lecture 32: diseases and disorders 4: pregnancy

Question 1

What happens during early pregnancy?

Answer 1

• up to 12- 16 weeks placenta invades the inner 1/3 of the uterine myometrium
• remodels the maternal spiral aterioles
  
  • converts to high capacitance (i.e. accommodates large volumes) and low resistance system
  • net result - slow moving rivers of blood allowing optimal exchange of nutrients and waste between mother and foetus

Question 2

What is spiral arteriole remodelling?

Answer 2

• normal placental remodelling
• increased risk of foetal growth restriction and preeclampsia
• watch this

Question 3

What is miscarriage?

Answer 3

• spontaneous abortion
• biology
  
  • occurs in 10-15% of clinically recognised pregnancies
  • 50% have chromosomal errors
  • thus about 50% due to genetic errors, possibly 50% due to implantation errors
  • risk increases with maternal age
• clinical presentation and diagnosis
  
  • vaginal bleeding and abdominal pains/cramping
  • clinical investigations:
    
    • serum hCG does not rise (or falls) when taken 48hrs apart
    • on ultrasounds, absence of foetal cardiac activity (diagnostic if no foetal heart and the gestational sac size is greater than 25mm, or crown-rump length more than 7mm)
• overview of management
  
  • surgical: suction curettage
  • medical: expectant management ± misoprostol (prostaglandins) to induce uterine contractions

Question 4

What is ectopic pregnancy?

Answer 4

• pregnancy implants outside of the uterus, mainly the fallopian tubes
• biology
  
  • occurs in 1-2% of all pregnancies
  • never viable
  • a serious gynaecological emergency: can rupture through the fallopian tube, causing massive haemorrhage
• clinical presentation and diagnosis
  
  • vaginal bleeding and abdominal pains/cramping
    
    • thus, can masquerade as miscarriage
    • often pain is far more severe
  • clinical investigations:
    
    • serum hCG and ultrasound (may see ectopic mass outside uterus)
    • if hCG is more than 1500 IU/L, a gestational sac should be visible in the uterus if it is a normal pregnancy
    • if not, there should be a high index of suspicion it is an ectopic pregnancy

Question 5

How is ectopic pregnancy managed?

Answer 5

• surgery
  
  • a mainstay of treatment
  • two types:
    
    • salpingostomy: cut along the top of the ectopic, pull out the sac, leaver rest of tube
    • salpingectomy: take out the entire tube, including the ectopic
  • laparoscopic salpingectomy is the most common surgical treatment approach
• medical
  
  • if the ectopic pregnancy is small (e.g. serum hCG less than 3000 IU/L and sac size on ultrasound smaller than 3-4cm), could treat with methotrexate
• expectant management:
  
  • if the ectopic pregnancy is very small (e.g. serum hCG less than 500 IU/L), can watch and monitor hCG levels

Question 6

What are foetal anomalies?

Answer 6

• structural foetal anomalies
  
  • about 2% incidence of major foetal structural anomalies
    
    • some associated with chromosomal/genetic abnormalities
    • increased chance of genetic abnormalities if multiple anomalies
  • about 4-5% incidence of minor anomalies
  • possibly minor increase with IVF
• approach to management
  
  • ultrasound diagnosis
  • consider amniocentesis for genetic analysis
    
    • either cytogenetic analysis (including FISH), or prenatal microarray
  • further management depends on type of abnormality
    
    • ranges from postnatal repair (cardiac abnormalities), foetal surgery (diaphragmatic hernia) or termination (multiple abnormalities)

Question 7

What is downs syndrome?

Answer 7

• extra chromosome 21 (three instead of 2)
• discrete syndrome (intellectual and physical disabilities, characteristic facies)
• 1 in 600-700
• significantly increased risk with increasing maternal age
  
  • e.g. age 30: 1 in 940
  • age 40: 1 in 85
• management
  
  • may decide for no testing
  • screening tests
    
    • e.g. first trimester combined screening (blood test 10 week and ultrasound at 12 weeks), or new Non-invasive prenatal test (blood test, highly accurate)
  • the only way to diagnose for sure is an amniocentesis
  • no curative options
  • either termination of pregnancy or continue with the pregnancy

Question 8

At what point in early pregnancy are these complications a risk?

Answer 8

• miscarriage: high risk at start, decreases with increased time of pregnancy
• ectopic pregnancy: equal risk over first ten weeks (detection)
• strucutral anomalies: equal risk over first 10 weeks (detection)
• downs syndrome: equal risk over first 20 weeks (detection)

Question 9

What are complications of later pregnancy?

Answer 9

• spotaneous preterm labour
• foetal growth restriction
• preeclampsia
• gestational diabetes

Question 10

What happens when a complication arises in later pregnancy?

Answer 10

• the aim of obstetric care is to deliver the baby at a gestation which allows the best chance of a good outcome, while minimising risks to the mother and baby
• i.e. the more advanced in gestation, the lower the threshold for delivery

Question 11

What is preterm delivery?

Answer 11

• 5-10% incidence
• defined as delivery less than 37 weeks: more severe if delivery less than 32-34 weeks
• threshold of viability around 24 weeks
• 60% are spontaneous preterm birth (i.e. the uterus starts contracting)
• remaining 40% are ‘iatrogenic’, the clinicians had to deliver the baby early for other reasons, mainly preeclampsia or foetal growth restriction
• the cost:
  
  • the preterm foetus is at risk of complications of prematurity
  • more serious complications with earlier gestations
  • immediate: death, intracerebral bleeding, respiratory distress syndrome bronchopulmonary dysplasia, necrotising enterocolitis
  • later in life: cognitive delay, mental disability

Question 12

How is threatened spontaneous preterm labour managed?

Answer 12

• give corticosteroids to prepare foetus
  
  • injected into mother
  • shown to be beneficial in accelerating foetal lung maturation and has other benefits (decreases death by 50%, respiratory distress syndrome by 50% etc)
• give agents to try to decrease the contractions
  
  • nifedipine (blocks caclium receptor)
  • atosiban (blocks oxytocin receptor, not licensed in Australia)
  • we do not know whether these agents work
• transfer the mother to a hospital where the paediatric team can care for the preterm foetus
  
  • e.g. level 3 (tertiary hospital) if threatened preterm birth at less than 34 weeks gestation

Question 13

What is foetal growth restriction?

Answer 13

• or intrauterine growth restriction
• the foetus does not grow to its genetic potential
• it affects 5-10% of all pregnancies
• 80% of foetal growth restriction is due to abnormal placental implantation
  
  • placenta in a state of chronic hypoxia
  • does not supply foetus with sufficient oxygenation and nutrients
• the remaining 20% are associated with foetal:
  
  • structural abnormalities
  • chromosomal or genetics
  • infections

Question 14

What is the normal growth trajectory?

Answer 14

Question 15

What happens with foetal growth restriction in regards to growth trajectory?

Answer 15

Question 16

Of what are growth restricted foetuses at higher risk?

Answer 16

• still birth

Question 17

What is the approach to managing foetal growth restriction?

Answer 17

• overall approach is to time delivery, balancing risks of prematurity and perceived risk of stillbirth to baby
• deliver if growth restricted (less than 10th centile) and the foetus has reached term (more than 37 weeks gestation)
• if preterm growth restriction, perform serial ultrasound tests of foetal wellbeing, and try to leave the foetus in utero for as long as possible before delivery
• foetal tests of wellbeing include:
  
  • measuring blood flows in umbilical artery (more resistance to flow with a sicker, hypoxic baby)
  • measure amniotic fluid around baby (decreased fluid with sicker baby)

Question 18

What is preeclampsia?

Answer 18

• factors are released from the placenta into the maternal circulation, causing organ injury
• defective implantation
• endothelial dysfunction → release of placental factors
• end-organ injury
  
  • e.g. blood pressure, kidney, brain, liver

Question 19

What are maternal organ systems affected by preeclampsia?

Answer 19

• mediated vai maternal endothelial dysfunction
• maternal blood vessels
  
  • hypertension always part of the diagnostic criteria
• kidney
  
  • most common organ affected
  • if affeted, increased urinary protein, abnormal renal function tests (blood test)
• liver
  
  • more severe form if affected, can cause liver rupture
  • if affected, abnormal liver function tests, sharp pains
• haematological system
  
  • low platelets, low clotting factors (very dangerous)
  • if affected, abnormal blood tests
• nervous system/brain
  
  • can cause the dreaded eclamptic fit, and potentially a stroke (bleed into the brain)
• foetus
  
  • preeclampsia can be associated with foetal growth restriction
  • if present, it adds complexity to the management (need to watch both mother and foetus)
• factors released from the placenta cause maternal multi-organ injury
  
  • once there is organ injury, there is usually progression of organ damage
  • other organ systems may become affectyed
  • the only cure is delivery - there is no other treatment
  • in preterm preeclampsia, the clinician is sometimes forced to deliver the baby early to save the mother
  • but this inflicts the foetus with ‘iatrogenic’ prematurity
  • thus, the need to deliver the mother preterm comes at a cost to the foetus

Question 20

How is preeclampsia managed?

Answer 20

• preterm preeclampsia
  
  • try to coast the pregnancy along to a gestation where foetal outcomes can be optimised
  • to do this, the maternal condition has to be very closely monitored
  • the patient needs delivery if there is signficant deterioration
  • situations mandating delivery irrespective of foetal gestation include:
    
    • significant liver or renal injury
    • occurrence of an eclamptic fit
• preeclampsia that has reached term
  
  • induce and deliver the patient

Question 21

What is gestational diabetes?

Answer 21

• 5-10% of all pregnancies
• excessive blood glucose, caused by peripheral insulin resistance
• drive in part by ‘diabetogenic’ proteins released from placenta (e.g. human placental lactogen)
• worsened in the patient has preexisting metabolic syndrome/obese
• the complications that can arise:
  
  • foetal overgrowth: macrosomia, leading to caesarean sections, shoulder dystocia, neonatal problems
  • foetal growth restriction
  • increased amniotic fluid leading to unstable lie
  • if very poorly controlled sugars, foetus may be at increased risk of still birth

Question 22

How is gestational diabetes diagnosed?

Answer 22

• oral glucose tolerance test: mother given a load of glucose to drink and their blood sugars at 1 and 2 hours tested
• diagnosis made if 2 hours sugars are more than 8mmol/L
• usually performed at 28 weeks gestation

Question 23

How is gestational diabetes managed?

Answer 23

• the mother
  
  • control of blood sugars
    
    • regular monitoring of blood sugar levels (BSLs), 4 times a day
    • aim for 2 hours after meals of less than 6.5 mmol/L
  • otions for sugar control
    
    • diet control (achieved in 70-80% of cases; low GI foods)
    • insulin (or metformin), if diet cannot lower blood sugar levels to target
• the baby
  
  • measure foetal growth at around 32-34 weeks by ultrasound
  • may offer tests of foetal wellbeing
  • if on insulin, some will offer induction of labour at 39 weeks gestation
• the aftermath:
  
  • the diabetes will immediately end after birth
  • BUT, mother has a 50% lifetime risk of developing type II diabetes

Question 24

What is risk and timing of later pregnancy complications?

Answer 24

• spontaneous preterm birth from 22 weeks onward increased risk to term
• foetal growth restriction: from 20 weeks onward increasing risk
• preeclampsia: same
• gestational diabetes: continuous risk from around 28 weeks onward

Question 25

What is timing of clinical care in human pregnancy?

Answer 25

• first visit: before 10 weeks, ultrasound and blood tests
• 10-13 weeks: downs syndrome test offered
• 20 weeks: foetal anomaly ultrasound
• 28 weeks: gestational diabetes test
• also:
  
  • with each antenatal visit we screen for major complications:
    
    • preeclampsia: blood pressure
    • foetal growth restriction: tape measure on abdomen → refer for an ultrasound if it measures as small
• for:
  
  • miscarriage or ectopic pregnancy: presents with symptoms or incidentally at early pregnancy ultrasound
  • spontaneous preterm labour: patient presents with uterine contractions

Question 26

What are developing treatments for ectopic pregnancy?

Answer 26

• medication treatment
• phase I trial - GEM study

Question 27

What is a new diagnostic method?

Answer 27

• measuring mRNA in maternal blood
• circulating RNA from the foetus

Question 28

What are developing treatments for preeclampsia?

Answer 28

• therapeutic strategies: targeting the placental factors
• nanoparticles to deliver drugs directly to the placenta
• therapeutic neutralising antibodies
• small molecules (conventional drugs)