• Information
  1. Definitions and Diagnosis
  2. Causes of Preterm Labor
  3. Systems Anomalies in LBW and VLBW Infants
  4. Specific Complications of Prematurity / Low Birthweight
  5. Cerebral Palsy
  6. Pulmonary Dysfunction
  7. Treatment of Preterm Infants
  8. Prognosis
  9. Preventing Preterm Labor

A. Definitions and Diagnosis [1]

1. Normal Pregnancy is 39 weeks
   1. Delivery Dates usually from Last Menstrual Period (LMP) + 2 weeks (ovulation)
   2. Premature Infants defined as <37 weeks
   3. Risks to mother and fetus are greatest with <34 weeks' gestation
2. Epidemiology
   1. Overall, ~12% preterm births in USA and ~7% in other developed countries
   2. Increasing rates mainly due to labor associated with artificially conceived multiple births
3. Three Categories
   1. Spontaneous labor with intact membranes
   2. Preterm premature rupture of membranes (PPROM)
   3. Labor induction or Caesarian delivery for maternal or fetal indciations
4. Preterm Labor/Delivery
   1. Initiation of labor prior <37 weeks from LMP is called preterm or premature labor
   2. About 8% of pregnancies are complicated by preterm labor
   3. Preterm labor accounts for >85% of complications and costs associated with delivery
   4. Very early birth, <32 weeks, occurs in ~2% of all pregnancies
   5. Birth <32 weeks is most common cause of perinatal morbidity and mortality
   6. Extremely preterm infants (20-25 weeks) have very poor acute and long-term prognosis
5. Diagnosis of Preterm Labor / Parturition [2]
   1. Uterine contractions preterm are a poor predictor of actual labor
   2. Cervical dilatation, softening, shortening, can occur without imminent labor
   3. Preterm "labor" resolves spontaneously in ~30% of women
   4. Fetal fibronectin (vaginal fluid) and ultrasonography may accurately predict preterm labor
   5. Short cervical length and elevated cervical-vaginal fetal fibronectin are risk factors [1]
6. Birth Weights
   1. Normal >2500-3500 gm
   2. Low (LBW) 1500-2500 gm
   3. Very Low (VLBW) 1000-1500gm
   4. Extremeley Low (ELBW) <1000gm
7. Good Prognostic Factors [16]
   1. Higher birth weight
   2. Greater gestational age
   3. Receipt of antenatal glucocorticoids
   4. Singleton birth
   5. Female sex
8. Long Term Complications (Birth at 23-27 weeks) [62]
   1. Cerebral palsy: 9.1% versus 0.1% at term
   2. Mental retardation: 4.4% versus 0.4% at term
   3. Receiving disability pension: 10.6% versus 1.7%

E. Causes of Preterm Labor [1,2]

1. Pathophysiology of Preterm Birth [2]
   1. Four well described pathways, which may be initiated months before preterm labor
   2. Excessive myometrial and fetal membrane overdistention
   3. Decidual hemorrhage
   4. Precocious fetal endocrine activation
   5. Intrauterine infection or other inflammation
   6. Combinations of these processes may accelerate the process further
2. Maternal Risks
   1. Previous history of preterm labor or delivery is major risk factor [41]
   2. Multiple gestations
   3. Uterine anomalies
   4. Smoking cigarettes: 8-12% of preterm deliveries are attributable to smoking
   5. Maternal infection (especially chorioamnionitis, urinary tract infection) [13,15]
   6. Short cervical length (evaluate with endovaginal sonography at 16-18 weeks) [28]
   7. Spontaneous delivery at <34 weeks occurs in 34% of women with cervix <15mm [53]
   8. Race: preterm births are twice as high amongst black women compared with white women
   9. Low socioeconomic status
   10. Very young or very old maternal age
   11. Low weight before pregnancy
   12. Maternal chronic disease
   13. Antiretroviral therapy is not associated with increased risk for prematurity [42]
3. Maternal Diseases Associated with High Risk Pregnancy
   1. Diabetes Mellitus
   2. Sickle Cell Anemia
   3. Renal Insufficiency
   4. Rheumatologic Disease - systemic lupus, scleroderma, others
   5. Other underlying disease
4. Vaginal / Cervical Infections [25]
   1. Bacterial Vaginosis - Gardnerella vaginalis and other organisms
   2. Chlamydia
   3. Ureaplasma
   4. Peptostreptococci
   5. Bacteroides Species
   6. Metronidazole treatment of asymptomatic pregnant women 23-24 weeks' gestation with bacterial vaginosis has shown conflicting effects on rate of preterm delivery [23,25]
   7. Clindamycin 300mg bid x 5 days in women with bacterial vaginosis or abnormal bacterial flora 12-22 weeks' gestation reduced preterm delivery/miscarriages by >60% [38]
   8. Metronidazole treatment of Trichomonas vaginalis infection does not prevent preterm delivery [29]
   9. Randomized trial data recommend against routine screening for bacterial vaginosis in asymptomatic women at low risk for preterm delivery [30,31]
5. Preterm Premature Rupture of Membranes (PPROM; ~40%) [25]
   1. Likely that a significant proportion of these cases due to asymptomatic infection
   2. Colonization of placental membranes with bacteria likely increases preterm risk
   3. These infections stimulate prostaglandins, which induce myometrial contractions
   4. Infections also cause fetal distress, and metalloproteases weaken placental membranes
   5. Elevated levels of inflammatory mediators such as IL-6 found in amniotic fluid
   6. Elevated levels of calgranulin B and a fragment of IGF-1 found in intra-amniotic infection [43]
   7. Elevated cervical-vaginal fetal fibronectin predict preterm labor [1]
   8. PROM ensues due to infection
6. Preeclampsia
   1. Responsible for ~20% of preterm deliveries
   2. Delivery often pre-term for maternal (severe preeclampsia) and fetal (IUGR) reasons
7. Third Trimester Bleeding
8. Fetal Distress
9. Deficiency in Prostaglandins
   1. Choriodecidua is enriched in 15-hydroxyprostaglandin dehydrogenase (15-HPDH)
   2. 15-HPDH is responsible for degrading the primary prostaglandins
   3. Thus, PGE2 may be allowed to reach the myometrium and initiate contractions
   4. May account for ~15% of idiopathic preterm labor
10. History of invasive treatment for cervical pre-/cancerous lesions associated with 2-3X increased risk of premature delivery, low birth weight, and caesarian section [5]

B. Systems Anomalies in LBW and VLBW Infants

1. Essentially all organ systems are affected
   1. Pulmonary
   2. Gastrointestinal
   3. Immunologic
   4. Hematologic
   5. Central nervous system
   6. Ophthalmologic
   7. Cardiovascular
   8. Renal
   9. Endocrine
   10. Number of disturbances and outcomes related to prognostic factors listed above
2. Pulmonary Disease
   1. Respiratory Distress Syndrome
   2. Pulmonary Interstitial Emphysema
   3. Bronchopulmonary Dysplasia (BPD)
   4. Chronic Lung Disease
   5. Apnea of Prematurity
3. Gastrointestinal
   1. Hyperbilirubinemia
   2. Feeding intolerance
   3. Necrotizing Enterocolitis
   4. Failure to thrive
   5. Growth failure
   6. Short-bowel syndrome
   7. Cholestasis
4. Central Nervous System
   1. Intraventricular Hemorrhage (IVH) - no effect of ibuprofen on rates [4]
   2. Periventricular white-matter injury
   3. Hydrocephalus
   4. Longer term: cerebral palsy, cerebral atrophy, neurodevelopmental delay, hearing loss
   5. Ophthalmological problems
5. Cardiovascular
   1. Hypotension
   2. Patent ductus arteriosus
   3. Pulmonary hypertension
   4. Systemic hypertension in adulthood
6. Immunologic
   1. Hostpial-acquired infection
   2. Immune deficiency
   3. Perinatal infection
   4. Sepsis
7. Endocrine
   1. Hypoglycemia
   2. Transiently low thyroxine levels
   3. Cortisol deficiency
   4. Impaired glucose regulation, increased unslin resistance
   5. Isolated reduction in insulin sensitivity [45]
   6. VLBL associated with insulin resistance, glucose intolerance, elevated blood pressure [21]
8. All risks increase with decreasing birth weights and other factors as above

C. Specific Complications of Prematurity / Low Birthweight

1. Necrotizing Enterocolitis (NEC) [50,51]
   1. Severe inflammatory disorder of intestine occurs in premature infants
   2. A major cause of medical emergency, morbidity and death in neonates
   3. >90% of infants who develop NEC are preterm
   4. Degree of prematurity and birthweight are independent (related) risk factors for NEC
   5. >90% of infants who develop NEC have been fed eneterally
   6. Ingestion of human milk appears to be protective against NEC, with 3-10X reduced risk
   7. For perforated NEC, laparotomy and peritoneal draininge had similar outcomes [50]
   8. Mortality rate for perforated NEC is ~40% and has not improved in past 30 years
   9. NEC is distinct from spontaneous intestinal perforation (apparently increasing in frequency)
2. Neonatal Sepsis [18]
   1. Strongly associated with low Apgar scores
   2. Previously, most due to gram positive organisms, mainly group B streptococcus
   3. Increasingly caused by E. coli and other gram negative infections (~60%)
   4. E. coli resistance to ampicillin is increasing
   5. Increasing incidence of fungal infections, particularly candida
   6. May be associated with development of cerebral palsy
3. Fungal Infections [31]
   1. Increased risk of invasive fungal infections in preterm infants
   2. Especially high risk in infants <1000gm at birth
   3. Fungal colonization occurred in ~60% of <1000gm infants by 6 weeks
   4. Invasive fungal disease occurred in 20% of <1000gm infants by 6 weeks
   5. Prophylactic fluconaozle 3-6mg/kg qd in preterm neonates reduced invasive fungal infections and fungal colonization without significant side effects [19]
4. Patent Ductus Arteriosus (PDA)
   1. In normal infants, PDA usually closes by day 3 of birth
   2. In premature infants, failure of PDA to close is common
   3. Can usually be closed with cyclooxygenase inhibition using ibuprofen
   4. Prophylactic ibuprofen in premature infants (<28-31 weeks) incresases PDA closure and the need for surgical ligation but not mortality [3,4]
5. Retinopathy of Prematurity
   1. Most common cause of blindness in premature infants
   2. Currently accounts for about 12% of blindness in children in industrialized countries
   3. Due primarily to oxygen toxicity, exposure during neonatal intensive care
   4. Monitoring blood gases carefully reduces risk of blindness
6. Cognitive and Behavioral Outcomes [33,39]
   1. Highest risk of neurologic and developmental disability in extreme preterm (20-25 weeks' gestation) infants assessed at 30 months [26] and 6 years [46]
   2. ~50% had some significant developmental disability [26]
   3. At 6 years of age, 86% had significant moderate or severe disability [46]
   4. Increased risk for reduced cognitive scores and behavioral abnormalities related to gestational age at birth [33]
   5. However, most VLBW infants have improvement in verbal and IQ test scores over time [37]
   6. ELBW or very preterm infants have cognitive, educational and behavioral impairments by school age [39]
   7. Neonatal infections among ELBW infants associated with poor neurodevelopmental and growth outcomes in early childhood in large study [44]
   8. Infants with early onset IVH with significant central nervous system injury tend to lag win development scores compared with VLBW infants without IVH [37]
   9. Inhaled nitric oxide reduced brain injury (23.9% versus 17.5%) in preterm infants 500gm - 1250gm, gestational age <34 weeks [11]
   10. Inhaled nitric oxide appears to improve developmental outcomes, mainly cognition, at 2 years in premature infants with severe respiratory failure [48]
7. Cerebral Palsy and Pulmonary Dysfunction (see below)

D. Cerebral Palsy (CP) [12]

1. Due to permanent static lesion of cerebral motor cortex within 2 years of birth
2. About 50% of CP is associated with premature birth [13,14,15]
   1. Occured in ~4% of very low birthweight (1000-1500gm) babies in 1996 [17]
   2. Occurs in ~14% of extremely low birthweight babies
   3. Occurs in ~19% of survivors born 22-26 weeks gestation <1000gm
   4. Occurs in ~12% of survivors born 27-32 weeks gestation <1000gm
   5. ~11% of children with CP born at <28 weeks gestation
3. Other Risk Factors [14,15]
   1. Specific hypoxic event during gestation or after birth in <50% of cases
   2. Is not associated with lack of oxygen (asphyxiation) during birth
   3. Maternal fever exceeding 38°C in labor was associated with nearly 10X risk of CP
   4. Association with maternal infection occurred in normal weight babies
   5. Association with chorioamnionitis (4.0X risk) occurred in normal term babies [13]
   6. Urinary tract infecdtion present in ~20% of mothers with CP infants [15]
   7. 12% from multiple pregnancy (expected 1.5% in general population) [15]
   8. Among infants with CP born <34 weeks, most had white matter disease on MRI [15]
4. Symptoms
   1. Following birth, 28% with recurrent seizures, hairing impairment 7%, visual anomalies 33% [15]
   2. Over longer term, vary from mildly symptomatic to spastic quadraplegic type
   3. Spasticity is most common
   4. Lesions do not change as children grow, but manifestations of deficits do change
   5. Motor function improves in most children with CP, but at a rate slower than normal
5. Treatment
   1. Physiotherapy, occupational and speech therapy, pharmacologic therapy
   2. Spasticity: oral drugs, chemodenervation agents (alcohol, botulinum toxin A), intrathecal agents (such as baclofen) and/or surgery

E. Pulmonary Dysfunction [57]

1. Respiratory Distress Syndrome (RDS)
   1. Formerly called Hyaline Membrane Disease
   2. Histopathology is similar to ARDS
   3. Occurs primarily in premature infants
   4. Due to insufficient surfactant production by Type II Alveolar Cells
   5. Treat with exogenous surfactant and glucocorticoids which induce surfactant synthesis
   6. In women at risk for preterm birth <32 weeks, antenatal exposure to glucorticoids (such as
2. 4mg betamethasone weekly) until 32 weeks or delivery, reduced infant RDS ~20% [7]
   1. Natural and synthetic surfactants available for prevention and treatment of RDS [24]
   2. Exogenous surfactant improves lung function and mortality [24]
   3. Inhaled nitric oxide reduces death and chronic lung disease by ~25%, and combined periventricular leukomalacia + severe intraventricular hemorrhage ~45% [40]
   4. Inhaled nitric oxide reduces risk of any chronic lung disease and improved neurodevelopment in premature infants [40,48]
3. Pulmonary Interstitial Emphysema [60]
   1. Usually occurs in premature infants; occasionally in full term
   2. Typically in positive-pressure ventilation in infants with RDS
   3. Air in interstitial pulmonary tissue surrounding bronchi and blood vessels
   4. Multiple gas filled cysts can accumulate
   5. Recurrent pneumothorax is common
   6. Mortality rates high, morbidity with BPD
4. Bronchopulmonary Dysplasia (BPD) [34]
   1. Chronic pulmonary disorder occurring in premature infants (<30 weeks), <1500gm
   2. BPD occurs in ~20% of these <30 week infants
   3. increases morbidity and mortality (frequent hospital readmissions in first 2 years)
   4. Infants with respiratory insufficiency receiving supplemental oxygen and ventilatory support have the highest incidence
   5. Increasing incidence with decreasing birthweight
   6. Incidence up to 85% in 500-699gm infants; <5% in infants >1500gm
   7. Pathogenesis poorly understood but appears to be abnormal postnatal lung growth
   8. Acute and chronic lung injury occurs with fibrosis and remodeling
   9. High airway oxygen levels and pressures (barotrauma) may contribute
   10. Factors increasing inflammation (including oxygen and baro- toxicity) contribute
   11. Pulmonary hypertension, particularly on hypoxia, is prominent
   12. Increased risk for respiratory syncytial virus (RSV); prophylaxis indicated
   13. Inhaled nitric oxide reduces risk of BPD in premature infants, particularly >1000 gm (see below) [10,11,40,47]
   14. Exogenous surfactant reduces rate of death from BPD but does not prevent disease
   15. Few BPD patients remain oxygen dependent >2 years of age
   16. Minimizing use of mechanical ventilation, reduce oxygen toxicity, reduce pulmonary pressures will liekly reduce BPD incidence and severity
   17. Systemic glucocorticoids improve lung mechanics, gas exchange, and oxygen dependency but carry significant adverse risks
   18. Caffeine IV in infants 500-1250gm until gestational age 34 weeks reduced BPD [6]
   19. High dose anti-oxidants are being evaluated to prevent BPD
5. Chronic Lung Disease [35]
   1. Combination of syndromes described above
   2. Pulmonary immaturity, high ventilatory pressure, oxygen toxicity contribute
   3. Current treatment aims at mitigating each of these factors
   4. Minimal or no reduction of chronic lung disease in preterm infants by use of high frequency oscillatory ventilation [35,36]
   5. Inhaled nitric oxide reduces risk of any chronic lung disease in premature infants [40]
   6. inhaled nitric oxide does not appear to worsen lung development in premature infants <1000gm [10,11,47]
6. Apnea of Prematurity [6,56]
   1. Cessation of breathing for >15 seconds with hypoxemia or bradycardia
   2. Increased risk in infants 500gm-1250gm
   3. Risk exists for until infants reach gestational age 34-35 weeks
   4. Very common reason for initiating drug therapy in neonates
   5. Methylxanthines are prescribed until infants reach low risk age
   6. Caffeine 20mg/kg initially, then 5mg/kg qd, all intravenously is given
   7. Caffeine reduces apneic episodes and incidence of BPD
   8. Caffeine reduces risk of death or neurological disability from 46% (placebo) to 40%
   9. Caffeine associated with reduced incidence of cerebral palsy from 7.3% (placebo) to 4.4%
7. Glucocorticoids significantly reduced severe lung disease in high risk preterm infants [7]

F. Treatment of Preterm Infants

1. Glucocorticoids are effective for many of the problems of infants
   1. betamethasone 12mg im q24 hrs x 2 doses or Dexamethasone 6mg q12 hrs x 2 doses
   2. Few adverse effects on mother or infant
   3. Should be given to all infants <34 weeks and most 34-38 weeks each week
   4. Should be used for PROM (though less effective in this situation)
   5. Decreases risk of death, RDS, and IVH in preterm infants
   6. Glucocorticoids should be used in preterm infants >1000gm
   7. Glucocorticoids increase gastrointestinal perforation and do not reduce death or chronic lung disease in extremely low birthweight (<100gm) babies [27]
   8. Systemic glucocorticoids given to preterm infants at risk may decrease risk of BPD [34]
   9. Reduced risk of pulmonary disease when betamethasone 11.4mg IM weekly given to women at high risk of prematurity <32 weeks gestation [7]
   10. Inhaled glucocorticoids do not reduce risk of BPD, but reduced use of systemic steroids
   11. Antenatal thyrotropin releasing hormone (TRH) adds no benefit to glucocorticoids
   12. Single dose of antinatal glucocorticoids as effective as multiple doses in women at risk for preterm delivery, with reduced side effects [30]
   13. With multiple versus single doses of antenatal glucocorticoids, at 2-3 years there were no significant differences in clinical outcomes amongst the two groups of infants [54,55]
   14. Reduced use of postnatal glucocoticoids may lead to reduced neurosensory disabilities [22]
2. Mechanical ventilation is required in most infants at risk for RDS (500-800gm)
3. Respiratory Distress Syndrome (RDS)
   1. Glucocorticoids - helps induce local surfactant production and lung maturation
   2. Exogenous Surfactant - very effective
   3. Nitric oxide appears beneficial in various forms of respiratory failure
4. Nitric Oxide
   1. Nitric oxide (inhaled) may reduce pulmonary hypertension and ventilator time [8,9]
   2. Nitric oxide begun age 7-21 days in infants birthweight <1250gm reduced development of BPD and hospital stay without any short-term safety concerns [10]
   3. Nitric oxide for preterm infants <34 weeks and weight 1000-1250gm reduced incidence of BPD ; no effect on BPD in infants 500-1000gm [11]
   4. Nitric oxide for preterm infants <34 weeks and weight 500-1250gm reduced incidence of brain injury (17.5% with nitric oxide; 24% with placebo) [11]
   5. Nitric oxide has had variable effects on overall mortality in hypoxic premature infants [8,10]
   6. Nitric oxide appears beneficial in term and in some (mainly >1000gm) preterm infants [61]
5. NEC is very difficult to treat and may require intestinal resection
6. Magnesium
   1. Some reduced risk of CP and mortality in preterm infants [20]
   2. Significantly reduced risk of substantial gross motor dysfunction [20]
   3. No effect on infant mortality when used in preterm labor [20]
7. Fluconazole given intravenously for first 6 weeks of life prevented invasive fungal disease [31]

G. Prognosis

1. Mainly depends on length of gestation and size of infant
2. Overall mortality in infants 501-800gm is ~45%
3. Initiation of mechanical ventilation is a risk factor against survival
4. Premature female infants at a given weight are at lower risk of death compared with male
5. Blacks have a lower death rate than whites
6. Hospitalization was 115 days for survivors in the 501-800gm class
7. Young adults from very low birth weight infants have increased risks of neurosensory impairment and 5 point lower IQ than normal weight infants [32]
8. Outcomes for Extremely Low Birth Weight Infants [22]
   1. Cerebral palsy in 14%; 0% in normal birth weight infants (NBW)
   2. Vision <20/200 in 10%; 3% in NBW
   3. Intelligence quotient (IQ) <85 in 38%; 14% in NBW
   4. Limited academic skills in 37%; 15% in NBW
   5. Poor motor skills 47%; 10% in NBW
   6. Poor adaptive functioning 69%; 34% in NBW
   7. Asthma 20%; >8% in NBW
   8. Mild hearing loss: >10%; >5% NBW

H. Preventing Preterm Labor [1,2]

1. Treatment of pregnant women with infections clearly reduces risk of preterm birth
   1. Urinary tract (UTI) and vaginal infections are of particular concern
   2. Strongly consider treatment of bacterial vaginosis with metronidazole for at least 7 days
   3. Treatment of asymptomatic UTI in pregnancy reduces preterm birth rates
   4. Glucocorticoids are given to all women at risk of preterm delivery at 34 weeks gestation
   5. Routine screening of low-risk women for bacterial vaginosis is not recommended [58,59]
2. Agents to Postpone Parturition (Delivery) [2]
   1. Agents that inhibit myometrial contraction are called tocolytics
   2. Calcium channel blockers
   3. ß2-adrenergic agonists
   4. Cyclooxygenase (COX1/2) inhibitors
   5. Oxytocin receptor antagonists
   6. Nitric oxide donors
   7. Magnesium sulfate is not effective and should not be used
   8. May only be effective in early phases of labor
   9. May delay labor 24-48 hours, allow glucocorticoids to induce surfactant production
   10. Do not use tocolytics for more than 48 hours
3. Calcium Channel Blockers
   1. Reduce risk of birth within 7 days by 24% compared with other tocolytic agents
   2. Nifedipine is most often used and is reasonable first choice tocolytic
   3. Associated with reduced risk of neonatal respiratory distress, necrotizing enterocolitis, intraventricular hemorrhage, neonatal jaundice
4. ß2-Adrenergic Agonists
   1. Albuterol
   2. Terbutaline
   3. Ritodrine (the only tocolytic actually approved by FDA)
   4. Isoxsuprine
   5. Increase cAMP in muscle cells and inhibit contraction
   6. Reduces preterm delivery rate ~37% (delay in delivery >48 hours)
   7. Have not shown reduction in neonatal morbidity or mortality
5. Cyclooxygenase (COX) inhibitors
   1. Indomethacin is typically used; naproxen and fenoprofen also effective
   2. COX-2 specific agents are likely preferred
   3. Nonspecific COX inhibitors promote closure of ductus arteriosus after 32 weeks
   4. Associated with significant neonatal complications and should be tertiary therapy
   5. Very reasonable choice for gestations <32 weeks
6. Progesterones
   1. 17alpha-hydroxyprogesterone caproate (17-HPC) weekly 250mg IM beginning 16-20 weeks' singleton gestation reduced risk of delivery <35 weeks by 33% [41]
   2. 17-HPC weekly at 16-20 weeks' twin gestation did not reduce premature delivery rate [52]
   3. Vaginal progesterone 200mg qhs reduced deliveries of <34 weeks gestation from 34% on placebo to 19% and reduced neonatal morbidity in women with a short (<15mm) cervix [53]
7. Other Agents
   1. Atosiban - oxytocin receptor antagonist; no benefit noted across 6 trials
   2. Potassium channel opener (levcromakalim) - under investigation
   3. ß3-adrenergic agonists
   4. Various kinase inhibitors
8. Ineffective
   1. No convincing evidence that bed rest and/or hydration prevent premature birth
   2. Hydration may induce congestive heart failure, as pregnancy is a fluid overloaded state
   3. Early identification of preterm labor with home monitoring appears not to affect outcomes
   4. Zinc and/or folate supplementation does not affect preterm birth rates
9. In women with an incompetent or weak cervix, stitches in the cervical area ("cerlage") do appear to reduce preterm births (but 25 cerclages for every preterm birth prevented)

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