Preterm birth

Question 1

Presentations where progesterone and cerclage have proven benefit

Answer 1

Progesterone (best evidence):
- Singleton + short cervix on TVUS mid-trimester (commonly </= 25mm; strongest if very short) -> vaginal progesterone reduces PTB

Cerclage (proven benefit groups)
- Hx-indicated (true cervical insufficiency): e.g. prior painless mid-trimester dilatation/2nd trimester loss/very early PTB compatible w cervical insufficiency
- USS & hx-indicated: prior spontaneous PTB + CL <25mm before 24w -> cerclage reduces recurrent PTB
- “Rescue/emergency” physical exam indicated: painless cervical dilatation in 2nd trimester (often w membranes visible) can benefit in selected cases

Question 2

Presentations where prophylactic cerclage alone has proven benefit

Answer 2

• Hx-indicated prophylactic cerclage for classic cervical insufficiency (recurrent painless 2nd trimester loss/very early PTB)
• USS-indicated cerclage (prior sPTB + CL <25mm <24w) or rescue cerclage (painless dilatation 2nd trimester)

Question 3

3 pharmacological interventions for PTL

Answer 3

• Nifedipine tocolysis to gain time
• Antenatal corticosteroids
• Magnesium sulphate for neuroprotection

Question 4

Proven benefits of nifedipine from Cochrane review of PTB:

Answer 4

• Increased latency: delays birth 48 hours (and often up to 7 days) -> allows steroids/MgSO4 time to work
• Compared w other tocolytics (esp beta agonists), associated w better neonatal outcomes in some analyses (e.g. less RDS/NEC/NICU admission in comparisons), w fewer maternal side effects

Question 5

Proven benefits of antenatal corticosteroids (Cochrane)

Answer 5

• Reduced perinatal/neonatal death
• Reduced RDS
• Probably reduced IVH (and reduced NEC)

Question 6

Proven benefits of magnesium sulphate for neuroprotection (Cochrane)

Answer 6

• Reduced cerebral palsy
• Reduced combined outcome death or CP/ improves long-term neuro outcomes (depending on analysis)

Question 7

Spectrum of neurodevelopmental disabilities in early childhood related to preterm birth?

Answer 7

• Motor impairment: cerebral palsy, fine/ gross motor delay
• Cognitive/ learning: intellectual disability, learning difficulties, executive function
• Language/ communication: speech/ language delay
• Behavioural: ADHD, autism traits
• Epilepsy/ seizures
• Sensory impairment: vision, hearing loss

Question 8

Benefits of antenatal corticosteroids:

Answer 8

• A course given within 7 days prior to PTB reduces perinatal & neonatal death and RDS
• There is moderate certainty evidence that also reduce IVH and neurodevelopmental delay in childhood

Question 9

What are the benefits of steroids in planned CS birth at term?

Answer 9

• NICE recommends that planned CS birth should NOT be routinely carried out before 39+0
• For planned CS between 37+0 - 38+6 weeks, antenatal corticosteroids may reduce admission to NNU for respiratory morbidity, but it is uncertain if there is any reduction in RDS, TTN or NNU admission overall; and steroids may result in harm to the neonate including hypoglycaemia & potential developmental delay (Cochrane review)
• A/W results of C*steroid trial
• As the risk of respiratory distress at term is low (approx 5%) and usually mild and transient, and there is low certainty of benefit, this should be discussed when counselling the woman

Question 10

Steroid administration <24+0 weeks

Answer 10

• Benefits at the threshold of viability are supported by systematic review and meta-analysis of observation studies => should be discussed with the woman in the context of her individual circumstances and preferences
• Benefits: reduced mortality, and reduced IVH/periventricular leukomalacia
• Consider from 22+0 when the woman, in discussion w the perinatal care team, has made an informed decision that active care for the baby is appropriate

Question 11

Potential harms of antenatal corticosteroids?

Answer 11

• Likely to affect maternal glucose tolerance for up to 5/7 after administration (w higher risk in diabetic women)
• Likely to reduce birthweight if birth >7 days after steroids
• No benefits are likely to be seen if birth is more than 7 days after starting treatment
• May increase psychiatric and behavioural diagnoses if children born at term
• Effect of unnecessary antenatal corticosteroids (i.e. if birth >7 days after steroids) are not well described. While no long term harms have been proven, large scale observational studies necessary for pharmacovigilance are lacking

Question 12

Are there benefits for antenatal corticosteroids between 35+0 to 36+6 weeks? What are the harms?

Answer 12

• Likely to reduce: respiratory support (RR 0.8)
• BUT likely to increase neonatal hypoglycaemia (RR 1.6), and MAY increase psychiatric and behavioural diagnoses if children born at term.

Question 13

Benefits and harms of steroids before planned CS at 37-39 weeks

Answer 13

• MAY decrease admission to NNU with respiratory morbidity
• BUT MAY reduce educational attainment at school age
• Uncertainty about any reduction in RDS, TTN, or NNU admission overall

Question 14

Rescue steroid course if treatment >7 days ago?

Answer 14

• Likely to reduce need for respiratory support (RR 0.91, NNT 11.9)
• BUT also likely to reduce birthweight (mean difference 80g), head circumference and length, and neonatal BP

Question 15

At what gestational age may neonatal stabilisation and resuscitation be considered?

Answer 15

• Babies born from 22+0 weeks
• When a woman has made an informed decision, that active care for the baby is appropriate, then active obstetric management, including the administration of corticosteroids, is important

Question 16

Corticosteroids in multiple pregnancy?

Answer 16

• Consider targeted steroids for early birth in line with recommendations for singletons
• Uncertainties around the benefits and risks of steroids in multiple pregnancy should be discussed

Question 17

Use of antenatal corticosteroids in women w diabetes?

Answer 17

• Diabetes is not an absolute contraindication
• Additional insulin should be given and close monitoring undertaken

Question 18

Antenatal corticosteroids for PPROM

Answer 18

• Should be offered
• Reduce risk of RDS and IVH
• There is currently limited evidence to recommend repeat courses if remains at imminent risk of PTB 7/7 after administration. However, a further course may reduce the need for neonatal respiratory support

Question 19

Route and choice of antenatal corticosteroid?

Answer 19

• Dexamethasone reduces the risk of IVH (compared to betamethasone)
• Betamethasone reduces the risk of chorio (c.f. dex)
• Other routes of administration are not recommended as there is insufficient evidence

Question 20

How long after administration is a course of antenatal corticosteroids most effective?

Answer 20

• Reduces neonatal death when the first dose is given within the 48 hours prior to birth
• Benefits are also seen when the first dose is given within 24 hours of birth, and antenatal corticosteroids should still be given if birth is expected within this time
• Are most effective in reducing RDS in pregnancies that birth between 24 hours and 7 days of administration of the second dose

Question 21

Potential long term consequences from antenatal corticosteroids

Answer 21

Uncertain long-term metabolic and neurological / behavioral / psychological consequences

Question 22

Contraindications to antenatal corticosteroids?

Answer 22

• Birth should not be delayed to administer when there are serious concerns about maternal or fetal condition that will be alleviated by expedited birth
• In the presence of systemic infection, the potential beneficial effects of antenatal corticosteroids intended for the baby are balanced against the effect of exacerbating the severity of systemic infection both for the woman and her baby
• Steroids suppress the immune system, so there is a potential for worsening infection
• There is no evidence to suggest that a single course increases infections or antibiotic use, but caution should be used when there is existing systemic infection

Question 23

In what circumstances should antenatal course of corticosteroids be repeated?

Answer 23

• No reduction in serious morbidity or long-term benefits have been seen w repeat steroids, but babies who receive repeat doses are smaller (lower birthweight and reduced length)
• Limited evidence to recommend repeat courses of antenatal steroids if woman remains at imminent risk of PTB 7 days after initial course. However, further course may reduce the need for neonatal respiratory support
• The maximum number of steroid courses given in any one pregnancy should not exceed 3

Question 24

Optimal timing for antenatal steroids?

Answer 24

• When birth is planned or expected within the next 48 hours and gestational age is </= 34+6
  *Give even if preterm birth is likely within 24 hours
  *Regardless of the reason the woman is considered at risk
• Consider the use of adjust prediction tests including fetal fibronectin and assessment of cervical length
• Where appropriate, monitor for signs of puerperal sepsis

Question 25

Antenatal corticosteroid options:

Answer 25

- Betamethasone 24mg in divided doses, completed between 12 and 36 hours (2 x IM doses of 11.4mg 24h apart) - OR dexamethasone 24mg in divided doses completed between 24 and 40 hours (4 x IM doses of 6mg, 12 hours apart)

Question 26

Repeat antenatal corticosteroids (Liggins)

Answer 26

Use repeat steroids in women at risk of early preterm imminent birth following a single course of antenatal steroids - When gestational age is 32+6 or less - When PTB is planned or expected within the next 7 days, even if birth likely within 24h - Use either a single repeat dose of 12mg betamethasone (can do a further single dose after 7 days if woman is still at risk), - OR a single repeat course of 24mg betamethasone in divided doses completed within 24h (do not give any further repeat courses)

Question 27

What is the proposed mechanism of action by which magnesium reduces the risk of cerebral palsy in women at risk of PTB?

Answer 27

- Non-competitive antagonist of NMDA receptors -> reducing excitotoxic injury caused by excessive glutamate release during hypoxic-ischemic events -> limits calcium influx into neurons which is a key pathway in neuronal injury and apoptosis - Stabilizes cell membranes, reduces oxidative stress, and may decrease inflammation, all of which contribute to protection against white matter injury and subsequent cerebral palsy in preterm infants