Prematurity and its complications

• Prematurity means birth before 37 completed weeks of gestation. About 1 in 10 babies worldwide is born preterm, and preterm birth is the leading cause of neonatal morbidity and mortality worldwide. ^{[1] [5]}
• The earlier the birth, the higher the risk: the lungs, brain, eyes and gut of a very preterm baby are not ready for life outside the uterus.
• The most important preventions are antenatal corticosteroids for the mother, delivered when preterm birth is expected, together with magnesium sulfate for neuroprotection. ^[1][2]
• The complications that dominate neonatal care are respiratory distress syndrome, bronchopulmonary dysplasia, intraventricular haemorrhage, retinopathy of prematurity, necrotising enterocolitis and apnoea of prematurity.
• Modern neonatal care has made survival at 24 to 26 weeks possible, but complications remain very common, so prevention and gentle, lung-protective care matter as much as treatment.

By the end of this page you should be able to:

1. Define prematurity, classify it by gestational age, and state how birth weight and sex modify risk.
2. Explain why preterm infants are at high risk of respiratory, neurological, visual and gastrointestinal complications.
3. Describe how antenatal corticosteroids, magnesium sulfate, tocolysis and delayed cord clamping reduce these risks, with their gestational windows.
4. Recognise, stage and outline the management of bronchopulmonary dysplasia, retinopathy of prematurity, intraventricular haemorrhage and apnoea of prematurity.
5. Cross-check respiratory distress syndrome and necrotising enterocolitis as part of the same clinical picture.
6. Adapt prevention and follow-up to low-resource settings.

Prematurity is not one disease but one circumstance: an infant is required to live, breathe and feed before the organ systems that do those jobs have finished developing. The World Health Organization's 2022 recommendations for care of the preterm or low-birth-weight infant guide the care of these babies, while the WHO 2022 recommendations on antenatal corticosteroids and NICE guideline NG25 (last updated June 2022) guide the obstetric side. ^[3][4][2] Survival has improved dramatically, and with it a population of extremely preterm survivors whose lungs and brains were injured at the margins of viability. This page treats prematurity as a clinical topic in its own right, then works through the complications one by one, ending with the evidence-based ways to prevent them.

Classification is by gestational age, and the lower the gestation, the steeper the risk of every complication:

Birth before 28 weeks is the end of the period in which the germinal matrix of the developing brain is still present and in which retinal vascularisation is far from complete, which is why two of the most serious complications, intraventricular haemorrhage and retinopathy of prematurity, cluster below this gestation.

Sex matters too: male fetuses are at higher risk than females for respiratory distress syndrome, and growth restriction or chorioamnionitis can shift the risk in either direction.

Globally, prematurity affects about 10% of births, and the burden is concentrated in South Asia and sub-Saharan Africa. ^[1] Rates of preterm birth have not fallen despite better antenatal care. The epidemiology of the complications is best expressed by gestation:

• Respiratory distress syndrome affects about 45% of preterm infants overall, rising as gestation falls. ^[1]
• Bronchopulmonary dysplasia is the commonest severe respiratory disease of extremely preterm infants and occurs most often below 28 weeks. ^[5]
• Intraventricular haemorrhage occurs in up to 40% of infants below 28 weeks and about 27% of those born before 32 weeks. ^[7]
• Retinopathy of prematurity occurs mainly in infants below 28 weeks and in those weighing less than 1500 g at birth. ^[6]
• Apnoea of prematurity affects about 90% of infants under 1000 g, roughly a quarter under 2500 g, and more than half born below 32 weeks. ^[8]

Necrotising enterocolitis, the commonest gastrointestinal emergency of preterm infants, is also gestation-dependent; see the cross-check below.

Preterm birth usually has a cause that can be grouped:

• Spontaneous preterm labour: infection or inflammation (chorioamnionitis), cervical shortening or insufficiency, multiple pregnancy, previous preterm birth, uterine anomalies.
• Preterm prelabour rupture of membranes (P-PROM): infection ascending through the membranes.
• Iatrogenic or medically indicated preterm birth: pre-eclampsia, severe fetal growth restriction, placental abruption, severe maternal disease, antepartum haemorrhage. These babies are often growth-restricted and may be small for gestational age.

Risk factors for recurrence and for the complications include maternal diabetes, hypertension, obesity or undernutrition, infection (urinary, genital, periodontal), substance use (smoking, alcohol), and socioeconomic deprivation. NICE guideline NG25 notes that stillbirth rates are more than double in black babies and about 50% higher in Asian babies compared with white babies, and twice as high in the most deprived areas. ^[2] Cervical length below 25 mm on transvaginal ultrasound between 16 and 24 weeks identifies women at increased risk.

Preventing the birth itself when possible, and optimising the condition of the baby if it occurs, are the two halves of the problem.

The mechanisms of prematurity all come down to timing. Three principles explain almost everything:

1. Surfactant deficiency. Type II pneumocytes mature late in gestation, so surfactant production is limited and alveoli collapse on expiration (respiratory distress syndrome), and ventilation and oxygen injury follow (bronchopulmonary dysplasia). Antenatal corticosteroids accelerate lung maturation and cut this pathway.
2. A germinal matrix that has not involuted. The periventricular germinal matrix, the source of neurones and glia, contains fragile vessels and begins to involute only after 24 weeks. Before involution it bleeds easily into the ventricles (intraventricular haemorrhage) when blood pressure or venous return fluctuates. ^[7]
3. A retina that is only partly vascularised. Retinal vessel growth begins at the optic disc and reaches the nasal side only after 8 months of gestation; the temporal retina is not fully vascularised until term. Exposure to higher oxygen tension after birth shuts down vessel growth (phase 1), and the subsequent hypoxic retina then drives disordered neovascularisation (phase 2) - retinopathy of prematurity. ^[6]

On top of these, the preterm gut has immature barrier function and pattern recognition (necrotising enterocolitis), and the brainstem respiratory centres are immature (apnoea of prematurity).

Prematurity is not diagnosed, it is measured. The key data are:

• Gestational age is best established by first-trimester ultrasound dating, failing which by the mother's certain dates or by clinical estimation (neuromuscular maturity, new Ballard score). Postnatal, postmenstrual age matters more than postnatal age for several complications.
• Birth weight and its centiles define small-for-gestational-age and intrauterine growth restriction.
• Severity of illness scores (CRIB II, SNAPPE-II) combine gestation, birth weight and early clinical state.
• Complications are diagnosed by their own investigations: chest radiograph and pulse oximetry for respiratory distress syndrome; cranial ultrasound for intraventricular haemorrhage; indirect ophthalmoscopy for retinopathy of prematurity; abdominal radiograph for necrotising enterocolitis.
• NICE NG25 gives an obstetric pathway: transvaginal ultrasound cervical length and fetal fibronectin testing, tocolysis with nifedipine (offered from 26+0 to 33+6 weeks, considered from 24+0 to 25+6), and antenatal corticosteroids. ^[2]

No single "cut-off" is used for a decision; gestational age, fetal condition and the mother's condition together determine whether to deliver and how to prepare.

This is where most of the evidence is, and most of the benefit. The interventions below apply to singleton and multiple pregnancies (NICE NG25 focuses on singletons; high-risk multiple pregnancies follow local protocols).

This is the most important neonatal intervention in all of medicine. A single course of 24 mg of betamethasone or dexamethasone, given as several doses over 24 to 48 hours when preterm birth is expected within a week, mimics the missed endogenous cortisol surge and matures the fetal lungs. ^[1] It reduces neonatal death by 22% and respiratory distress syndrome by 29% in babies born at 24+0 to 37+0 weeks. ^[1]

NICE NG25 gives the gestational windows (last updated 2022): ^[2]

• 22+0 to 23+6 weeks: discuss with the woman and the multidisciplinary team in the context of her individual circumstances.
• 24+0 to 33+6 weeks: offer maternal corticosteroids.
• 34+0 to 35+6 weeks: consider maternal corticosteroids. ^[2]
• Less than 34+0 weeks, more than 7 days after the first course, and at very high risk of birth within 48 hours: consider a single repeat course. No more than two courses in total. ^[2]

WHO's 2022 recommendations on antenatal corticosteroids likewise recommend their use when preterm birth is expected, while clinical guidelines vary between countries in gestational age limits, dose timing and eligibility. ^[1][3]

Intravenous magnesium sulfate reduces cerebral palsy in very preterm infants, almost certainly by stabilising blood pressure and cerebral blood flow around birth. ^[2]

• 23+0 to 23+6 weeks: discuss in the context of individual circumstances.
• 24+0 to 29+6 weeks: offer intravenous magnesium sulfate when established preterm labour or a planned preterm birth within 24 hours.
• 30+0 to 33+6 weeks: consider.

Dose: a 4 g intravenous bolus over 15 minutes, followed by 1 g per hour until birth or for 24 hours, whichever comes first, with monitoring for magnesium toxicity (pulse, blood pressure, respiratory rate and deep tendon reflexes) at least every 4 hours. ^[2]

• Tocolysis. Nifedipine delays preterm labour long enough to give corticosteroids and to transfer. Nifedipine is offered from 26+0 to 33+6 weeks and considered from 24+0 to 25+6; betamimetics are not recommended for tocolysis. ^[2] (This is an off-label use in many settings.)
• Prolonged membrane rupture (P-PROM). Women with P-PROM receive oral erythromycin 250 mg four times a day for up to 10 days, or until established labour, as prophylaxis against intrauterine infection; co-amoxiclav is avoided. ^[2] Corticosteroids and magnesium sulfate are also used here.
• Cord clamping. Wait at least 60 seconds before clamping the cord of preterm babies, with the baby positioned at or below the level of the placenta, unless maternal or fetal conditions demand earlier clamping. This improves placental transfusion and reduces intraventricular haemorrhage. ^[2][7]
• Delivery at a centre with neonatal capability. For very preterm birth, in-utero transfer to a unit with appropriate care improves both survival and morbidity; intramuscular progesterone and cervical cerclage reduce recurrence in women with a short cervix and a history of preterm birth. ^[2]
• Delayed cord clamping and non-invasive respiratory support together with surfactant are perinatal strategies that reduce complications. ^[7]

Respiratory distress syndrome (RDS) is the commonest severe respiratory disease of preterm infants and the immediate respiratory problem at birth: type II pneumocytes are immature, surfactant is deficient and alveoli collapse on expiration. It is covered as its own topic (Neonatal respiratory distress syndrome), and many of its risk factors (male sex, caesarean section without labour, maternal diabetes) and treatments (CPAP, surfactant, gentle volume-targeted ventilation) belong to a single continuum with prematurity rather than to a separate disease. ^[1] Antenatal corticosteroids cut the risk of RDS by 29%, so what presents as a nursery problem is usually prevented, or softened, antenatally. ^[1]

Pathogenesis has shifted over decades. Older "classic" BPD followed severe RDS with high-pressure ventilation and high oxygen, producing fibrocystic, thickened airways and cor pulmonale. Modern "new" BPD follows gentler care but occurs in babies ventilated in the late canalicular and early saccular stages of lung development: the lungs are characterised by impaired alveolarisation, a relative paucity of oversized airspaces, dysregulated and leaky capillaries, and pulmonary oedema. ^[5] Immaturity drives it, and infection, patent ductus arteriosus and necrotising enterocolitis add risk.

Prevention is more effective than treatment:

• Caffeine, started early, lowers the odds of BPD (adjusted odds ratio 0.63; 95% CI 0.52 to 0.76). ^[5]
• Vitamin A, 5000 international units intramuscularly three times a week for the first 4 weeks, reduces the composite of BPD or death before 36 weeks (relative risk 0.89; 95% CI 0.80 to 0.99). ^[5]
• Low-dose hydrocortisone, 8.5 mg/kg total over the first 10 days, modestly improves BPD-free survival (odds ratio 1.48; 95% CI 1.02 to 2.16). ^[5]
• Avoid early dexamethasone (before 7 days), which prevents BPD but is linked to neurodevelopmental impairment. ^[5]
• Inhaled budesonide in the first 12 hours reduces BPD but was associated with increased mortality at follow-up, so routine early use is not encouraged. ^[5]

For babies who remain ventilator-dependent from about 7 to 28 days, current paediatric guidance is to consider a short course of low-dose dexamethasone guided by the baseline risk of BPD (dexamethasone reduces oxygen dependency at 36 weeks; relative risk 0.76; 95% CI 0.66 to 0.87), while moderately late hydrocortisone can facilitate extubation. ^[5] BPD is therefore a condition with a prevention package rather than a single drug.

Follow-up: infants with BPD need surveillance into childhood (lung function, exercise tolerance, wheeze) and have an excess of respiratory hospitalisations and a higher risk of long-term lung disease.

Pathogenesis runs in two phases. Phase 1, from birth to about 30 weeks postmenstrual age, is driven by relative hyperoxia and the loss of the maternal-fetal interface: normal vessel growth stops and existing vessels can be lost. Phase 2 begins when the increasingly active retina becomes hypoxic relative to its inadequate vessel supply, driving release of vascular endothelial growth factor (VEGF) and erythropoietin, neovascularisation into the vitreous, and, in the worst cases, retinal detachment. ^[6]

Oxygen is the lever on both sides: high early oxygen concentrations damage retinal vessel development, while later desaturations feed the proliferative phase, so oxygen targets and monitoring matter from the first hour of life.

Classification uses the International Classification of Retinopathy of Prematurity (ICROP) into five stages:

Screening is the treatment, in the sense that ROP is largely preventable blindness only when found early: screening starts at the sixth postnatal week or 31 weeks postmenstrual age, then every one to two weeks until the disease regresses or vascularisation completes (usually 40 to 50 weeks postmenstrual age). ^[6] Infants are examined with dilated indirect ophthalmoscopy.

Treatment options follow severity:

• Type 1 ROP (zone I, stage 3 with plus disease, or zone II stage 2 or 3 with plus) is treated with laser photocoagulation of the avascular peripheral retina, still the commonest approach, or intravitreal anti-VEGF (bevacizumab or ranibizumab), which is preferred in posterior disease but raises questions about recurrence and neurodevelopmental follow-up.
• Advanced disease (stages 4 and 5) needs vitrectomy and scleral buckling.

Every treated infant, and most who had any ROP, needs follow-up for refractive error, strabismus and amblyopia.

The germinal matrix is a highly vascularised, poorly supported bed at the caudothalamic groove that begins to involute only after about 24 weeks. Bleeding reflects its fragility plus pressure-passive cerebral blood flow: preterm infants do not autoregulate, so hypercarbia, acidosis, anaemia, hypoglycaemia, or rapid fluid loads convert directly into venous congestion and rupture. Severity is graded with the Papile or Volpe systems; severe (grade III to IV) haemorrhage, with ventricular dilatation or parenchymal extension, carries mortality and long-term motor and cognitive disability. ^[7]

Prevention is antenatal and perinatal:

• Antenatal corticosteroids and magnesium sulfate are the primary antenatal preventive measures. ^[7]
• Delayed cord clamping, non-invasive ventilation where feasible, surfactant administration, and careful circulatory management are perinatal measures. ^[7]
• IVH prevention bundles (minimal handling, midline head position, normothermia between 36.5 and 37.5 degrees Celsius, clustered care, avoidance of rapid fluid boluses or rapid blood draws, pain control) aim to keep cerebral blood flow steady in the first 72 to 96 hours. ^[7]
• Early postnatal prophylactic indomethacin probably reduces severe IVH modestly in some studies, but has not shown improved long-term neurodevelopmental outcome and carries renal and gastrointestinal risks; it is therefore used selectively rather than routinely. ^[7]

Screening is cranial ultrasound in infants below 32 weeks. There is no curative treatment for established IVH; care is supportive, with neurosurgical drainage for post-haemorrhagic ventricular dilatation.

AOP affects about 90% of infants under 1000 g, roughly a quarter of those under 2500 g, and more than half below 32 weeks. ^[8] It needs to be prevented as well as treated: recurrent apnoea and desaturation can worsen long-term neurodevelopment and trigger severe retinopathy of prematurity through intermittent hypoxia, although disentangling the causal effect remains a research question.

First-line treatment is caffeine, supported by the influential CAP trial. WHO's 2022 recommendations suggest caffeine to prevent AOP in infants born before 34 weeks, with a loading dose of 20 mg/kg and maintenance of 5 mg/kg/day, discontinued at 34 weeks postmenstrual age provided the baby has been apnoea-free for at least 5 days. ^[8] European, UK, US and Australasian guidelines differ: maintenance doses range from 5 to 10 mg/kg/day, and loading doses up to 20 mg/kg are used; higher doses can be used to reduce extubation failure but have been linked to serious adverse events such as cerebellar haemorrhage, so more work is needed. ^[8]

Where caffeine is unavailable or prohibitively expensive (as in many low-income settings), aminophylline or theophylline is used, at a loading dose of 5 to 6 mg/kg followed by 1 to 2 mg/kg every 6 to 8 hours (or 2.5 mg/kg twice daily), with monitoring of drug levels if possible. ^[8] Doxapram is a second-line respiratory stimulant for infants not responding to methylxanthines, given as an infusion of 2.0 to 2.5 mg/kg over 10 to 15 minutes then 0.5 to 2.0 mg/kg per hour, but robust evidence from large trials is lacking. ^[8]

Caffeine also reduces apnoea after extubation, shortens respiratory support and reduces bronchopulmonary dysplasia, which is why it has become one of the most prescribed drugs in neonatology. ^[5][8]

Necrotising enterocolitis (NEC) is the commonest gastrointestinal emergency and cause of gastrointestinal morbidity of preterm infants, presenting after the first week with feeding intolerance, abdominal distension and blood in the stool, with pneumatosis intestinalis on abdominal radiograph as the pathognomonic finding. It is covered as a separate topic (Necrotising enterocolitis). Risk is increased by prematurity, formula feeding, bacterial colonisation and the use of indomethacin. Prevention centres on breast milk (maternal or donor), standardised feeding protocols, avoidance of prolonged early antibiotics, and careful handling; corticosteroids and indomethacin for other indications must be weighed against their own gastrointestinal risks. It belongs in the prematurity picture because the same immature gut that cannot yet absorb well is also the gut that necroses. ^[7]

Prognosis is dominated by gestational age. In modern tertiary networks, more than 75% of infants born at 24 to 26 weeks now survive, though bronchopulmonary dysplasia remains high at roughly 60%. ^[5] Survival is now far better at 28 weeks and beyond. For survivors, the burden is neurodevelopmental (disability scales increase with decreasing gestation, intraventricular haemorrhage and bronchopulmonary dysplasia), respiratory (reduced lung function into adolescence and adulthood) and visual (myopia and strabismus after retinopathy of prematurity). Growth and feeding problems, late metabolic and cardiovascular disease, and educational difficulty are all more common than in term-born peers. Many infants born at 22 to 23 weeks who survive have significant disability, and honest counselling of families on this point is an obstetric duty.

Most preterm births occur in low- and middle-income countries, where the same simple interventions save the most lives:

• Antenatal corticosteroids and magnesium sulfate are cheap, effective and usually available; the barrier is recognition of threatened preterm labour and access to care, not the drugs. ^[1][3]
• Essential newborn care (warmth, clean delivery, early and exclusive breastfeeding, kangaroo mother care) halves mortality for small babies.
• Kangaroo mother care and continuous positive airway pressure are the mainstay where neonatal units are limited.
• Oxygen should be titrated carefully, both because of retinopathy of prematurity and because of oxidative injury to the lungs and brain; pulse oximetry is worth more than additional oxygen.
• Caffeine is often unavailable and aminophylline is substituted; expanding access to caffeine is a global priority. ^[8]
• Screening for retinopathy of prematurity and cranial ultrasound for intraventricular haemorrhage are frequently unavailable; bedside examination and referral pathways must be built deliberately.

Prevention runs from before conception to childhood. The sharpest levers:

1. Reduce preterm birth itself: antenatal care, treatment of infection and hypertension, progesterone and cerclage for the high-risk cervix, smoking cessation, spacing of pregnancies, caesarean section only when indicated.
2. Prepare the preterm baby: antenatal corticosteroids and magnesium sulfate, tocolysis to buy time, delivery at a capable centre, delayed cord clamping, cord blood management.
3. Protect the preterm baby after birth: warmth, gentle ventilation with tight oxygen targets, caffeine, cautious fluid management, infection control, breast milk, and careful handling to keep cerebral blood flow steady.
4. Screen the right infants for the right complication: cranial ultrasound for intraventricular haemorrhage below 32 weeks; indirect ophthalmoscopy for retinopathy of prematurity at the sixth postnatal week or 31 weeks postmenstrual age; ongoing neurodevelopment and hearing follow-up for all very preterm survivors.

• Prematurity is birth before 37 completed weeks and affects about 10% of births. ^[1]
• Risk of every complication rises steeply with decreasing gestation; below 28 weeks is the zone of greatest danger for brain, lung and retina. ^[5][7][6]
• Antenatal corticosteroids (24 mg of betamethasone or dexamethasone over 24 to 48 hours) are the single most effective preventive treatment, reducing neonatal death by 22% and respiratory distress syndrome by 29% for births at 24+0 to 37+0 weeks. ^[1]
• Magnesium sulfate given intravenously to women at 24+0 to 29+6 weeks (4 g over 15 minutes plus 1 g per hour) protects the fetal brain. ^[2]
• NICE NG25 sets gestational windows for corticosteroids, magnesium sulfate and nifedipine tocolysis; WHO's 2022 guidance provides a parallel, internationally applicable view. ^[2][3]
• Respiratory distress syndrome is the immediate respiratory problem of prematurity and is covered separately (Neonatal respiratory distress syndrome).
• Bronchopulmonary dysplasia is chronic dependence on respiratory support to at least 36 weeks postmenstrual age; prevention relies on caffeine, vitamin A and judicious use of postnatal steroids. ^[5]
• Retinopathy of prematurity is a two-phase vascular disease of the developing retina; it is prevented largely by correct oxygen management and careful screening from the sixth postnatal week or 31 weeks postmenstrual age. ^[6]
• Intraventricular haemorrhage arises in the germinal matrix, mainly below 28 weeks; prevention is antenatal (corticosteroids, magnesium sulfate) and perinatal (gentle, stable care). ^[7]
• Apnoea of prematurity is treated first-line with caffeine (20 mg/kg loading, 5 mg/kg/day maintenance, stopped at 34 weeks after 5 apnoea-free days), with aminophylline as the low-resource alternative. ^[8]
• Necrotising enterocolitis is the commonest gastrointestinal emergency of preterm infants and is covered separately (Necrotising enterocolitis).
• Delayed cord clamping (at least 60 seconds) benefits the preterm infant's circulation and may reduce intraventricular haemorrhage. ^[2][7]

Neonatal respiratory distress syndrome; Necrotising enterocolitis; Neonatal resuscitation at birth; Bronchiolitis; Cyanotic and acyanotic congenital heart disease; Neonatal sepsis; Neonatal jaundice.