Lecture 13: Problem in Pregnancy - A Clinical Overview

Why Are We Here?

• Survival depends on the placenta functioning well enough during pregnancy.

• The placenta must support fetal growth to allow birth at a viable age, weight, and strength.

• Successful placental function enables life outside the uterus.

What is Placental Dysfunction and Why is it a Clinical Concern?

• Placental dysfunction is a spectrum of clinical and subclinical disease

  • No distinct placental phenotype or signature that differentiates normotensive poor growth, hypertensive poor growth, or intermediate cases (underlying pathology is largely similar)

• It is characterised by shallow placentation (poor EVT spiral artery remodelling and a small, abnormally sized and shaped placenta)

• This gives rise to a placenta that is unable to keep up with fetal demand for oxygen and nutrients

• This leads to a clinical presentation of fetal growth restriction and the maternal syndrome of pre-eclampsia

  • It is not understood as to why some individuals develop only one of these conditions while others have both

• If left unchecked and without intervention or delivery, this inability to meet fetal demand worsens due to placental dysfunction, leading to fetal/neonate mortality

What is Maternal Syndrome and How Does it Occur?

• It is a multi-system disorder characterised by

  • Hypertension

  • Protinurea (protein in urine)

  • Inappropriate activation of maternal clotting in the blood

  • Liver and renal dysfunction

• It is caused by poor placentation, which leads to placental hypoxia

• This creates a vicious cycle of further placental damage and the release of adverse factors into the maternal bloodstream, causing further placental hypoxia and damage

• Some individuals have immune or vascular reactivity, which triggers maternal dysfunction

  • Some individuals develop uterine or fetal growth restriction

What factors influence how an individual responds to a poorly functioning placenta?

• Immune factors: Obesity and COVID are associated with differences in maternal immune response.

• Endothelial function: Some individuals enter pregnancy with pre-existing widespread vessel dysfunction, which can easily become abnormal.

• Cardiac function: Individuals may entery pregnancy with suboptimal heart function and so may struggle to meet the increased cardiovascular demands of pregnancy

How Does Placental Dysfunction Begin

• It begins with difficulties in:

  • Initial vasodilation (in response to oestrogen and other substances release by the placenta/corpus luteum)

    • Dilation is poor in individuals with pre-existing endothelial dysfunction (hypertension/diabetes)

  • Uterine arterial circulation remodelling by EVTs → remodel VSMCs in the arterial wall

    • In placental dysfunction, this is poor

  • Renin-Angiotensin System Upregulation (Na⁺/ water retention → increase blood volume)

• Impairment in these adaptations expains why pregnancy, blood pressure and the CVS fail to adapt correctly

What are the main circulations in the feto-placental unit?

• Two separate blood flows to the placenta:

1. Maternal uterine artery: Delivers oxygen and nutrients from maternal blood into the intervillous space of the placenta.

2. Umbilical arteries: Carry fetal blood flow to the placenta, returning deoxygenated, nutrient-depleted blood from the fetus to the placenta.

   • Notable as one of the few arteries carrying deoxygenated blood.

• There are 2 umbilical arteries (deoxygenated blood; fetus to placenta) and 1 umbilical vein (oxygenated blood; placenta to fetus).

How Can Doppler Ultrasound Be Used to Assess Blood Flow in the Umbilical Artery?

• Doppler ultrasound measures the speed of blood flow by detecting shifts in the frequency of ultrasound waves caused by movement (of RBC).

• Provides a pattern of blood flow velocity in the umbilical artery.

• Reflects downstream resistance in the placental circulation.

• Assesses how effectively the fetal heartbeat propels blood through the umbilical cord loops and into the placenta’s microcirculation and back.

What is indicaties Normal Umbilical Artery Blood Flow on a Doppler ultrasound trace?

• High peaks and troughs in blood flow velocity:

  • Peaks correspond to fetal heart contraction (systole) → blood flows faster.

  • Troughs correspond to heart relaxation (diastole) → heart fills for the next beat.

• Reflects a well-developed placental vascular tree with branching and coiling of arterioles and capillaries down to the terminal villi → allows free blood flow

What does progressive worsening on Doppler ultrasound of the umbilical artery indicate, and what are the potential consequences?

• Indicates increased resistance to blood flow in the placenta due to:

  • Impaired vascular tree development (less branching and coiling)

  • Placental injury (infarction or arterial blockage causing partial placental death)

• As this resistance worsens, blood flow pauses/ becomes absent during diastole (heart relaxation phase).

  • In extreme cases, there is a reversal of flow from the placenta back into the umbilical arteries, → may trigger delivery.

How does uterine artery blood flow change across pregnancy

• Outside pregnancy (and early pregnancy), a normal resistance pattern is seen.

  • Sharp systolic spike due to strong adult cardiac contraction and high pressure.

  • Resistance to flow in uterine arteries → low diastolic flow (notch on doppler trace).

    • The notch is normal in the non-pregnant and early pregnancy states.

• As pregnancy progresses, extravillous trophoblasts (EVTs) remodel uterine arteries by removing the elastic lamina and smooth muscle.

  • Arteries become wide, low-pressure conduits.

  • The notch disappears, and there is continuous flow throughout the maternal cardiac cycle.

• Degrees of change depending on gestational stage.

  • Early pregnancy: intermediate patterns of resistance as remodelling occurs.

  • Later pregnancy: Fully remodelled, low-resistance waveform seen.

Why is Placental Dysfunction Clinically Significant and How Can it Be Assessed?

• Placental dysfunction underlies significant maternal and fetal morbidity and mortality, contributing to both global and national disease burden.

• Fetal growth restriction (FGR) and pre-eclampsia (PET) share similar underlying placental abnormalities at the Molecular, Microscopic and Macroscopic levels

• Clinical phenotype is influenced by:

  • Pre-existing maternal physiology

  • Fetal genotype (may determine disease expression)

• Placental vascular development and function can be assessed using Doppler ultrasound.

How is fetal growth assessed in pregnancu using symphysiofundal height measurements?

• A standard assessment of fetal growth for a low-risk pregnant individual

  • Measure from the top of the pubic bone (symphysis pubis) to the top of the uterus (fundus) using a tape

• It is quick, cheap and widely available; but is insensitive/non-specific

How is fetal growth assessed in pregnancy using 2D Ultrasounds?

• Serial and repeated growth scans are conducted throughout a pregnancy if risk factors are present

• Measure growth of the head, abdomen and femur; measurements are placed in a formula to estimate size and then compared to a growth chart

• It offers better sensitivity

• It is expensive, takes time, is only available in hospitals and often overestimates fetal growth

• Until evidence demonstrates its benefit for low-risk mother and babies, it is unlikely to be integrated into standard care (difficult to persuade clinical commissioners)

How is fetal growth assessed in pregnancy using 3D Ultrasounds?

• It assesses soft tissue deposition, e.g. fats

• It takes time → until potential automation by AI and machine learning, unlikely to be part of routine care

  • Difficult to conduct within the time scale that the patient is to be looked after

• Expensive

• Only available in research centres

• Not a real-time measurement

• Until evidence demonstrates its benefit for low-risk mother and babies, it is unlikely to be integrated into standard care (difficult to persuade clinical commissioners)

Why is the Consensus Definition of Fetal Growth Restriction Limited in Clinical Practice?

• Definition: An inability of a baby to meet their own genetic growth potential

• This definition is not useful in clinical practice

  • When a pregnant individual enters the clinic, the initial growth potential is not known.

  • Clinicians must rely on pattern recognition to identify babies that are unlikely to have met their growth potential; May include babies who are actually growing normally.

  • Often, only symphysiofundal height (tape-measure) data is available → limited information, not always practical.

What clinical features suggest fetal growth restriction (FGR)?

• Small baby

• Small abdominal circumference

• Slow weight gain compared to peers

• OR milder size abnormalities plus evidence of placental dysfunction

• NHS suggest a growth threshold for FGR of <20 g/day after 32 weeks’ gestation

  • Identifies fetuses who were small relative to peers

How is fetal growth restriction (FGR) identified in real-world clinical practice?

• In practice, the speed and pattern of fetal growth raise suspicion of FGR.

• Saving Babies’ Lives Care Bundle v2 suggests a growth of <20 g/day is concerning, but is open to interpretation.

• Small for gestational age (SGA) (<10th centile) is commonly used as a proxy for FGR:

  • Detects ~53% of cases.

  • Identifies a population at higher risk, not an absolute diagnosis.

  • Limited accuracy in identification as growth assessment is subjective and prone to under- or overestimation.

• Clinical approach:

  • Emphasis on pattern recognition, not single measurements.

  • Lesser degrees of smallness in association with Doppler evidence of placental dysfunction indicate those likely to experience FGR due to placental dysfunction

  • Flatlining growth patterns are particularly concerning.

How is the risk of fetal growth restriction predicted during pregnancy?

• Use of risk-based prediction

• Low-risk pregnancies: Typically no routine ultrasound growth scans.

• Risk assessment (RCOG): Uses a range of maternal and pregnancy factors to identify individuals who should receive growth scans and closer surveillance.

  • Approach is limited as the largest burden of disease occurs in first-time pregnancies in apparently healthy individuals, limiting the effectiveness of risk-based prediction alone.

  • Up to 50% of all small babies are missed with current methods

What is pre-eclampsia (PE), and why is it of clinical concern?

• A multisystem disorder driven by widespread endothelial dysfunction.

  • Endothelial cells line blood vessels and respond to hormonal and other signals.

• This dysfunction can affect multiple organ systems, including:

  • Cardiovascular system

  • Brain and central nervous system

  • Kidneys

  • Liver

  • Lungs

  • Gastrointestinal tract

Why is Pre-Eclampsia a Major Clincial Concern?

• It causes significant maternal morbidity and mortality in the UK and globally.

• UK triennial reports (maternal death inquiries) show that although deaths are rare, they still occur; ~9 deaths in or shortly after pregnancy reported in the UK.

• Globally, there are approximately 250,000 near-miss cases (severe PE with survival).

• Many deaths are associated with deficiencies in care.

• The current UK maternal death rate from PE is ~5 times higher than its historical best level.

What are the inequalities in preeclampsia incidence and outcomes in the UK?

• Ethnicity:

  • Black mothers are 1.5× more likely to develop PE than white mothers.

  • Black and brown POC account for 75% of PE burden.

  • Risk of dying from PE for POC is ~7× higher than for white individuals.

  • Black women with pre-existing hypertension are 6× more likely to develop PE than white women with pre-existing hypertension.

• Representation vs outcomes:

  • Black women make up 16% of PE complications, despite representing 5% of the obstetric population.

• Socioeconomic factors:

  • Higher PE incidence with social deprivation (IMD 1 = most deprived) → stepwise increase among white IMD1 women

  • Black women are twice as likely to live in deprived areas (IMD1) and have higher PE rates compared to white women in IMD1

    • Difference was still greater in IMD2.

What is the ISSHP (2021) Definition of Pre-Eclampsia?

• Preeclampsia (PE): A pregnancy disorder based on placental dysfunction and characterised by (a constellation of) maternal symptoms experienced.

• Key criteria:

  • New or worsening hypertension after 20 weeks’ gestation.

  • With, Organ dysfunction, which can include:

    • Proteinuria (no longer required for diagnosis)

    • Evidence of placental dysfunction, e.g.:

      • Small fetal size

      • Absent end-diastolic flow in the umbilical artery

      • Notch in uterine arteries in the second half of pregnancy

What are the normal and abnormal blood pressure patterns in pregnancy, and how do they relate to preeclampsia?

• Normal pattern:

  • Mid-pregnancy drop in BP due to vascular dilatation/remodelling.

  • Gradual rise back to pre-pregnancy levels due to activation of the renin–angiotensin system (RAS).

• Abnormal patterns:

  • Poor vascular remodelling, excessive vasoconstriction, or overactive RAS can cause:

    • Rapid rise in BP in the second half of pregnancy.

    • Failure of mid-pregnancy BP drop → higher baseline BP; subsequent climb in blood pressure that follows climbs from a higher level

  • These abnormal patterns contribute to the hypertensive component of preeclampsia diagnosis

How is the risk of preeclampsia predicted and what preventive measures are recommended?

• Clinical obstetrics uses checklist-based risk factors to identify individuals at risk of PE (a sign/symptom of placental dysfunction).

• Moderate risk factors include: First pregnancy, age ≥40, pregnancy interval ≥10 years, BMI ≥25, family history of PE, multiple pregnancy.

• If an individual has ≥2 moderate risk factors or ≥1 high-risk factor, aspirin is recommended, from early pregnancy until 36 weeks.

  • Prevents up to 90% of early-onset PE if taken appropriately.

  • Compliance is low: only 20–40% of advised individuals take it.

What are the hormone patterns observed in normal pregnancy and their significance?

• Changes in hormone production by the placenta and trophoblast are tightly regulated throughout pregnancy.

  • Released into maternal circulation to intentionally modify maternal physiology.

• Tightly controlled balance between pro- and anti-angiogenic factors in pregnancy

  • Produced by the trophoblast and released into maternal circulation to support placental and maternal adaptation.

How do hormone patterns (sFlt-1 and PlGF) relate to placental dysfunction and preeclampsia?

• sFlt-1 / PlGF imbalance → Excessive sFlt-1 relative to PlGF is associated with:

  • Pre-eclampsia

  • Normotensive FGR

• PLGF deficiency is seen in individuals wth placental dysfunction:

  • Primary deficiency: low PLGF production from the start

  • Secondary deficiency: PLGF production declines and failsearlier than expected

• Excessive sFlt-1 seen in Pre-eclampsia

  • Rapid accumulation of sFlt-1 (excessive levels from the start or due to placental injury).

  • Results in high sFlt-1: PlGF ratio, contributing to maternal endothelial dysfunction.

How is PLGF-based testing used to predict preeclampsia?

• Based on the principle that excessive sFlt-1 + low PLGF causes an imbalance in the PLGF:sFlt-1 ratio early in pregnancy

  • PLGF: supports trophoblast cell health.

  • sFlt-1: acts on endothelial cells → contributes to placental hypoxia.

• PLGF-based testing measures PLGF and sFLT-1 balance, when placental dysfunction is suspected

  • Helps predict cases of pre-eclampsia requiring delivery within 14 days (high accuracy).

  • Guides clinical decisions: whether immediate delivery or further observation is needed.

  • Can reduce adverse maternal outcomes from PE.

  • But does not significantly change perinatal mortality or NICU admissions.

How do fetal growth, maternal blood pressure, and hormone patterns reflect placental function?

• Fetal growth restriction (FGR): Predominantly a fetal manifestation of placental insufficiency.

• Pre-eclampsia (PE): Predominantly a maternal manifestation of placental insufficiency.

• Fetal growth, maternal BP changes, and hormone patterns reflect adequacy of placental function.

• Various techniques exist to predict which pregnancies are at risk.

Why is prediction of placental dysfunction and pre-eclampsia important?

• Limited treatment options:

  1. Antihypertensives treat maternal hypertension but not fetal growth restriction (FGR) alone.

  2. Delivery is often the only intervention, frequently premature and iatrogenic.

• Other organ systems have multiple treatments; for placental dysfunction, prediction is key to anticipate complications and guide the timing of delivery.

Why is Pre-Term Birth a Major Clinical Concern

• Preterm birth is a major contributor to morbidity and mortality

  • Contributes to the global burden of health and disease

• Preterm babies are at risk of:

  • Recurrent hospital admissions in childhood

  • Special educational needs

  • Survival not guaranteed

• Many surviving babies may still experience long-term health or developmental issues.

What clinical considerations guide management and counselling for extreme preterm birth?

• Fetal weight and gestational age are used to predict survival:

  • After 500 g and ≥24 weeks: ~50% chance of survival

  • Smaller or earlier babies have lower survival → aim to prolong pregnancy, if possible (saftey concerns)

• BAMP counselling tools provide guidance for parents of extreme preterm babies.

• Clinical balance: Aim for maximum fetal maturity (prolong pregnancy) while avoiding potential stillbirth due to delayed delivery

: What are the potential consequences for offspring before birth in pregnancies with growth restriction or pre-eclampsia?

• Stillbirth

• Preterm delivery

  • Often iatrogenic (due to intervention)

  • In growth-restricted or preeclamptic pregnancies, spontaneous preterm labour may occur; unclear if this is a natural or deliberate exit mechanism

What are the potential consequences for offspring after birth in cases of growth restriction or pre-eclampsia?

• NICU Admission and Prolonged Hospital Stay (up to ~14 weeks or longer).

• Respiratory Distress (underdeveloped lungs, insufficient alveoli, low surfactant production → difficult to inflate lungs).

• Seizures (due to hypoxic ischemic encephalopathy, leading to further neurological issues).

• Infection

• Neonatal Death (3/10 stillborn, 7/10 born alive, 3 will die in the neonatal period).

• Deafness / Retinopathy (can improve but may persist).

What are the long-term consequences for offspring born with growth restriction or in pre-eclampsia pregnancies?

• Chronic Lung Disease: May require long-term oxygen support.

• Cerebral Palsy: More common in preterm babies due to brain injury

  • (e.g., muscle issues like stiff arm or leg).

• Special Education Needs due to developmental delays.

• Cardiometabolic Programming: Increased risk of diseases like diabetes, obesity, hypertension, and ischemic heart disease due to adverse intrauterine conditions.

What are the potential iatrogenic impacts (treatment-related impacts) of early delivery in cases of placental dysfunction?

• Prematurity: Babies are born earlier than they would otherwise be, which can lead to various complications.

• Antenatal Corticosteroid Exposure (especially at ~34 weeks+):

  • Increases the risk of ADHD and neurodevelopmental disorders compared to age-matched children not exposed to corticosteroids.

• Sometimes, babies may be delivered earlier than necessary, (incorrect clinical decision)

What are the benefits of antenatal corticosteroid use for pregnancies at <34 weeks?

• Accepted as "A Good Thing" for preterm deliveries <34 weeks.

• Reductions in:

  • Perinatal death

  • Respiratory distress

  • Intraventricular hemorrhage

  • Other adverse outcome

What are the potential drawbacks of antenatal corticosteroids for pregnancies 34-37 weeks?

• Less Effective at 34-37 week:

  • No overall reduction in short-term or long-term respiratory morbidity.

  • No reduction in NICU admission or length of stay.

• Growing evidence of their potential harm:

  • Hypoglycemia.

  • Neurodevelopmental disorders.

• Fetal Hypothalamic-Pituitary Axis activation near term could explain the differences in outcomes.

What are the potential consequences for a mother with pre-eclampsia, around the time of birth?

• Pulmonary Oedema: Fluid trapped in the lungs, leading to respiratory distress.

• Uncontrolled Hypertension: Can lead to stroke.

• Renal Failure: May involve incomplete recovery of kidney function.

• Placental Abruption: Premature separation of the placenta from the uterine wall, leading to sudden haemorrhage; 50% mortality for the baby.

• Psychological Effects: Trauma and possible PTSD from the experience.

What are the potential long-term consequences of pre-eclampsia for a mother?

• Next pregnancy is high risk → Requires additional monitoring and possible repeat caesarean (increasing morbidity).

• Cardiovascular Disease: 4-fold increase in the chance of death from cardiovascular disease, even if pre-eclampsia resolves.

• Ongoing Health Risks → signature for pre-eclampsia persists

  • Increased risk of diabetes, hypertension, and kidney disease.

  • Higher risk of dementia in later years.

What strategies can be used prior to pregnancy to prevent placental dysfunction (FGR or PET)?

• Weight Loss: Enter pregnancy at an optimal weight.

• Smoking Cessation: Reduces risk of FGR.

  • Smoking may be protective against pre-eclampsia (PE), but vaping is associated with preterm birth (long-term data still pending).

• Control of Comorbidities: Planning and managing pre-existing conditions for the best chance at a fully functioning placenta.

• Timing of Pregnancy:

  • Have children in your 20s (avoid IVF; linked to placental dysfunction).

  • Spacing of pregnancies: Have kids no less than 2 years apart and no longer than 10 years. → remodelling of the uterine circulation doesn’t immediately return to normal; next pregnnacy can build on already remodelled uterine arteries

• Partner Consideration: Significant male contribution to complications like PE.

What strategies can be used during pregnancy to prevent placental dysfunction (FGR or PET)?

• Aspirin (150mg): For those at increased risk of pre-eclampsia (PET).

• Calcium/Vitamin D Supplementation:

  • Common deficiencies.

  • Vitamin D helps maintain healthy blood vessels.

• Stay Active: Limit excessive weight gain.

• Tight Control of Hypertension: Monitor and manage blood pressure.

• Avoid Going Overdue: Longer pregnancies can increase the risk of placental insufficiency (baby's demands will outweigh what the placenta can supply—most pregnancies don’t go past 40 weeks.

What are the effects of low-dose aspirin in preventing pre-eclampsia (PE) and other pregnancy complications?

• In "at-risk" pregnancies:

  • Reduces PE by 2.3 times.

  • 90% adherence to treatment led 90% reduction in PE.

  • 40% reduction in small for gestational age (10th percentile birth weight).

  • 70% reduction in preterm birth (less than 10th percentile).

• Ineffective if:

  • Started after 16 weeks of gestation (when maximum placental remodelling occurs).

  • Used for late-onset PE (after 37 weeks).

What postnatal health optimisation is recommended for individuals with pre-eclampsia (PE)?

• Annual GP Health Check → Essential for detecting undiagnosed high blood pressure and renal dysfunction that can occur after PE.

• But there is limited knowledge and resources in general practice and the NHS to effectively address these health concerns.