Premature Birth

Marek Gowkielewicz

Department of Gynecology and Obstetrics

University of Warmia and Mazury
Premature labor (p.l.)- definition

• < 37 weeks
• onset of p.l. (4 contractions in 20 min or 8 in 60 min)
• secondary conditions : effacement (> 50 %) or cervical dilatation (> 2
cm) or progressive change in dilatation or PROM
• threatened p.l. – contractions without cervical change
• 10-15 % of all pregnancies
• PROM in 35 %
• iatrogenic 25 %
Premature labor (p.l.)- etiopathogenesis

• increase in myometrial gap junctions

• ↑ oxytocin receptors
• ↑ myometrial contractile efficiency
• changes in cervical collagens and matrix

 contractions  effacement and dilatation  expulsion of the fetus

Premature labor (p.l.)- causes

• stress
• maternal and fetal cortisol
• CRH release in decidua, trophoblast, membranes
• 17 alpha-hydroxylase activity
• ↓ progesteron, ↑ estrogen production
• ↑ prostaglandin
Premature labor (p.l.)- causes

• pathologic uterine overdistination

• ↑ gap junctions
• ↑ oxytocin receptors
• ↑ prostaglandin
Premature labor (p.l.)- causes

• decidual hemorrhage
• tissue factor  thrombin  decidual membrane receptors  ↑
proteases and metalloproteinases  cervical ripening and uterine
contractions
Premature labor (p.l.)- causes

• infection
• ↑ cytokins
• ↑ matrix metalloproteinases
• ↑ prostaglandin
• some organisms produce collagenases, elastases, phospholipases
Premature labor (p.l.)- causes

• abnormal cervical function

• congenital abnomalities
• previous cervical surgery
Premature labor (p.l.)- prediction

• history (17-40 %)
• home uterine activity monitoring
normal: till 30th week 1/hour in prima, 2/hour in multigravida,
beyond 30th 2/hour;
more than 3/hour at 26-28th or more than 5/hour at 30-32th
 p.l.  intervention
• biochemical markers (under study: salivary E3/P, salivary E3, serum
collagenase, neutrophil collagenase, tissue inhibitor of metalloproteinases,
serum relaxin, CRH)
• inflammation and infection markers (e.g. IL6, TNF – no practical application)
Premature labor (p.l.)- prediction

• Cervical assesment (less than 25 mm, sludge) - TV

• Cervicovaginal fibronectin – source: fetal amnion
normal presence < 20th and > 36th week
between 20-36th reflects stromal remodeling of cervix before
onset of labor
value > 50 ng/ml – positive  40 % p.l. within next seven days
value < 50 ng/ml – negative  < 1 % undergo p.l.
Premature labor (p.l.)- prevention

• patient education
• behavioral alternation (bed rest ?, limitation of physical activity, coital
abstinance , cessation of smoking)
• treatment of infection (BV, urine, dentist, vacc.)
• cervical cerclage
• progesteron therapy
Premature labor (p.l.)- treatment

• the goal: delay the delivery for:

- corticosteroids
- transfer to tertiary care center
- decrease neonatal morbidity / mortality
Premature labor (p.l.)- treatment

• Bed rest no evidence

• Hydration / sedation no evidence
• Corticosteroids (24-34th week)  reduce occurence and severity of
neonatal respiratory disease
• Antibiotics, only:
- PROM
- treatment of specific infection
- prophylaxis of Gullian-Baree syndrome (Haemophilus influenzae,
Campylobacter, Mycoplasma pneumoniae)
• Tocolytics
Premature labor (p.l.)- contraindications t.t.

• maternal
- severe hypertensive disease
- uncontrolled diabetes
- cardiac arythmias
- haemorrhage
- ARDS / pulmunary edema
- cervical dilatation > 4 cm
- hyperthyroidism
Premature labor (p.l.)- contraindications t.t.

• fetal
- > 34 weeks
- IUD
- Rh-incompability (haemolitic disease)
- IUGR
- congential anomalies incompatible to life
- PROM
Premature labor (p.l.)- treatment

• Betamimetics
- β-2 receptors  smooth muscle relaxation
- activate AMP to cAMP  ↓myosin light chain kinase (MLCK) activity
via phosphorylation and reduction intracellular Ca (Ca uptake by
sarcoplasmic reticulum)  ↓ myocyte contractility
- only ritodrine approved by FDA (iv, starting dose 50-100 μg/min,
increased every 20 min, max dose 350 μg/min, after success 60 min of
this dose and ↓ dose by 50 μg/min every 30 min till 50 μg/min; at
least 12 hours
- terbutaline – off label
Premature labor (p.l.)- treatment

• Betamimetics; maternal side effects:

- hypotension, tachykardia, pulmunary edema (3-5%), myocardial
ischemia, arrythmia,
- tremor (10-15 %), palpitation (33 %), nervousness (5-10 %),
restlesness (5-10 %), nauseae, vomiting, headache
- Hyperglicemia, hypokalemia, ketoacidosis
Premature labor (p.l.)- treatment

• Betamimetics; fetal side effects:

- supraventricular tachykardia, atrial flutter
- pulmunary edema, cardiac septal hypertrophy, myocardial ischemia,
hydrops
- hyperinsulinemia, hypoglycemia, hyperbilirubinemia
Premature labor (p.l.)- treatment

• Betamimetics; contraindications:
- cardiac arrhythmia
- poorly controlled thyreotoxicosis, diabetes, hypertension, anemia
Premature labor (p.l.)- treatment

• Betamimetics; efficacy:
- effective in delaying birth for 48 hours
Premature labor (p.l.)- treatment

• Magnesium sulfate
- inhibition of calcium channels (via voltage change and
hyperpolaryzation of membrane)
- directly comptes with intracellular Ca and ↓ calcium-calmodulin
binding affinity to MLCK  ↓ myocyte contractility
- i.v., bolus 4-6 g/100 mL within 20 min, later 1-3 g/hour, maintain for
12-24 hours
Premature labor (p.l.)- treatment

• Magnesium sulfate; maternal side effects:

- dose related
- flushing, perception of warmth, nausea, emesis, dizziness, blurred
vision, muscle weakness, nystagmus, diplopia, dryness of the mouth,
shortness of breath
- pulmunary edema (1 %)
- Therapeutic level 5-8 mg/dL
Premature labor (p.l.)- treatment

• Magnesium sulfate; fetal side effects:

- crosses placenta
- concentration 10% lower than maternal
- nonreactive heart rate (50 %)
- longer than 7 days  demineralization of bones (50 %)

- But !!! Neuroprotectal effect and ↓ cerebral palsy !!!

Premature labor (p.l.)- treatment

• Magnesium sulfate; contraindications:

- myasthenia gravis
- heart block
- myocardial damage

- using with calcium channel blockers  severe hypotension

Premature labor (p.l.)- treatment

• Magnesium sulfate; efficacy:

- Cochrane base: noneffective in p.l. but…
- reduces the risk of cerebral palsy
Premature labor (p.l.)- treatment

• Prostaglandins synthetase inhibitors:

- ↓ activity of COX ↓prostaglandin E and F  ↓ myocyte contractility
- indomethacin, ketorolac, sulindac
- maternal side effects…
- fetal side effects (after 48 h): constriction of DV (50 % after 32th, before
5-10 %) pulmonary hypertension; reversible function of kidney 
oligohydramnion; intraventricular hemorrhage, necrotizing
enterocolitis, hyperbilirubinemia
- efficacy: without improvements in fetal morbidity / mortality
Premature labor (p.l.)- treatment

• Calcium channel blockers:

- Via voltage dependent channels  ↓ influx of Ca into the cell, ↑
efflux of Ca from the cell, ↓ release of Ca from sarcoplasmic
reticulum  smooth muscle relaxation
- Nifedipine, orally, RCOG initial dose 20 mg, followed by 10-20 mg 3-
4x/day
- Dose of 60 mg  risk of side effects
Premature labor (p.l.)- treatment

• Calcium channel blockers; maternal side effects:

- transient hypotension (17 %)
- flushing, dizzinness, nauseae, vomiting, headache, palpitation

- maternal hydratation !!!

Premature labor (p.l.)- treatment

• Calcium channel blockers;

- no fetal side effects
- contraindiciations: hypotension, congestive heart failure, aortic
stenosis
- efficacy: more effective than β-m, improvements in neonatal
outcomes, less side effects than β-m
Premature labor (p.l.)- treatment

• Oxytocin antagonists
- via oxytocin receptors  ↓conversion of phospatidiloinositol to
inositol triphosphate  reduction intracellular Ca (↓ release Ca from
sarcoplasmic reticulum)  ↓ myocyte contractility
- atosiban, i.v., protocol, 48 hours
- maternal side effects: nauseae, vomiting, headache, dysgeusia, chest
pain
- fetal side effects: no
- expensive
Premature labor (p.l.)- delivery

- tertiary center
- cesarean section (controversial in very low weight) or natural birth ?
- c.s. cripples uterus, needs vertical cut
- episiotomy
Racusin DA, Antony KM, Haase J, Bondy M, Aagaard KM. Mode of Delivery in
Premature Neonates: Does It Matter?. AJP Rep. 2016;6(3):e251-e259.
doi:10.1055/s-0036-1585577
Premature labor (p.l.)- neonatal complications

- Respiratory: apnea, hyaline membrane disease, bronchopulmonary dysplasia

- Neurologic: perinatal depression, intracranial hemorrhage
- Cardiovascular: hypotension, patent DA, congestive heart failure
- Hematologic: anemia, hyperbilirubinemia
- Gastrointestinal: necrotizing enterocolitis
- Metabolic: hypoglycemia, hypocalcemia
- Renal: acid base and electrolyte imbalance due to low eGFR
- Temperature regulation: hypo- and hyperthermia
- Immunologic: ↑ risk of infection
- Ophtalmologic: retinopathy of prematurity
 Chapter 4th by Monika Bhatia in
„Management of High-Risk Pregnancy – A Practical Approach”
Gestational age Birth weight Survivors (%) Intact Survivors (%)
(not blind, deaf, retarded or with
cerebral pasly)

24-25 500-750 60 35

25-27 751-1000 75 60

28-29 1001-1250 90 80

30-31 1251-1500 96 90

32-33 1501-1750 99 98

>34 1751-2000 100 99

• I used mainly from chapter written by Monika Bhatia in „Management
of High-Risk Pregnancy – A Practical Approach”