Preterm birth

Question 1

Incidence of PTB

Answer 1

5-10% of births
7% in NZ, 8% in Australia
Extreme PTB <28 weeks = 0.5% in NZ

Question 2

Definition of extreme preterm, very preterm, and moderate-late preterm - gestations

Answer 2

extremely preterm = less than 28 weeks
- combined 2% of births in Australia

very preterm = 28 to 32 weeks
- combined 2% of births in Australia

Moderate to late preterm = 32 to 37 weeks
7% of births in Australia

Question 3

Broad causes of PTB - rule of thirds

Answer 3

1/3 = iatrogenic e.g. PET, severe IUGR

1/3 = following PPROM

1/3 = spontaneous labour

Question 4

Causes of preterm birth = PICFUPS

Answer 4

P = previous PTB (15% with 1x PTB, 30% with 2x, 45% with 3x)

I = infection
Intrauterine = ascending (BV, trich, chlamydia, gonorrhoea, GBS, gardnerella, mycoplasma, ureaplasma, kleibsiella, E coli), transplacental via maternal blood stream (bacteraemia), from abdomen via tubes (e.g. appendicitis, TOA), introduced via procedure (e.g. amniocentesis)
Extrauterine = sepsis e.g. urosepsis, pneumonia, viral, peridontal disease

C=cervix
Shortened cervix - previous LLETZ >1cm, cone biopsies, previous D+Cs/STOPs, cervical trauma in previous deliveries, CS at full dilatation

F=fetal
Chromosomal or congenital abnormalities

U=uterine (OUT)
Overdistension (polyhydramnios, LGA, multiple pregnancy), uterine structural abnormalities (bicornuate/septate), trauma

P=placenta
Placental abruption, placental insufficiency

S=social
Substance use (smoking, ETOH, drugs)
Low SES, Maori/Pacific/Indigenous
Low pre-pregnancy weight
AMA
Stress, IPV

Question 5

History taking

Answer 5

PC - abdo pain, back pain, ROM, FM, localising sx of infection
Pregnancy this far
PTB risk factors
Gestation accurate?
Whether appropriate to do fFN = no bleeding, PPROM, VE, intercourse

Question 6

NICE Guidance on USS Cx length vs fFN

Answer 6

Treat as TPTL if 29+6 or less based on clinical assessment only

If 30+0 or more
Offer TV ultrasound first line
If > 15mm - unlikely preterm labour, consider other diagnoses and offer inpatient observation vs outpatient
If 15mm or less - diagnose preterm labour

Offer FFN if TVUSS not available or acceptable
If 50ng/ml or less - unlikely preterm labour, consider other diagnoses and offer inpatient observation for outpatient
If >50ng/ml - diagnose preterm labour

Question 7

Maternal and Fetal Impacts of PTB

Answer 7

Maternal
Increased operative birth
Increased PPH
Reduced bonding due to increased NICU admissions
Increased postpartum depression and anxiety
Morbidity related to underlying cause - infection, abruption, PET

Fetal
Intrapartum hypoxia
Low birth weight
Hypothermia
Hypoglycaemia
Respiratory - TTN, RDS, surfactant deficiency, BPD, apnoeas
Cardiac - PDA
Gut - NEC
Brain - IVH
Jaundice
Retinopathy
Neonatal death

Question 8

Counselling in event of PTL or TPTL

Answer 8

Discuss implications for mother and baby, short and long term consequences

Consider gestation - active management vs palliative

If active: steroids, tocolysis unless contraindications, MgSO4, benzylpenicillin, NICU availability - transfer in-utero or ex-utero

Question 9

BV
Definition
Associated organisms
Does routine treatment of BV reduce PTB?
Who should we treat for BV?

Answer 9

Imbalance of vaginal flora - reduction in protective acids producing lactobacilli and overgrowth of BV associated organisms:
Gardnerella vaginalis,
bactericides, peptostreptococcus, mycoplasma species, atopbium species, moriluncun species

Routine treatment of BV in pregnancy is not associated with reduced PTB or PPROM

Treat those with other risk factors for preterm birth
Treat those who are symptomatic

Question 10

MgSO4 for neuroprotection: dose and monitoring

Answer 10

Dose
4g bolus over 25-20 minutes
Then IV infusion 1g per hour until birth or for 24 hours (Which ever is sooner)

Monitoring
At least 4 hourly HR, BP, RR, deep tendon reflexes, UO

Question 11

Rescue cerclage indications and contraindications

Answer 11

Indications

• 16+0 - 27+6
• Dilated cervix, exposed, unruptured membranes

Contraindications

• Vaginal bleeding
• Uterine contractions
• Signs of infection
• Ruptured membranes

Question 12

Caesarean section - choice of uterine incision

Answer 12

Depends on presence of lower segment, position of fetus, multiple pregnancy, placental location, membranes ruptured

Options - classical, upper transverse, J or T

Classical facilitate atraumatic and rapid delivery of the fetus

Question 13

Ventouse and forceps contraindicated before what gestation?

Answer 13

Ventouse contraindicated < 34 weeks
Forceps relatively contraindicated < 34 weeks - perform with caution, do not perform rotational forceps, only if certain of position

Question 14

FSE and FBS contraindicated before what gestation?

Answer 14

34/40

Avoid FSE if <34+0/40 unless it is not possible to monitor externally
AND has been discussed with a senior obstetrician AND benefits outweigh risks
AND alternatives and inappropriate to the woman

FBS - avoid if less that 34+0/40

Question 15

Cervical length measurements and risk of PTB <37 weeks

Length 30mm, 27mm, 22mm

Answer 15

30mm (10th centile) - RR 3.8
27mm (5th centile) - RR 5.4
22mm (2.5th centile) - RR 6.3
(Median length at 20 week is 42mm)

Question 16

USS technique for cervical measurement

Answer 16

Consider TA scan with partially full bladder as potential firstline screening test. If >35mm do not need TV USS.

Most accurately measured using TV ultrasound

• Empty bladder
• Probe in anterior fornix, minimising pressure on cervix
• Measure from internal to external os, take smallest of three measurements over 5 minutes (As cervix is dynamic)

Transperineal not adequately studied

Question 17

Cervical USS assessment - Predictive value of funnelling and shortening with fundal pressure, or presence of amniotic sludge?

Answer 17

Associated with PTB but don’t contribute to predictive monitoring beyond the cervical length itself

Question 18

Progesterone vs cerclage in LOW RISK WOMEN? RR?

Answer 18

Progesterone - RR 0.66 (ie reduces risk by 34%) reduces risk of preterm delivery before 34 weeks or fetal death. NNT = 11.

Progesterone also reduces risk of RDS, composite neonatal morbidity and mortality,
birthweight <1.5kg, admission to NICU

Cervical cerclage

• RR 0.74 if low risk
• RR 0.61 if previous PTB.

No clear benefit of cerclage to progesterone, therefore progesterone is generally preferred treatment as avoids surgical risks.

Question 19

Role of progesterone vs cerclage in WOMEN WITH RFS FOR PRETERM BIRTH? RR?

Answer 19

1. Previous PTB
   - benefit from progesterone or cerclage, consider cervical length surveillance to guide decision and if progressive shortening consider cerclage.
2. Multiple pregnancy
   - Cervical length has predictive value however there
   is conflicting evidence regarding therapeutic intervention.
3. Previous cervical excisional procedure - can help stratify risk for women and determine appropriateness of intervention

Question 20

Possible interventions for shortened cervix or women with multiple RFs

Answer 20

1. Conservative:
   - If no risk factors or patient declines
   - Consider cervical length monitoring
2. Progesterone
   - CONSIDER if history of PTB <34 weeks but normal cervical length
   - RECOMMEND if CL <25mm (singleton or multi)
3. Cervical cerclage
   - CONSIDER if history of PTB, PPROM or cervical surgery AND cervix <25mm

• No significant difference between two interventions and increased risk with cerclage
• Therefore, progesterone should be firstline in these women with serial cervical length in 1-2 weeks
• If further shortening of cervix despite progesterone, consider cerclage

Question 21

PV progesterone mechanism of action?

Answer 21

Reduces myometrial sensitivity to oxytocin
Blocks adrenergic receptors and prostaglandin synthesis
Stimulates lymphocyte associated synthesis of progesterone induced blocking
factor

Progesterone insufficiency thought to trigger uterine contractility

Question 22

Second and third trimester timing of progesterone

Answer 22

From 16-24 weeks, until 34-36 weeks

Question 23

Progesterone benefits, and safety profile

Answer 23

Reduced risk of PTB in meta-analysis - RR 0.66. NNT 11.

Also reduced risk of RDS, composite neonatal morbidity and mortality, birthweight <1.5kg, admission to NICU

No evidence of teratogenicity or adverse childhood outcomes (2 year follow up - OPPTIMUM trial)

Question 24

Cerclage timing

Answer 24

From 12-14 weeks for history indicated (2 or more early PTB)

From 16-24 weeks for ultrasound indicated

Question 25

Risks of cercvical cerclage

Answer 25

ROM, chorioamnionitis, bleeding, cervical trauma, anaesthetic risks Average additional gestational time added - prolongs pregnancy for average of 6 weeks. Could still end up with a pre-viable or very preterm baby

Question 26

Types of cervical cerclage

Answer 26

Transvaginal - Shirodkar (buried, needs spinal to remove) - McDonald Transabdominal - When vaginal sutures have failed - Bladder is reflected and suture placed over the internal os - Stays in place, delivery via CS

Question 27

Contraindications to cerclage

Answer 27

Rupture of membranes APH Evidence of infection Uterine activity

Question 28

Gestation range for insertion of rescue cerclage

Answer 28

16-28 weeks with a dilated cervix and exposed membranes - discuss with SMO and paeds

Question 29

Rescue cerclage insertion process

Answer 29

``` Trendelenburg Consider uterine relaxant Reduce prolapsed membranes with smooth surfaced device such as inflated IDC balloon Use McDonalds suture Remain in hospital for 1 night Follow up 2 weeks post insertion ```

Question 30

Contraindications to MgSO4

Answer 30

myasthenia gravis myocardial compromise/ conduction defects (anti-inotropic effects) Caution with impaired kidney function - use 0.5g/hr

Question 31

MgSO4 for neuroprotection in PTB - mechanisms of action

Answer 31

Exact mechanism not fully understood. Likely combination of following Down regulation of excitatory stimuli - blocks NMDA receptors, preventing influx of calcium causing neuronal cell death - blocking NMDA receptors also decreases seizure threshold Cerebral vasodilation through ca antagonism - leading to an increase in cerebral blood flow - minimising hypoxic ischaemic changes Reduction of pro-inflammatory cytokines Anti-apoptotic effect

Question 32

Steroids and Cochrane review 2017 - what are the benefits to infants? What do steroids not have an impact on?

Answer 32

Reduced rates of: - Neonatal Death RR 0.72 - Respiratory Distress RR 0.66 - Need for mechanical ventilation RR 0.68 - Intraventricular Haemorrhage RR 0.55 - Necrotising Enterocolitis RR 0.50 - Systemic infection in the first 48 hours of life RR 0.6 ``` No effect on: Chronic lung disease Mean birthweight Death in childhood or adulthood Neurodevelopment Chorioamnionitis/endometritis ```

Question 33

Steroids optimal treatment to delivery interval

Answer 33

>24 hours <7 days No confirmed benefit in infants delivered >7 days after dose (possible some small benefit up to 14 days) Still some benefit in those delivered less than 24 hours after the first dose

Question 34

Adverse effects of single course (1x pair) of steroids?

Answer 34

No known short term maternal or fetal adverse effects after single course No known longer term risks of a single course in terms of cognitive/neurological effects Insufficient evidence regarding multiple doses

Question 35

Contraindications to steroids

Answer 35

Requirement for acute delivery - do not delay delivery for purpose of steroid effect Contraindication in systematic infection - TB, sepsis Consider in chorioamnionitis but do not delay delivery for purpose of steroid effect

Question 36

Steroids and elective CS? RCOG and Aus/NZ recommendations? ASTECs study

Answer 36

RCOG suggest giving for elective CS up until 38+6 Aust/NZ Practice guideline suggest >34+6 if confirmed fetal lung immaturity ASTECS study - reduced admission to SCBU with RDS (RR 0.46) but very low baseline risk at advancing gestation and no BSL measurements and long term outcomes

Question 37

Indication and gestation for rescue steroids (after initial pair)

Answer 37

Give if at ongoing risk of preterm delivery >7 days after single course Give up to 3 x further rescue doses 1 week apart up til 32+6 (Aus/NZ Practice Guideline)

Question 38

ACTORDS study - repeat steroid doses - outcomes RR

Answer 38

Reduces RDS RR 0.82 reduces severe lung disease RR 0.6 reduces O2 use, mechanical ventilation, surfactant use. Decreased birthweight, head circumference and length at birth but not at discharge. Increased CS rate No difference in rate of NICU admission, APGAR scores, NEC, Retinopathy of prematurity, IVH 2 year follow showed increase need for attention problems assessment but no difference in major neurosensory disability

Question 39

Rescue steroids Cochrane 2015 study results

Answer 39

Associated with reduced RDS (RR 0.83) Associated with reduced serious infant outcome (RR 0.84) Associated with reduced mean birthweight -76g (no difference when adjusted for birthweight) No significant harm or benefit at 2 and 3 years (although ACTORDS found increased risk of need for assessment for attention problems)

Question 40

What is fFN? When is it normally present in the cervicovaginal secretions?

Answer 40

Extracellular matrix glycoprotein present at the decidual-chorionic interface <16 weeks (prior to fusion of chorion and amnion) and >37 week

Question 41

Why do we use the fFN test?

Answer 41

To help predict likelihood of preterm labour and guide use of steroids and tocolytics

Question 42

fFN cause of false positives? Negative predictive value?

Answer 42

False positives: semen, blood, digital cervical examination, lubricant 99.7%

Question 43

fFN positive predictive values? 10, 50, 200, 500 ng/ml?

Answer 43

``` Positive predictive value increases the higher the number 10ng/ml = 11-19% PPV 50ng/ml = 20-32% PPV 200ng/ml = 37- 61% PPV 500ng/ml = 46-75% PPV ```

Question 44

fFN sensitivity, specificity, positive and negative predictive values

Answer 44

Sensitivity 65%, PPV 43% | Specificity 93%, NPV 97%

Question 45

QUIPP tool for PTB

Answer 45

Use in two clinical settings: 1. Asymptomatic women at high risk for PTB in preterm surveillance clinics (based on 1803 women) 2. Symptomatic women e.g. abdominal pain, contractions, tightenings (based on 1032 women) Relies on: A clinical history for current risk factors and symptoms FFN OR TV USS cervical length measurements (both is better, don't need both) ``` 1. Symptomatic Symptom present Y/N Previous cervical surgery Y/N Previous preterm Y/N Previous PPROM Y/N Number of fetuses Gestation of test Shortest cervical length AND/OR fFN result ``` ``` 2. Asymptomatic Previous cervical surgery Y/N Previous preterm Y/N Previous PPROM Y/N Previous late miscarriage 16-24/40 Y/N Number of fetuses Gestation of test Shortest cervical length fFN result ``` ``` Gives results as percentage: Within 1 week Within 2 weeks Within 4 weeks Before 30/40 Before 34/40 Before 37/40 ```

Question 46

PPROM incidence and risk factors

Answer 46

2-3% of pregnancies PPROM precedes 1/3 of preterm births RFs: Previous PPROM Infection - vaginal, urine, systemic infection Uterine overdistension: multiple pregnancy, LGA, polyhydramnios Uterine trauma Short interpregnancy interval Smoking/substance use

Question 47

Amnisure or Actim PROM tests to diagnose PPROM

Answer 47

Amnisure - Measures alpha micro globulin - Not affected by semen of small amounts of blood - Specificity = 87-100% - Sensitivity around 94-98% - Can be positive in up to 1/3rd of term woman with intact membranes in labour Actim PROM test - Measures insulin-like growth factor binding protein (secreted by decidual and placental cells in high concentrations in amniotic fluid) - Not affected by infection, urine, semen or small amounts of blood - Specificity 98% - Sensitivity 93%

Question 48

Likelihood of labouring after PPROM - Median time to delivery in general - Median time to deliviery for 24-28 weeks; 31 weeks

Answer 48

Medium time to delivery is 7 days (80% deliver within 7 days) 10 days at 24 -28 weeks 5 days at 31 weeks 25% deliver within 48 hour

Question 49

Risks of PPROM - fetal

Answer 49

Preterm labour, complications of prematurity (hypoxia, NEC, IVH, respiratory, low birthweight) Chorioamnionitis Ongoing pregnancy with PPROM: fetal lung hypoplasia, limb contractures, growth restriction

Question 50

Likelihood of lung hypoplasia if PPROM at 21 weeks, vs 29 weeks

Answer 50

If PPROM at 21 weeks - 90% have lung hypoplasia | If PPROM at 29 weeks - 10% have lung hypoplasia

Question 51

ORACLE 1 trial for PPROM Abx used? Findings

Answer 51

PPROM < 37/40, randomised to erythromycin, co-amoxiclav, both or neither. Associated with prolongation of pregnancy, reduced surfactant use, reduced oxygen use at 28 days, reduced abnormal cerebral ultrasound Increased NEC with augmentin (RR 4)