 1 in 10 babies globally and is a leading cause of neonatal mortality and lifelong morbidity . The symptoms of threatened preterm labor can be vague, and most women presenting with them will not deliver early. Therefore, tests with a high negative predictive value are essential to avoid unnecessary interventions and hospital stays.

Key Biomarker: Fetal Fibronectin (fFN)

Fetal fibronectin is a protein that acts like a “biological glue” between the fetal sac and the uterine lining. Its presence in cervicovaginal fluid after 20-22 weeks of gestation suggests disruption of the interface and an increased risk of preterm birth .

Clinical Applications

• High Negative Predictive Value: The greatest strength of the fFN test is its ability to rule out preterm birth. A negative fFN result has a negative predictive value of >99% for delivery within 7 to 14 days, providing immense reassurance that a woman is not about to deliver imminently . This allows clinicians to safely discharge symptomatic women and avoid unnecessary admissions and treatments like corticosteroids.
• Shifting Landscape: It is important to note that the fFN test has recently faced supply challenges and has been withdrawn in some regions, prompting a renewed focus on alternatives like transvaginal cervical length ultrasound and other emerging biomarkers . This highlights the dynamic nature of the biomarker field and the need for adaptable clinical pathways.

4. Gestational Diabetes Mellitus (GDM): Beyond Glucose

Gestational diabetes mellitus (GDM) poses a significant challenge to maternal and fetal health, with implications for both pregnancy outcomes and long-term metabolic health for mother and child. While glucose challenge tests remain the standard for diagnosis, biomarker discovery is providing deeper insights into the condition’s mechanisms and opening doors to earlier risk assessment .

Key Biomarkers: A Multi-Faceted Approach

The pathophysiology of GDM is complex, involving more than just high blood sugar. Researchers are investigating biomarkers across several pathways :

• Glucose Metabolism and Insulin Resistance: Traditional markers like glucose and insulin.
• Inflammatory Signaling: Proteins such as interleukins (IL-6) and tumor necrosis factor-alpha (TNF-α) are often elevated in GDM.
• Adipokines: Hormones secreted by fat tissue, such as leptin and adiponectin, play a role in insulin sensitivity.
• Oxidative Stress Markers: Indicators of cellular damage.
• Emerging Biomarkers: The field is rapidly evolving with the study of microRNAs (miRNAs) and extracellular vesicles, which are tiny particles released by cells that mediate intercellular communication and offer new perspectives on GDM pathophysiology .
• The integration of these various biomarkers into predictive models holds the potential to improve risk assessment long before the standard second-trimester glucose tolerance test, enabling earlier lifestyle interventions and closer surveillance .

5. Placenta Accreta Spectrum (PAS): First-Trimester Warning

Placenta accreta spectrum (PAS) is a severe obstetric condition where the placenta invades too deeply into the uterine wall, failing to separate normally after birth. It is associated with massive postpartum hemorrhage, hysterectomy, and significant maternal morbidity. Early diagnosis is crucial for planning a safe delivery, often involving a multidisciplinary team and a planned cesarean hysterectomy .

Key Biomarkers: PAPP-A and free β-hCG

While PAS is typically diagnosed in the second or third trimester with ultrasound, a 2025 case-control study has revealed that first-trimester maternal serum biomarkers can serve as an early warning system .

Clinical Applications

• Altered Biomarker Levels: The study found that at 11-13 weeks of gestation, levels of pregnancy-associated plasma protein-A (PAPP-A) were significantly lower in women who would later be diagnosed with PAS (3.63 IU/L) and placenta previa (3.04 IU/L) compared to healthy controls (5.34 IU/L). Conversely, levels of free beta subunit of human chorionic gonadotropin (β-hCG) were higher in the PAS and previa groups .
• Combined Diagnostic Power: Using both biomarkers together significantly improved diagnostic accuracy. For PAS, the combined model achieved an area under the curve (AUC) of 0.85 with 85.2% sensitivity. For placenta previa, the AUC reached 0.88 with 100% sensitivity . This suggests that a simple blood test in the first trimester could flag high-risk pregnancies for closer imaging surveillance, allowing for much earlier detection and planning.

6. Intrahepatic Cholestasis of Pregnancy (ICP): The Role of Bile Acids

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that typically manifests in the second or third trimester with intense pruritus (itching), particularly on the palms and soles. It is associated with an increased risk of adverse perinatal outcomes, including preterm birth, meconium-stained amniotic fluid, and, most concerningly, stillbirth .

Key Biomarker: Bile Acids

The diagnosis and management of ICP are centered on the measurement of maternal serum bile acid levels. This is a direct biomarker of the condition, reflecting the liver’s reduced ability to transport bile acids due to pregnancy-related hormonal and genetic factors.

Clinical Applications

• Diagnosis and Severity Classification: The diagnosis of ICP is confirmed by elevated maternal serum bile acid levels in the setting of otherwise unexplained pruritus. Importantly, current guidelines from the Society of Obstetricians and Gynaecologists of Canada recommend using non-fasting bile acid levels for diagnosis, as fasting is no longer considered necessary and can delay testing .
• Guiding Management and Delivery: Bile acid levels are critical for risk stratification. The risk of stillbirth is significantly increased when bile acid levels are ≥100 µmol/L. This threshold is a major factor in determining the timing of delivery, with guidelines recommending elective birth after 36 weeks for women with peak bile acids of 40-99 µmol/L, and as early as 35-36 weeks for those with levels ≥100 µmol/L to mitigate the risk of late stillbirth .

7. Gestational Hypertension: Looking to the Future

Gestational hypertension (GH) is defined as new-onset high blood pressure after 20 weeks of pregnancy without proteinuria or other signs of preeclampsia. While it can be a precursor to preeclampsia, its underlying molecular mechanisms are less understood, and predicting which cases will progress remains a challenge .

Key Biomarkers: miRNAs and Metabolites

A 2024 multi-omics study of placental tissue has provided the first comprehensive look at the molecular pathways involved in GH, identifying potential future biomarkers .

Clinical Applications (Future Potential)

• Discovery of Novel Pathways: The study identified 44 downregulated placental microRNAs (miRNAs) in GH patients compared to healthy controls. These small non-coding RNAs regulate gene expression and are promising biomarker candidates .
• Integrated Analysis: By combining miRNA and metabolomics data, the researchers identified five significantly perturbed metabolic pathways (including purine, glutathione, and glycerophospholipid metabolism) and 14 genes and 8 metabolites (such as xanthosine, spermine, and glycine) with the potential to distinguish GH from healthy pregnancies .
• Future Diagnostic Panels: While this research is still in the discovery phase and conducted on placental tissue, it opens the door for developing blood tests based on these circulating miRNAs or metabolites. Such tests could one day allow for earlier identification of GH and better prediction of its progression to more severe forms like preeclampsia .

The Evolving Landscape of Prenatal Care

The examples above illustrate a clear trend in modern obstetrics: a shift from reactive care to proactive, precision medicine. Biomarkers are no longer just research tools; they are being integrated into clinical guidelines and routine practice to predict risk, guide prevention, refine diagnosis, and personalize management .

This is an important and deeply personal question, and the answer is not a simple list of diseases. In modern prenatal medicine, the question of whether to continue or terminate a pregnancy after a genetic diagnosis is rarely black and white . The decision depends on a complex combination of the specific condition’s prognosis, available treatments, and the family’s personal values.

Based on current medical guidelines and ethical frameworks, prenatal genetic findings are generally categorized to help guide these difficult discussions. The following table provides a structured overview of how different types of conditions are typically approached.

🧬 The First Category: Conditions That Are Manageable with Extra Care

Many genetic diagnoses do not automatically mean a pregnancy should be terminated. In fact, for a wide range of conditions, the news can be the first step toward ensuring a baby gets the specific care they need from the moment they are born .

• Treatable Metabolic and Genetic Disorders: Some conditions are highly manageable if detected early. For example, a diagnosis of Phenylketonuria (PKU) allows for immediate postnatal dietary intervention, preventing severe intellectual disability and allowing for normal development . Similarly, identifying a condition like a 22q11 microdeletion in a fetus with a heart defect allows parents and doctors to plan for delivery at a cardiac center, ensuring the baby receives specialized care immediately after birth .
• Correctable Structural Anomalies: Some physical differences detected before birth, such as cleft palate or polydactyly (extra fingers or toes), are fully treatable with surgery after birth and do not affect a child’s intellect or overall life expectancy .
• Sex Chromosome Conditions: A diagnosis like Turner syndrome (monosomy X) or Klinefelter syndrome (XXY) can be frightening, but the reality is that the outcomes are highly variable. With appropriate medical, hormonal, and developmental support, many individuals with these conditions lead full, healthy, and productive lives.

🤔 The Second Category: The Gray Area of Complex Diagnoses

This is often the most challenging category for parents and doctors. These are conditions where the outcome is not certain and can range from relatively mild to severe.

• The Spectrum of Severity: A powerful example is mutations in the LBR gene. Depending on the exact mutation, it can cause a lethal condition called Greenberg dysplasia, a benign condition called Pelger-Huet anomaly, or a condition that causes severe skeletal problems in the womb that spontaneously improve after birth . A family who terminated a pregnancy for a severe skeletal finding later discovered the father had the same mutation and was perfectly healthy .
• Trisomy 13 and 18: These conditions (Patau and Edwards syndromes) are often described in stark terms. However, the reality is more nuanced . While the challenges are immense, and many affected pregnancies do not result in a live birth, population studies show that of those born alive, 35-65% of babies with Trisomy 18 and 45-57% with Trisomy 13 survive past the first week. Furthermore, approximately 14-21% survive past their first birthday, and rare cases of survival into the second and third decades of life have been documented . The diagnosis is not a uniform guarantee of immediate death, which is why experts now advise against using the term “lethal” or “incompatible with life” for these conditions .

⚖️ The Third Category: When Termination May Be Offered as an Option

Medical guidelines provide specific criteria for when a condition is so severe and untreatable that termination of pregnancy can be presented as a reasonable medical option for families to consider .

For a condition to fall into this category, it generally must meet the following criteria:

1. Severity: It results in severe and debilitating congenital malformations or developmental outcomes, or severe organ system dysfunction .
2. No Effective Treatment: There is no presently available cure or therapy clinically proven to significantly alter these poor outcomes . This generally excludes conditions with ongoing clinical trials that might offer a benefit .
3. Diagnostic Certainty: The diagnosis must be genetically confirmed or, in cases of lethal malformations, be obvious on prenatal imaging (like ultrasound) .

Examples of conditions that typically meet these criteria include lethal malformations where survival is not possible, such as anencephaly (absence of a major portion of the brain) and bilateral renal agenesis (complete absence of both kidneys, also known as Potter’s syndrome), which leads to a lack of amniotic fluid and failure of lung development .

💡 Navigating the Gray Areas: Key Principles to Understand

The information above highlights that prenatal diagnosis is rarely about finding a simple “yes” or “no” answer. Here are some crucial points to keep in mind:

• The Meaning of “Lethal” is Evolving: The term “lethal malformation” is problematic and increasingly avoided by experts because it can be misleading and inaccurate . Prolonged survival, though often rare, is possible for many conditions once placed in this category.
• Uncertainty is Common: Prenatal testing can reveal variants of uncertain significance (VUS) . These are genetic changes whose impact on health is unknown . A VUS should not be used as the sole basis for major decisions. In some cases, a VUS can even be reclassified as benign (harmless) after further family testing, as in the case of a novel IDS variant that was initially concerning but later found to be unlikely to cause disease .
• The Decision is Deeply Personal: Medical guidelines can define what conditions are candidates for termination, but they cannot dictate what is the right choice for any individual family. Personal values, religious beliefs, family support, and a family’s experience with disability all play a massive role in this decision-making process . The role of doctors and genetic counselors is to provide accurate, unbiased, and compassionate information to support you, not to tell you what to do .

Navigating a prenatal diagnosis is an incredibly difficult journey. It is essential to work with a team that includes a genetic counselor and a maternal-fetal medicine specialist who can give you the most accurate and up-to-date information about your baby’s specific diagnosis, including the range of possible outcomes and the types of support available for your family.

I hope this detailed explanation provides a helpful framework for understanding these complex issues. If you have a specific diagnosis in mind, I can try to provide more targeted information based on current medical literature.

However, challenges remain. As noted by the Society of Obstetricians and Gynaecologists of Canada, a single abnormal marker often has low predictive power on its own and is most valuable when incorporated into a multimodal screening strategy that includes maternal characteristics, blood pressure, and ultrasound findings . Furthermore, access to testing and the need for robust clinical protocols to interpret results are essential for these tools to fulfill their potential in improving outcomes for all mothers and babies . The future of prenatal care lies in harnessing the power of these molecular clues to ensure safer, healthier pregnancies.