Preterm Labor and Delivery Overview: Risk Factors, Prevention & Treatment

Preterm Labor & Delivery A S H T O N T. A V E R I T T D N P, CRNA Introduction Preterm delivery is defined as delivery before 37 weeks gestation. It occurs in 5% to 9% of pregnancies in developed countries and is responsible for 75% to 80% of all neonatal deaths and significant neonatal morb...

Preterm Labor & Delivery A S H T O N T. A V E R I T T D N P, CRNA Introduction Preterm delivery is defined as delivery before 37 weeks gestation. It occurs in 5% to 9% of pregnancies in developed countries and is responsible for 75% to 80% of all neonatal deaths and significant neonatal morbidity. Preterm delivery leads to a large economic burden on society. In the US, the cost associated with preterm birth was at least 26.2 billion dollars. There is notable racial/ethnic disparity in the frequency of preterm birth. In 2015, 9.0% of non-Hispanic whites, 13.8% of non-Hispanic blacks, and 9.5% of Hispanics delivered preterm. Late preterm is defined as 34 0/7 to 36 6/7 completed weeks gestation. Early preterm is defined as less than 34 completed weeks of gestation. Introduction The concern about preterm birth is not confined to the United States; the World Health Organization (WHO) and other non-governmental organizations have identified the frequency of preterm birth as a critical health issue. Worldwide, yearly, 15 million infants are born preterm. More than 60% of preterm births occur in Africa and South Asia, with Malawi having the highest rate (18.1 per 100 live births). The global neonatal mortality rate is 19 per 1000 live births. Definitions A preterm infant is defined as one who is born between 20 0/7 weeks and 36 6/7 weeks, inclusive, after the first day of the last menstrual period. ACOG has defined peri-viable birth as birth between 20 weeks and 25 6/7 weeks gestation. If a good basis does not exist for establishing the gestational age from either maternal history or first-trimester ultrasound, the exact gestational age is difficult to determine. A low birth weight (LBW) does not necessarily signify that a neonate has been born preterm because newborns have an LBW because they are small for gestational age (SGA) rather than preterm. A neonate who weighs less than 2500 g at birth is considered to have an LBW, regardless of gestational age. An infant who weighs less than 1500 g at birth is considered to have a very low birth weight (VLBW) and an infant who weighs less than 1000 g at birth is considered to have an extremely low birth weight (ELBW). Definitions Classification of deliveries based on gestational age Classification Gestational Age Extremely preterm Less than 28 weeks Very preterm 28 0/7 to 31 6/7 weeks Moderate preterm 32 0/7 to 33 6/7 weeks Late preterm 34 0/7 to 36 6/7 weeks Early preterm 37 0/7 to 38 6/7 weeks Full term 39 0/7 to 40 6/7 weeks Late term 41 0/7 to 41 6/7 weeks Post term 42 0/7 weeks and beyond Neonatal Mortality The survival rate among neonates increases as the birth weight and/or gestational age increases. After data are controlled for gestational age and weight, male infants have a higher mortality than female infants. During the past 3 decades, there has been significant improvement in the survival rate for preterm infants, with the greatest improvement occurring in the subgroup with a birth weight between 501 and 1250 grams. The rate of neonatal survival now is approximately 94% for infants born at 28 weeks gestation. Infants born at the threshold of viability (22 to 24 weeks gestation) continue to have the greatest risk for poor outcomes. Neonatal Mortality Neonatal deaths by gestational age Completed weeks gestation Percentage of Deaths 22 93% 23 68% 24 38% 25 23% 26 15% 27 10% 28 8% Neonatal Mortality Neonatal survival was 9% at 22 weeks, 33% at 23 weeks, and then 65%, 81%, and 87% at 24-, 25-, and 26-week gestation, respectively. The majority of women received antenatal corticosteroids, and the majority of neonates received exogenous surfactant. A delay in delivery of even 1 week at this time in gestation leads to significantly better outcomes and reduced costs. Neonatal Morbidity Approximately 84% of preterm births occur between 32 0/7 and 36 6/7 weeks gestation. Compared with earlier gestational ages, mortality is less common, but morbidity is a relatively greater concern in this gestational age range. Researchers have examined the association between late preterm birth and neurocognitive performance in late adulthood; those who were born between 34- and 37 weeks gestation had lower scores on tests evaluating neurocognitive performance than those born after 37 weeks gestation. As with mortality, most morbidity decreases in frequency as gestational age increases. The incidence of high-grade (III or IV) intraventricular hemorrhage diminishes rapidly after 27 weeks gestation, and grade III or IV intraventricular hemorrhages are very rare after 32 weeks gestation. Neonatal Morbidity Selected outcomes for extremely preterm infants (22 – 24 weeks gestation) Outcome Percent Use of Antenatal therapy Maternal corticosteroid administration 64% Maternal antibiotic administration 66% Cesarean Delivery 38% Male gender 52% Multiple birth 27% Surfactant therapy after birth 66% Death before discharge 64% Survival without neurodevelopmental impairment 20% Survival without neurosensory impairment 29% Preterm Labor – Risk Factors Significant risk factors include a history of preterm delivery, non-Hispanic black race (irrespective of socioeconomic status), and multiple gestation. The process of normal parturition involves anatomic, physiologic, and biochemical changes that lead to (1) greater uterine contractility, (2) cervical ripening, and (3) membrane / decidual activation. The fetus also appears to play a role in parturition. Preterm delivery results from (1) preterm premature rupture of membranes (PPROM) in approximately 25% of cases, (2) spontaneous preterm labor in approximately 45% of cases, and (3) maternal or fetal indications for early delivery in approximately 30% of cases. However, the “spontaneous” causes do not have a uniform underlying pathophysiology, and it appears that preterm labor is a syndrome with multiple causes influenced by a number of genetic, biologic, biophysical, psychosocial, and environmental factors. Preterm Labor – Risk Factors Two factors of interest are the influences of infection and uterine distention on initiation of myometrial contractility. Infection is thought to be present in up to 40% of preterm deliveries. Although approximately 50% of preterm deliveries occur in women with no apparent risk factors, subclinical infection may precipitate preterm labor in some of these cases. In addition, infection compounds the effects of preterm birth with increased rates of neurologic injury. Multiple gestation accounts for 21.6% of all preterm births. In the past three decades, there has been a significant rise in the incidence of multiple gestation, attributed to a shift toward older maternal age at conception, and to increased use of assisted reproductive technology (ART). The twinning rate rose 76% from 1980 to 2009 (from 18.9 to 33.2 per 1000). Recently, rates of multifetal pregnancies have started to decline. Preterm Labor – Risk Factors The twin birth rate peaked at 33.9 twins per 1000 births in 2014 and has since decreased to 33.4 in 2016. Likewise, the triplet and higher-order multiple birth rate has fallen 48% since the 1998 peak (193.5) to a rate of 101.4 multiples per 100,000 births in 2016. Modification in ART may be contributing to changes in the preterm birth rate and recent declines in multiple gestation. In 2015, ART contributed to 1.7% of all infants born in the United States and 17.0% of all multiple-birth infants, including 16.8% of all twin infants and 22.2% of all triplets and higher-order infants. The risk for preterm birth is elevated even for singleton pregnancies conceived by ART. Placenta previa, gestational diabetes, pre-eclampsia, and neonatal intensive care unit admission were also more prevalent in the ART group. Preterm Labor – Risk Factors Factors associated with spontaneous preterm labor Demographic & Medical Characteristics Non-Caucasian race Extremes of age (less than 17 or greater than 35) Low socioeconomic status Low pre-pregnancy body mass index History of preterm delivery Periodontal disease Abnormal uterine anatomy Trauma Abdominal surgery during pregnancy Preterm Labor – Risk Factors Factors associated with spontaneous preterm labor Behavioral Factors Tobacco use Substance abuse Preterm Labor – Risk Factors Factors associated with spontaneous preterm labor Obstetric Factors Previous preterm birth Vaginal bleeding Infection (systemic, genital tract, periodontal) Short cervical length Multiple gestation Assisted reproductive technologies Preterm premature rupture of membranes Polyhydramnios Preterm Labor – Prediction The ability to prevent spontaneous preterm birth would be facilitated if it were possible to intervene prophylactically to prevent preterm labor or to effectively treat preterm labor once it occurs. Both prophylactic and treatment would require the ability to accurately predict which asymptomatic patients will go on to have spontaneous preterm delivery. Short cervical length, as assessed by transvaginal ultrasonography, is associated with a greater risk for preterm delivery. A history of cervical surgery, including conization and loop electrosurgical excision procedure, traditionally has been thought to be a risk factor for preterm birth because of associated cervical injury. However, this relationship may be related to environmental factors and/or behavioral factors that underlie the progression of cervical dysplasia. Preterm Labor – Prevention Few, if any, interventions have been shown to reduce the incidence of preterm labor and delivery. Interventions that have been studied include detection and suppression of uterine contractions, antimicrobial therapy, prophylactic cervical cerclage, maternal nutritional supplements, and reduction of maternal stress. Prophylactic cervical cerclage in the early second trimester has been performed to prevent preterm birth, typically in women with a history of mid-trimester pregnancy loss. Evidence supporting the efficacy of this practice is weak. Evidence does NOT support the administration of prophylactic antibiotics in asymptomatic women at risk for preterm labor. Likewise, evidence does not support the prophylactic use of beta-adrenergic receptor agonists to prevent preterm labor in high-risk women. Preterm Labor – Prevention Evidence suggests that progesterone therapy may be effective in reducing the rate of preterm birth in some patient populations. Progesterone therapy has also been shown to be beneficial in reducing the incidence of preterm delivery in the subset of women with a sonographically identified short cervix. Several studies have examined whether progesterone is efficacious in reducing preterm birth among women with multiple gestation. A recent meta-analysis comparing progesterone (both vaginally and intramuscularly), pessary, and cervical cerclage found that vaginal progesterone may be beneficial in twin pregnancy. Preterm Labor – Diagnosis Determining whether a woman is in early preterm labor or in false labor is often difficult. Criteria for the diagnosis of preterm labor include gestational age between 20 0/7 and 36 6/7 weeks gestation and regular uterine contractions accompanied by a change in cervical dilation, effacement, or both (or initial presentation with regular contractions and cervical dilation of 2 cm or more). Less than 10% of women with the clinical diagnosis of preterm labor give birth within 7 days of presentation.  Preterm Labor – Assessment & Therapy Initial assessment of the patient with possible preterm labor includes physical examination and external monitoring of contractions with a tocodynometer (and fetal heart rate if indicated by gestational age). Acute conditions associated with preterm labor should be considered, including infection and placental abruption. In many women who have preterm uterine contractions, these contractions will cease spontaneously. Once the diagnosis of preterm labor is established, the obstetric care provider must decide whether intervention is warranted. The administration of antenatal corticosteroids for fetal lung maturation and magnesium sulfate for fetal neuroprotection is associated with improved neonatal outcomes.  Preterm Labor – Assessment & Therapy Although widely used before 34 weeks gestation, acute tocolytic therapy remains a source of controversy. Tocolysis is currently recommended between 24- and 34 weeks gestation. There is no consistent evidence that the use of acute tocolysis reduces the chance of preterm birth or improves neonatal outcomes. However, because acute tocolysis has been associated with a short (approximately 48- hour) prolongation of pregnancy, it may be used to facilitate the transfer of the patient from a community hospital to a tertiary care facility that can provide optimal care for the preterm neonate. Moreover, a short course of tocolytic therapy may delay delivery for 24 to 48 hours, allowing maternal administration of (1) a corticosteroid to accelerate fetal lung maturity and (2) antibiotic therapy to prevent neonatal group B streptococcal infection. Preterm Labor – Assessment & Therapy Thus, ACOG supports the use of acute tocolysis to allow the administration of a complete course of antenatal corticosteroids but discourages the continued use of tocolysis after corticosteroid administration is complete. Criteria for the use of tocolytic therapy include (1) gestational age after viability (23 weeks) and before 34 weeks gestation, (2) reassuring fetal status, and (3) no overt clinical signs of infection. Preterm Labor – Assessment & Therapy Contraindications to Tocolytic therapy for preterm labor Fetal death Fetal anomalies incompatible with life Nonreassuring fetal status Chorioamnionitis Severe hemorrhage Preterm Labor – Corticosteroids The neonatal benefit of corticosteroid administration before preterm delivery has been demonstrated. Antenatal corticosteroid treatment significantly reduces the incidence of neonatal respiratory distress syndrome, intraventricular hemorrhage, and neonatal death in all subgroups of the population. The reduction in neonatal morbidity and mortality from corticosteroid administration is additive to the reduction observed with the use of neonatal surfactant alone. A single course of corticosteroids administered to women at risk for preterm birth after 34 weeks but before 37 weeks gestation resulted in a significantly lower incidence of severe neonatal respiratory morbidity. Preterm Labor – Corticosteroids Antenatal Corticosteroid Therapy Drug Dose and Route Frequency / Duration Betamethasone 12 mg IM Every 24 H X 2 Dexamethasone 6 mg IM Every 12 H X 4 Preterm Labor – Antibiotic Therapy The results of a large, multicenter, randomized controlled trial and a meta-analysis do NOT support the use of prophylactic antibiotic therapy in the management of preterm labor in patients with intact membranes as a method to reduce the likelihood of preterm birth. There was an increase in cerebral palsy in children born to mothers in preterm labor with intact membranes who received any prophylactic antibiotics versus no antibiotics. Accordingly, ACOG does NOT recommend empirical antibiotic therapy in this population. Prophylactic antibiotic administration remains appropriate in women who are positive for group B streptococcus (GBS) and who are thought to be in preterm labor. In patients with PPROM, antimicrobial therapy prolongs pregnancy and reduces both maternal and neonatal morbidity. Thus, when PPROM is diagnosed, ACOG recommends a 7-day course of antimicrobial therapy. Preterm Labor – Neuroprotection Several clinical trials have provided evidence that maternal administration of magnesium sulfate provides fetal neuroprotection when given to women at risk for preterm delivery. Investigators observed no significant difference between groups in the primary outcomes, which included total pediatric mortality, cerebral palsy, or both, at a corrected age of 2 years. However, they observed a significantly reduced rate of substantial gross motor dysfunction, as well as a reduced combined rate of death or substantial gross motor dysfunction, in the children exposed to magnesium sulfate in utero. ACOG has stated that, based on available evidence, magnesium sulfate, given before anticipated early preterm birth, reduces the risk of cerebral palsy in surviving infants. Because the best regimen for administering magnesium sulfate remains unclear, physicians electing to use magnesium sulfate for neuroprotection should develop specific guidelines based on the protocols of larger trials regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring. Preterm Labor – Rescue Cerclage Prophylactic cervical cerclage is typically performed when the cervix is closed. A rescue cerclage (also known as emergency or physical exam-indicated cerclage) is typically a procedure to prolong gestation in women with cervical dilation and/or prolapsed membranes. The efficacy and safety of this procedure remain controversial. Contraindications include (1) established preterm labor with impending preterm birth, (2) chorioamnionitis, (3) heavy vaginal bleeding, (4) preterm PROM, (5) fetal demise, (6) major fetal anomalies, and (7) fetal death. When placing the cerclage, prolapsing membranes need to be replaced in the uterine cavity to reduce the risk for iatrogenic preterm PROM. Purse-string sutures are placed around the circumference of the cervix. Preterm Labor – Rescue Cerclage Only one small randomized controlled trial has compared rescue cerclage with bed rest compared with bed rest alone. Improved outcomes were reported in the cerclage group, including prolongation of gestation by 4 weeks and reductions in the rates of neonatal intensive care unit admission and neonatal death. Preterm Labor – Cerclage Removal Cerclage removal does not routinely precipitate the labor process. When vaginal delivery is planned, it is recommended to proceed with removal at 36 to 37 weeks gestation. In cases of planned cesarean delivery, it is permissible to defer cerclage removal until delivery. However, labor may occur before the planned delivery date, and removal may need to be performed urgently. Management of preterm labor should not be influenced by the presence of a cerclage; if the patient demonstrates cervical change, painful contractions, or vaginal bleeding, the cerclage should be removed. Given current evidence, it is reasonable to either remove or retain the cerclage after diagnosis of preterm PROM. However, if cerclage is retained, women should receive 7 days of antibiotic prophylaxis. Preterm Labor – Cerclage Removal Cerclage removal is usually a straightforward procedure. With the patient in the dorsal lithotomy position, a speculum is inserted. The suture is grasped with rings, and the suture beneath the knot is transected with scissors. In most cases, elective removal of a cerclage in an office setting is appropriate. Occasionally the entire stitch becomes embedded within the cervical mucosa (buried), and neuraxial anesthesia may be required to facilitate cervical dissection and cerclage removal. Preterm Labor – Tocolysis Once the obstetrician has decided to begin tocolytic therapy, an appropriate agent must be selected. There are four classes of tocolytic agents currently in use (1) beta-adrenergic receptor agonists, (2) calcium entry-blocking agents, (3) magnesium sulfate, and (4) nonsteroidal anti-inflammatory drugs. A 2014 analysis suggested that magnesium sulfate is not efficacious and should not be used for tocolysis. Preterm Labor – Tocolysis Tocolytic Drugs for Preterm Labor Drug Contraindications Maternal Side Fetal Side Effects Effects Calcium entry-blocking Cardiac disease Transient hypotension, None identified. agents Renal disease flushing, headache, Maternal hypotension dizziness, nausea Cyclooxygenase Significant renal/hepatic Nausea Constriction of the ductus inhibitors (NSAIDs) impairment Heartburn arteriosus Active PUD Pulmonary hypertension Coagulation disorders Reversible renal Thrombocytopenia dysfunction NSAID-sensitive Asthma Intraventricular Other NSAID sensitivities hemorrhage Hyperbilirubinemia Necrotizing enterocolitis Preterm Labor – Tocolysis Tocolytic Drugs for Preterm Labor Drug Contraindications Maternal Side Effects Fetal Side Effects Beta-Adrenergic Cardiac dysrhythmias Dysrhythmias, pulmonary Fetal = tachycardia, Receptor Poorly controlled thyroid edema, myocardial hyperinsulinemia, Agonists disease ischemia, hypotension, hyperglycemia, myocardial Poorly controlled diabetes tachycardia and septal hypertrophy, mellitus Hyperglycemia, myocardial ischemia. hyperinsulinemia, Neonatal = tachycardia, hypokalemia, antidiuresis, hypoglycemia, altered thyroid function hypocalcemia, Palpitations, tremors, hyperbilirubinemia, nervousness, hypotension, intraventricular nausea/vomiting, fever, hemorrhage. hallucinations. Magnesium Myasthenia Gravis Flushing, lethargy, Lethargy, hypotonia, Sulfate Myotonic Dystrophy headache, muscle respiratory depression, weakness, diplopia, dry demineralization Preterm Labor – Physiology of Uterine Contractions Myometrial smooth muscle consists of thick (myosin) and thin (actin) filaments that slide past one another and thereby lead to the contractile force of uterine contractions. The myometrium also has pacemaker cells; electrical activity is spread by gap junctions between myometrial cells. A rise in intracellular calcium concentration from influx across the sarcolemma and/or release from internal calcium stores leads to contractions. Hormones and neurotransmitters may also regulate uterine activity through agonist- induced entry of calcium or other ions by means of receptor-controlled channels and the release of internally stored calcium. Calcium binds to calmodulin, which then activates myosin light-chain kinase (MLCK), leading to phosphorylation of the light-chain subunit of myosin. Preterm Labor – Physiology of Uterine Contractions This phosphorylation allows actin to bind to myosin, with the subsequent activation of myosin adenosine triphosphatase. Adenosine triphosphatase (ATP) is then hydrolyzed, and muscle shortening or contraction results. Increases in intracellular cyclic adenosine monophosphate (cAMP) cause muscle relaxation by (1) activation of a cAMP-dependent protein kinase, which decreases the activity of MLCK, and (2) a reduction of the intracellular calcium concentration. Preterm Labor – Physiology of Uterine Contractions The actual signals for the onset of contractions and labor, however, are complex and incompletely understood. Before labor, the uterus is in a state of functional quiescence as a result of various inhibitors, including progesterone, prostacyclin, relaxin, nitric oxide, parathyroid hormone-related peptide, corticotropin-releasing hormone, human placental lactogen, calcitonin gene-related peptide, adrenomedullin, and vasoactive intestinal peptide. Before term, the uterus goes through an activation phase characterized by (1) greater expression of a series of contraction-associated proteins (including myometrial receptors for prostaglandins and oxytocin), (2) activation of certain ion channels, and (3) an increase in connexin-43 concentration. Preterm Labor – Physiology of Uterine Contractions Expression of the oxytocin receptor in the human myometrium is tightly regulated during pregnancy. Its levels increase during gestation, with a relative paucity of receptors in mid-gestation, accumulation in the third trimester, and peak at labor onset. The receptors fall sharply in advanced labor and the postpartum period when the uterus becomes refractory to oxytocin. In recent years, the hormonal control of human parturition has been linked to progesterone signaling, and it appears that human parturition may be triggered by a functional progesterone withdrawal, mediated at least in part by changes in progesterone receptors transcriptional activity. It is also thought that parturition may be related to changes in inflammation, which itself is linked to functional progesterone withdrawal.  Preterm Labor – Efficacy of Tocolytic Therapy There is a consensus that cute tocolytic therapy (of any type) for the treatment of preterm labor offers only limited benefits and does not reduce the rate of preterm birth. According to a network meta-analysis, the probability of delivery being delayed by 48 hours was highest with prostaglandin synthesis inhibitors followed by magnesium sulfate, calcium entry-blocking agents, beta-adrenergic agonists, and the oxytocin receptor blocker, atosiban. No class of tocolytic was significantly superior to placebo in reducing neonatal respiratory distress syndrome. Meta-analysis has also suggested that calcium entry-blocking agents (nifedipine), which block calcium inflow into cells through voltage-dependent calcium channels, have benefits over beta-adrenergic receptor agonists for prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects. Preterm Labor – Efficacy of Tocolytic Therapy Although beta-adrenergic receptor agonists (ritodrine, terbutaline), which relax smooth muscle via beta-adrenergic receptor stimulation, were used as a tocolytic agent for many years, in current practice, they are utilized less than other tocolytic agents that are equally efficacious with fewer side effects. In 2011, the United States FDA issued a warning regarding terbutaline use. Specifically, it stated that injectable terbutaline should not be used in pregnant women for prolonged treatment (beyond 48-72 hours) of preterm labor in either the hospital or outpatient setting because of the potential for marked maternal cardiac problems and death. It also noted that oral terbutaline should not be used for the prevention or treatment of preterm labor because it was not effective and was associated with similar safety concerns. Preterm Labor – Efficacy of Tocolytic Therapy Prostaglandins are mediators in the final pathways of uterine contraction. They increase intracellular calcium concentrations, increase activation of MLCK, and promote gap junction formation. The non-selective cyclooxygenase inhibitor indomethacin is the agent in this case most often studied as a tocolytic agent. Serious maternal side effects are uncommon. Fetal concerns, in the setting of prolonged use (greater than 48 hours), include a risk of constriction of the ductus arteriosus and oligohydramnios (caused by fetal renal dysfunction). The oxytocin receptor antagonist atosiban has also been used as a tocolytic agent. Although available in Europe, the drug was not approved by the FDA because of the finding from an RCT that women in the atosiban group had a higher rate of fetal death. Preterm Labor – Efficacy of Tocolytic Therapy Magnesium sulfate also has been used as a tocolytic agent. A 2014 meta-analysis concluded that magnesium is ineffective in delaying or preventing preterm birth and has no apparent advantages for a range of neonatal and maternal outcomes as a tocolytic agent, and its use for this indication may be associated with an increased risk for total fetal, neonatal, or infant mortality. The nitric oxide donor nitroglycerin has also been evaluated for its efficacy as a tocolytic. However, findings from meta-analyses indicate that nitroglycerin does not result in significantly later gestational age at delivery or better neonatal outcomes compared with placebo or other tocolytic drugs. Preterm Labor – Efficacy of Tocolytic Therapy ACOG has stated that evidence supports the use of tocolytic treatment with beta- adrenergic receptor agonist therapy, calcium entry-blocking agents, or NSAIDs for short-term prolongation of pregnancy (up to 48 hours) to allow for antenatal maternal corticosteroid administration. Multiple clinical trials have demonstrated that prolonged use of tocolytic agents (as prophylactic therapy or after completion of acute treatment) does not alter outcomes. No matter which tocolytic agent is chosen, the risk for side effects appears to increase when more than one tocolytic agent is administered simultaneously. It is unclear whether a combination of tocolytic drugs for preterm labor is more effective for women and/or newborns because there is a lack of large, well-designed trials that include the outcomes of interest. Preterm Labor – The Preterm Infant Physiology The preterm fetus has lower hemoglobin concentration and oxygen-carrying capacity than a term fetus. Preterm infants are at risk for several complications, including (1) respiratory distress syndrome, (2) hyperbilirubinemia, (3) necrotizing enterocolitis, (4) intraventricular hemorrhage, (5) perinatal infection, (6) retinopathy of prematurity, (7) patent ductus arteriosus, (8) pulmonary hypertension, (9) water, and electrolyte imbalances, (10) acid-base disturbances, ((11) anemia, and (12) hypoglycemia. In the long term, preterm infants also are more likely to experience adverse outcomes such as (1) bronchopulmonary dysplasia, (2) reactive airway disease, (3) failure to thrive, (4) cerebral palsy, (5) neurodevelopmental delay, (6) hearing loss, (7) blindness, (8) pulmonary hypertension, (9) adult hypertension, and (10) impaired glucose metabolism. Preterm Labor – The Preterm Infant Method of Delivery For very preterm infants, especially less than 26 weeks gestation, there is controversy regarding the best mode of delivery. Preterm birth at any gestational age is NOT considered a contraindication for trial of labor. A systematic review comparing elective with selective cesarean delivery for preterm infants found no difference in outcomes between groups, although the confidence intervals were wide because of the small number of patients included in the analysis. Aside from operative risks in the index pregnancy, preterm cesarean delivery may increase maternal risk in subsequent pregnancies. The survival rate remains low for infants with a birth weight between 500 and 750 grams. In these cases, obstetricians must decide whether to recommend cesarean delivery for fetal indications, such as in the cases of non-reassuring fetal heart status or breech presentation. Preterm Labor – The Preterm Infant Ethical Issues The antenatal maternal administration of corticosteroids, the application of advanced neonatal ventilation techniques, the use of neonatal surfactant therapy, and the use of extracorporeal membrane oxygenation (ECMO) have reduced mortality and morbidity for preterm neonates. However, below a certain gestational age (less than 22 0/7 to 23 0/7 weeks), survival is not typically possible, and the relationship between new treatments and reduced mortality is not relevant. Around the time when survival becomes at least possible, the chance of survival, and particularly survival without long-term major adverse outcomes, remains low and difficult to predict. These uncertainties often lead to controversy about the decision to resuscitate (or not resuscitate) a preterm infant. Parents, obstetricians, and neonatologists should all be involved in the decision-making process. Preterm Labor – The Preterm Infant Ethical Issues Withholding and/or discontinuation of life-sustaining treatment during or following resuscitation are considered by many to be ethically equivalent, and it is considered reasonable to withdraw support when the possibility of functional survival is highly unlikely. In cases of very early gestation (gestational age less than 22 to 23 weeks), extremely low birth weight (less than 400 grams), and life-limiting anomalies, resuscitation is generally not indicated. Resuscitation is nearly always indicated in conditions associated with a high survival rate and acceptable morbidity. This will generally include infants with a gestational age of 25 weeks or above.  Preterm Labor – Anesthetic Management Anesthesia providers often participate in the care of women with preterm delivery. Many women who deliver preterm request neuraxial analgesia for labor and vaginal delivery. These patients may also require cesarean delivery, for example, in situations of non- reassuring fetal status, and may require urgent administration of anesthesia. The preterm fetus is more vulnerable than the term fetus to the depressant effects of analgesic and anesthetic drugs for the following reasons: (1) less protein available for drug binding, leading to a reduction in protein-drug affinity, (2) higher levels of bilirubin, which may compete with the drug for protein binding, (3) greater drug access to the CNS because of the presence of an incomplete BBB, (4) decreased ability to metabolize and excrete drugs, and (5) a higher incidence of acidosis during labor and delivery. Preterm Labor – Anesthetic Management (Vaginal Delivery) Neuraxial labor analgesia decreases maternal concentrations of catecholamines, ameliorates cycles of maternal hypoventilation and hyperventilation, and may thereby improve uteroplacental perfusion as long as hypotension is avoided. The timing of the intrapartum administration of neuraxial analgesia in preterm parturients may be problematic for several reasons: (1) there may be uncertainty as to whether women who have contractions are in labor, (2) even women with a clear diagnosis of preterm labor often have a prolonged latent phase of labor, with or without the use of tocolytic agents, and (3) once active labor begins, patients often progress through labor very quickly. Thus, in some cases, it may be appropriate to establish neuraxial analgesia even before it is clear that a preterm delivery will soon occur. An advantage of early initiation of neuraxial analgesia is the ability to rapidly convert labor analgesia to surgical anesthesia if emergency cesarean delivery should be necessary. Preterm Labor – Anesthetic Management (Cesarean Delivery) Administration of general anesthesia for preterm cesarean delivery is similar to that for parturients at term. Most anesthetic agents that are used for induction and maintenance of general anesthesia cross the placenta. If cesarean delivery is necessary, it is preferable to administer either epidural or spinal anesthesia to avoid the depressant effects of agents given for general anesthesia. Preterm infants exposed to epidural anesthesia for cesarean delivery had higher 1- and 5- minute APGAR scores than similar infants exposed to general anesthesia. Data from animal studies suggest that exposure of the immature brain to anesthetic agents such as propofol, thiopental, ketamine, and inhalation agents can trigger significant brain cell apoptosis in the developing fetal/neonatal brain and cause functional learning deficits in later life. Preterm Labor – Anesthetic Management (Cesarean Delivery) At the current time, there is minimal evidence to support altering the anesthetic technique for cesarean delivery merely because the infant is preterm. Preterm Labor – Anesthetic Management (Cerclage) Cerclage placement requires a T10 level of surgical anesthesia. Frequently, rescue cerclage placement is a brief surgical procedure lasting less than 30 minutes. Shorter-acting spinal anesthetics may accelerate recovery and discharge for those going home. Usually, cerclage removal does not require anesthesia, but surgical anesthesia may be necessary if the stitch is embedded under the cervical mucosa. Spinal anesthesia for cerclage removal requires a T10 sensory level and, depending on gestational age and fetal weight, may result in excessive blockade if doses typically used for early second-trimester cerclage placement are used. Preterm Labor – Anesthetic Management (VTE) Obstetric venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality. Antepartum hospitalization and prolonged immobility increase the risk for VTE, particularly among obese women. Several professional societies recommend pharmacologic VTE prophylaxis for prolonged antepartum admissions, although the suggested dosing regimens are not uniform. With the wider adoption of these VTE guidelines, an increasing number of pregnant women will present for neuraxial analgesia or anesthesia in the context of pharmacologic anticoagulation. Preterm Labor – Key Points Despite improved antenatal care, the incidence of preterm delivery in the US remains approximately 10%. Preterm birth is a leading cause of neonatal mortality. Survivors have an increased chance of disability. Spontaneous preterm labor or preterm premature rupture of membranes accounts for the majority of preterm births. Treatment with tocolytic therapy may prolong labor by up to 48 hours and thereby facilitate the transfer of the patient from a small community hospital to a tertiary care facility, maternal administration of a corticosteroid to accelerate fetal lung maturity, and maternal administration of magnesium for fetal neuroprotection. Long-term tocolytic therapy does not improve neonatal outcomes. Preterm Labor – Key Points Nifedipine and Indomethacin are used commonly to treat preterm labor in the United States; oxytocin receptor antagonists are used in Europe. Magnesium sulfate is not an effective tocolytic but is considered beneficial when used specifically for neuroprotection in reducing rates of cerebral palsy in preterm infants. Terbutaline is associated with a high incidence of maternal and fetal side effects, including hypotension, tachycardia (with or without cardiac arrhythmias and myocardial ischemia), pulmonary edema, hyperglycemia, and hypokalemia. Pulmonary edema is the most serious complication, and it may be life-threatening. Cyclooxygenase inhibitors reversibly inhibit cyclooxygenase, resulting in a transient effect on platelet function. However, their use does not necessitate the assessment of platelet or coagulation function before administration of neuraxial analgesia/anesthesia in a patient whose only risk factor for bleeding is recent ingestion of a cyclooxygenase inhibitor.