1. overview of preterm birth Reihaneh Pirjani, M.D. Perinatologist, Assistant Professor, Tehran University of Medical Sciences

2. Classification — Preterm births are described by gestational age, birth weight, and initiating factor.  ● Gestational age criteria :  World Health Organization :  Moderate to late preterm: 32 to <37 weeks  Very preterm: 28 to <32 weeks  Extremely preterm: <28 weeks  Centers for Disease Control and Prevention:  Preterm: <37 weeks  Late preterm: 34 to 36 weeks  Early preterm: <34 weeks

3. Classification — Preterm births are described by gestational age, birth weight, and initiating factor.  ● Birth weight criteria  Low birth weight (LBW): <2500 grams  Very low birth weight (VLBW): <1500 grams  Extremely low birth weight (ELBW): <1000 grams

4. Classification — Preterm births are described by gestational age, birth weight, and initiating factor.  ● Initiating factor: spontaneous or iatrogenic  Spontaneous: 70 to 80 percent, due to preterm labor (40 to 50 percent) or preterm premature rupture of membranes (20 to 30 percent).  Provider-initiated: 20 to 30 percent, due maternal or fetal issues (eg, preeclampsia, placenta previa, abruptio placenta, fetal growth restriction, multiple gestation).  Complications of pregnancy can lead to both spontaneous and provider-initiated preterm births.

5. Pathogenesis  The pathophysiology of preterm labor involves four primary pathogenic processes that result in a final common pathway ending in spontaneous preterm labor and delivery:  ●Activation of the maternal or fetal hypothalamic- pituitary-adrenal axis associated with either maternal anxiety and depression or fetal stress  ●Infection  ●Decidual hemorrhage  ●Pathological uterine distention

6. Diagnosis  the diagnosis of preterm labor based upon clinical criteria of regular painful uterine contractions accompanied by cervical change (dilation and/or effacement).  Because the clinical findings of early labor are poorly predictive of the diagnosis, over-diagnosis is common until labor is well established.

7. Diagnosis  Specific clinical criteria include persistent uterine contractions (4 every 20 minutes or 8 every 60 minutes) with documented cervical change or cervical effacement ≥80 percent or cervical dilation >2 cm.  These criteria were chosen because women who do not meet these criteria are often ultimately diagnosed with false labor and go on to have a late preterm or term delivery

8. Appropriate application of interventions that can improve neonatal outcome:  antenatal corticosteroid therapy,  group B streptococcal infection prophylaxis,  magnesium sulfate for neuroprotection,  transfer to a facility with an appropriate level nursery (if necessary).

9.  Pregnancies ≥34 weeks of gestation  The 34th week of gestation is the threshold at which perinatal morbidity and mortality are too low to justify the potential maternal and fetal complications and costs associated with inhibition of preterm labor, which only results in short term delay in delivery.  "Antenatal corticosteroid therapy for reduction of neonatal morbidity and mortality from preterm delivery"

10.  women in preterm labor ≥34 weeks are admitted for delivery.  After an observation period of four to six hours, women without progressive cervical dilation and effacement are discharged, as long as fetal well-being is confirmed (eg, reactive nonstress test) and obstetrical complications associated with preterm labor, such as abruptio placenta, chorioamnionitis, and preterm rupture of membranes, have been excluded.  follow-up in one to two weeks

11.  Pregnancies <34 weeks of gestation  In women <34 weeks with uterine contractions, cervical dilation ≥3 cm supports the diagnosis of preterm labor; further diagnostic evaluation with sonographic measurement of cervical length or laboratory assessment of fetal fibronectin does not enhance diagnostic accuracy. Treatment of preterm labor is initiated.

12.  The diagnosis of preterm labor is less clear in women with contractions, cervical dilation <3 cm, and intact membranes  Measurement of cervical length is useful for supporting or excluding the diagnosis of preterm labor when the diagnosis is unclear.

13.  the frequency of preterm birth is low in symptomatic women 30 mm  the frequency of preterm birth is increased but still relatively low in symptomatic women with cervical length 20 to 30 mm;  the frequency of preterm birth is high in symptomatic women with cervical length <20 mm

14.  Cervical length >30 mm — Symptomatic women with cervical length >30 mm are at low risk (<5 percent) of delivery within seven days  the addition of fFN testing does not significantly improve the predictive value of cervical length measurement alone.

15.  Cervical length 20 to 30 mm — Symptomatic women with cervical dilation <3 cm and cervical length 20 to 30 mm are at increased risk of preterm birth, but most of these women do not deliver preterm. send a cervicovaginal sample for fFN testing  If the fFN test is positive, we begin interventions to reduce morbidity associated with preterm birth.If the fFN test is negative, we discharge the patient after 6 to 12 hours of observation,

16.  Cervical length 25 percent) of delivery within seven days;  Therefore, do not send their cervicovaginal samples to the laboratory for fFN testing and we begin interventions to reduce morbidity associated with preterm birth

17. Treatment of women <34 weeks with suspected preterm labor  hospitalize women diagnosed with preterm labor <34 weeks of gestation and initiate the following treatments  A course of betamethasone to reduce neonatal morbidity and mortality associated with preterm birth.betamethasone  Tocolytic drugs for up to 48 hours to delay delivery so that betamethasone given to the mother can achieve its maximum fetal effect.betamethasone

18. Treatment of women <34 weeks with suspected preterm labor  ●Antibiotics for GBS chemoprophylaxis.  ●Magnesium sulfate for pregnancies at 24 to 32 weeks of gestation. In utero exposure to magnesium sulfate provides neuroprotection against cerebral palsy and other types of severe motor dysfunction in offspring born preterm.Magnesium sulfate

19.  Antibiotic therapy has no role in the treatment of acute preterm labor in the absence of a documented infection or GBS prophylaxis  Progesterone supplementation has no role in the treatment of acute preterm labor. Progesterone

20. Administration of tocolytic drugs  EFFICACY — can reduce the strength and frequency of uterine contractions. these drugs were more effective than placebo/control:  for delaying delivery for 48 hours (75 to 93 percent versus 53 percent for placebo/control)  for seven days (61 to 78 percent versus 39 percent for placebo/control),  but not for delaying delivery to 37 weeks  administration of tocolytic drugs did not result in statistically significant reductions in important clinical outcomes, such as neonatal respiratory distress and survival

21. Administration of tocolytic drugs  PATIENT SELECTION — Women in the early phases of acute preterm labor, when cervical dilation is not advanced, are optimum candidates for tocolytic therapy  Tocolysis is indicated when the overall benefits of delaying delivery outweigh the risks.  Because tocolytic therapy is generally effective for up to 48 hours, only women with fetuses that would benefit from a 48 hour delay in delivery should receive tocolytic treatment

22. Administration of tocolytic drugs  PATIENT SELECTION  Inhibition of acute preterm labor is less likely to be successful as labor advances to the point that cervical dilation is greater than 3 cm.  Tocolysis can still be effective in these cases, especially when the goal is to administer antenatal corticosteroids or safely transport the mother to a tertiary care center

23. Lower and upper gestational age limits  The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal- Fetal Medicine (SMFM) recommend not administering tocolysis before 24 weeks of gestation,  ACOG and SMFM that 34 weeks of gestation defines the threshold at which perinatal morbidity and mortality are too low to justify the potential maternal and fetal complications and costs associated with inhibition of preterm labor and short-term delay of delivery

24. Contraindications  Tocolysis is contraindicated when the maternal/fetal risks of prolonging pregnancy or the risks associated with these drugs are greater than the risks associated with preterm birth. Established contraindications to labor inhibition include:  Intrauterine fetal demise  Lethal fetal anomaly  Nonreassuring fetal status  Preeclampsia with severe features or eclampsia  Maternal hemorrhage with hemodynamic instability  Intraamniotic infection  Maternal contraindications to the tocolytic drug

25. TREATMENT GOALS  Delay delivery by at least 48 hours when it is safe to do so in order that antenatal corticosteroids (primary or rescue) given to the mother have time to achieve their maximum fetal/neonatal effects.

26. TREATMENT GOALS  Provide time for safe transport of the mother, if indicated, to a facility that has an appropriate level of neonatal care if the patient delivers preterm.  Prolong pregnancy when it is safe to do so and when there are underlying, self-limited conditions that can cause labor, such as pyelonephritis or abdominal surgery, and are unlikely to cause recurrent preterm labor.

27. For women at 24 to 32 weeks of gestation  use indomethacin for first-line therapy.indomethacin  Data from randomized trials suggest it is superior to placebo  do not use indomethacin for more than 72 hours because of concern about premature constriction of the ductus arteriosus and oligohydramnios.

28. For women at 32 to 34 weeks of gestation  use nifedipine as a first-line agentnifedipine

29. For women at 24 to 32 weeks of gestation  use nifedipine as a first-line agent for women who have a contraindication to indomethacin therapy :nifedipine  maternal platelet dysfunction or bleeding disorder,  hepatic dysfunction,  gastrointestinal ulcerative disease,  renal dysfunction,  asthma [in women with hypersensitivity to aspirin].aspirin

30.  If the first-line drug does not inhibit contractions, discontinue it and begin therapy with another agent.  For second-line therapy, use nifedipine at 24 to 32 weeks and terbutaline at 32 to 34 weeks and for patients at 24 to 32 weeks who received nifedipine as a first-line agent.nifedipineterbutaline  discontinue tocolytics 48 hours after administration of the first corticosteroid dose.

31.  In a 2012 systematic review and network meta-analysis of 95 randomized trials of tocolytic therapy for preterm labor, all of the commonly used tocolytic agents (cyclooxygenase inhibitors, beta-agonists, calcium channel blockers, magnesium sulfate, oxytocin receptor antagonists) were statistically more effective than placebo/no tocolytic for delaying delivery for 48 hours.magnesium sulfate  Cyclooxygenase inhibitors (eg, indomethacin) and calcium channel blockers (eg, nifedipine) had the highest probability of being the best therapy for preterm laborindomethacinnifedipine

32.  A single course of therapy does not delay delivery by weeks or months because tocolytics do not remove the underlying stimulus that initiated preterm labor (eg, subclinical intraamniotic infection, abruption, uterine overdistension) or reverse parturitional uterine changes (eg, cervical dilation and effacement).

33. MOST EFFECTIVE TOCOLYTIC DRUGS indomethacin indomethacin  Dose — The dose of indomethacin for labor inhibition is 50 to 100 mg loading dose (may be given orally or per rectum), followed by 25 mg orally every four to six hours.indomethacin  Monitoring — If indomethacin is continued for longer than 48 hours, sonographic evaluation for oligohydramnios and narrowing of the fetal ductus arteriosus is warranted at least weekly.indomethacin  Evidence of oligohydramnios or ductal constriction should prompt discontinuation of this therapy.

34. MOST EFFECTIVE TOCOLYTIC DRUGS indomethacin indomethacin  Constriction of the ductus arteriosus — Premature narrowing or closure of the ductus arteriosus can lead to pulmonary hypertension and tricuspid regurgitation in the fetus.  which the duration of indomethacin exposure exceeded 48 hoursindomethacin  Ductal constriction appears to depend upon both gestational age and duration of exposure. It has been described at gestations as early as 24 weeks, but is most common after 31 to 32 weeks

35. MOST EFFECTIVE TOCOLYTIC DRUGS indomethacin indomethacin  Constriction of the ductus arteriosus —  indomethacin is not recommended after 32 weeks of gestation.indomethacin  Before 32 weeks, fetal echocardiographic evaluation is useful for monitoring ductal effects if the duration of therapy exceeds 48 hours.  Sonographic signs of ductal narrowing include tricuspid regurgitation, right ventricular dysfunction and pulsatility index less than 1.9

36. MOST EFFECTIVE TOCOLYTIC DRUGS nifedipine nifedipine  The relative safety, maternal tolerance, ease of administration, and reduction in adverse neonatal outcomes support use of nifedipine rather than beta- agonists for inhibition of acute preterm labor.nifedipine

37. MOST EFFECTIVE TOCOLYTIC DRUGS nifedipine nifedipine  Contraindications —  known hypersensitivity to the drugs,  hypotension,  preload-dependent cardiac lesions,  should be used with caution in women with left ventricular dysfunction or congestive heart failure.  The concomitant use of a calcium-channel blocker and magnesium sulfate could act synergistically to suppress muscular contractility, which could result in respiratory depressionmagnesium sulfate

38. MOST EFFECTIVE TOCOLYTIC DRUGS nifedipine nifedipine  Dose —A common approach is to administer an initial loading dose of 20 to 30 mg orally, followed by an additional 10 to 20 mg orally every 3 to 8 hours for up to 48 hours, with a maximum dose of 180 mg/day.  The American College of Obstetricians and Gynecologists suggests a 30 mg loading dose and then 10 to 20 mg every four to six hours.  The half-life of nifedipine is approximately two to three hours and the duration of action of a single orally administered dose is up to six hours. Plasma concentrations peak in 30 to 60 minutes.nifedipine  Nifedipine is almost completely metabolized in the liver and excreted by the kidney.

39. MOST EFFECTIVE TOCOLYTIC DRUGS Beta-agonists  Beta-agonists — ritodrine and terbutaline have been studied in several randomized, placebo-controlled trials.terbutaline  Salbutamol and hexoprenaline have also been evaluated, but data are sparse  Although ritodrine is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of preterm labor, it is no longer available

40. MOST EFFECTIVE TOCOLYTIC DRUGS Beta-agonists  Mechanism of action — The beta-2 receptor agonists cause myometrial relaxation by binding with beta-2 adrenergic receptors and increasing intracellular adenyl cyclase. An increase in intracellular cyclic adenosine monophosphate activates protein kinase and results in the phosphorylation of intracellular proteins. The resultant drop in intracellular free calcium interferes with the activity of myosin light-chain kinase. Interference with myosin light-chain kinase inhibits the interaction between actin and myosin; thus, myometrial contractility is diminished. However, target cells eventually become desensitized to the effect of beta-agonists, thereby decreasing efficacy with prolonged use [62,63]. The reduction in response over time is known as tachyphylaxis62,63

41. MOST EFFECTIVE TOCOLYTIC DRUGS Beta-agonists  Maternal side effects —  related to stimulation of beta-1 adrenergic receptors, which increase maternal heart rate and stroke volume,  stimulation of beta-2 adrenergic receptors, which causes peripheral vasodilation, diastolic hypotension, and bronchial relaxation.  The combination of these two cardiovascular effects leads to tachycardia, palpitations, and lower blood pressure.  tremor,palpitations,shortness of breath, and chest discomfort,Pulmonary edema  hypokalemia (39 versus 6 percent with placebo), hyperglycemia (30 versus 10 percent with placebo), and lipolysis. Myocardial ischemia is a rare complication.

42. MOST EFFECTIVE TOCOLYTIC DRUGS Beta-agonists  Fetal side effects — Beta-agonists cross the placenta.  Fetal effects, such as fetal tachycardia, are analogous to the maternal effects  Neonatal hypoglycemia may result from fetal hyperinsulinemia in response to prolonged maternal hyperglycemia.

43. MOST EFFECTIVE TOCOLYTIC DRUGS Beta-agonists  Contraindications —  women with tachycardia-  sensitive cardiac disease,  poorly controlled hyperthyroidism  poorly controlled diabetes mellitus  Beta-agonists should be used with caution in women at risk for massive hemorrhage (such as women with placenta previa or abruption) since the resultant cardiovascular effects (tachycardia, hypotension) may interfere with the mother's ability to respond to ongoing hemorrhage, and may confuse the clinical presentation.

44. MOST EFFECTIVE TOCOLYTIC DRUGS Beta-agonists  injectable terbutaline should not be used in pregnant women for prolonged (beyond 48 to 72 hours) because of the potential for serious maternal heart problems and death.terbutaline  The FDA also opined that oral terbutaline should not be used for prevention  terbutaline injection for an individual patient in a hospital setting clearly outweighs the risk. terbutaline

45. MOST EFFECTIVE TOCOLYTIC DRUGS Beta-agonists  Dose — It is often given subcutaneously by intermittent injection. The dose is variable: 0.25 mg can be administered subcutaneously every 20 to 30 minutes for up to four doses or until tocolysis is achieved. Once labor is inhibited, 0.25 mg can be administered subcutaneously every three to four hours until the uterus is quiescent for 24 hours.  Terbutaline can also be administered as a continuous intravenous infusion. 2.5 to 5 mcg/min and increasing by 2.5 to 5mcg/min every 20 to 30 minutes to a maximum of 25 mcg/min, or until the contractions have abated. At this point, the infusion is reduced by decrements of 2.5 to 5 mcg/min to the lowest dose that maintains uterine quiescence. Terbutaline

46. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine consider magnesium sulfate an option for short-term prolongation of pregnancy (up to 48 hours) to allow administration of antenatal corticosteroids to pregnant women at risk for preterm delivery within 7 days

47. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  Maternal and fetal side effects —Diaphoresis and flushing are the most common side effects; magnesium toxicity is related to serum concentration.  Maternal therapy causes a slight decrease in baseline fetal heart rate and fetal heart rate variability, which are not clinically important. Antenatal fetal assessment test results (eg, biophysical profile score and nonstress test reactivity) are not significantly altered

48. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  Maternal and fetal side effects —  radiographic bone abnormalities in neonates with in utero exposure tomagnesium sulfate for more than seven days,magnesium sulfate  a significant difference in the serum values of magnesium, calcium, phosphorus, and osteocalcin (a marker of bone formation) at birth between neonates unexposed to magnesium sulfate and those who were exposed  these effects are transient  FDA advised against using magnesium sulfate infusions for more than five to seven days to stop preterm labor  The American College of Obstetricians and Gynecologists suggests limiting magnesium sulfate therapy to 48 hours in women between 24 and 34 weeks of gestation with preterm labor

49. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  If tocolysis is indicated because of persistent preterm labor in a patient receiving magnesium sulfate for neuroprotection, the most effective tocolytic with the most favorable side-effect profile should be usedmagnesium sulfate

50. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  Contraindications — Magnesium sulfate tocolysis is contraindicated in women with myasthenia gravis.Magnesium sulfate  Magnesium sulfate should also be avoided in women with known myocardial compromise or cardiac conduction defects Magnesium sulfate  Magnesium is eliminated by the kidneys. Thus, in women with impaired renal function doses of administration so the maintenance dose should be reduced or eliminated.  The concomitant use of a calcium channel blocker and magnesium sulfate could act synergistically to suppress muscular contractility, which could result in respiratory depressionmagnesium sulfate

51. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  Dose — Magnesium sulfate is usually administered as a 4-6 gram intravenous load over 20 minutes, followed by a continuous infusion of 2 g/hour Magnesium sulfate  Monitoring — In women with normal renal function, signs and symptoms of magnesium toxicity can be assessed by history and physical examinations. Routine magnesium levels are not necessary.

52. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  Since magnesium sulfate is excreted by the kidneys, dosing should be adjusted in women with renal insufficiency (defined as a serum creatinine greater than 1.0 mg/dL or an alternative drug should be used.magnesium sulfate  If magnesium sulfate is given, such women should receive a standard loading dose (since their volume of distribution is not altered), but a reduced maintenance dose (1 gram per hour or no maintenance dose if the serum creatinine is greater than 2.5 mg/dL ( micromol/L]) with close monitoring of the serum magnesium concentration every six hours.

53. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  Women with renal insufficiency should receive the maintenance phase of treatment only if a patellar reflex is present (loss of reflexes being the first manifestation of symptomatic hypermagnesemia), respirations exceed 12 per minute, and the urine output exceeds 100 mL per four hours. The urine output and deep tendon reflexes should be closely monitored. Magnesium levels may be useful in monitoring women on maintenance magnesium therapy who have concomitant renal disease.

54. MOST EFFECTIVE TOCOLYTIC DRUGS Magnesium sulfate  If life-threatening symptoms of magnesium toxicity occur (cardiac or respiratory compromise), calcium gluconate (1 gram intravenously over 5 to 10 minutes) is an effective counteractive therapy but should not be used to treat mild symptoms.calcium gluconate

55. INEFFECTIVE APPROACHES  Antibiotic therapy — Although subclinical genital tract infection clearly contributes to the pathogenesis of preterm birth, there is no evidence-based role for antibiotic therapy in the prevention of prematurity in patients with acute preterm labor  Progesterone supplementation — Women in acute preterm labor do not benefit from progesterone supplementationprogesterone  Bedrest, hydration, and sedation — There is no convincing evidence that bedrest, hydration, or sedation is effective for prevention or treatment of preterm labor.Furthermore, extended and hospitalized bedrest increase the risk of thromboembolic events

56. Neuroprotective effects of in utero exposure to magnesium sulfate  Prematurity is a powerful risk factor for the development of cerebral palsy   In utero exposure to magnesium sulfate before early preterm birth appears to decrease the incidence of cranial ultrasound abnormalities associated with cerebral palsy and, more importantly, the incidence and severity of cerebral palsy in offspringmagnesium sulfate

57. Neuroprotective effects of in utero exposure to magnesium sulfate The mechanism is not well understood, but potential neuroprotective actions include  antioxidant effects,  reduction in proinflammatory cytokines,  blockage of glutamate activated calcium channels,  stabilization of membranes,  increased cerebral blood flow,  prevention of large blood pressure fluctuations

58.  Randomized placebo-controlled trials of maternal administration of magnesium sulfate in women expected to have a preterm delivery within 24 hours have consistently demonstrated a decreased risk of cerebral palsy and severe motor dysfunction in offspring;  however, the possibility of an increased risk of death in a subgroup of fetuses or infants has not conclusively been excluded.

59. Neuroprotective effects of in utero exposure to magnesium sulfate Candidates for treatment Given the current data, administering magnesium sulfate for neuroprotection to women with preterm premature rupture of membranes, preterm labor with intaact membranes, or indicated preterm delivery appears to be reasonablemagnesium sulfate

60.  The optimal dose of magnesium, gestational age at administration, and reason for preterm birth warrant further study. Neither the neuroprotective mechanism nor the dose response to magnesium sulfate is well understood.magnesium sulfate While it seems likely that the neuroprotective We administer magnesium sulfate to women with preterm premature rupture of membranes or preterm labor who have a high likelihood of imminent delivery (ie, within 24 hours), or before an indicated preterm delivery.magnesium sulfate If emergency delivery is necessary given maternal or fetal status, it should not be delayed to administer magnesium sulfate

61.  A 4 gram intravenous loading dose followed by a 1 gram/hour infusion.  This therapy is discontinued by 24 hours after initiation if delivery has not occurred.  The upper limit of exposure is also not well defined. We recommend not continuing the magnesium infusion for longer than 24 hours if delivery has not occurred.

62. Neuroprotective effects of in utero exposure to magnesium sulfate Monitoring — Urine output and deep tendon reflexes should be closely monitored in all patients. The maintenance phase of treatment should be continued only if a patellar reflex is present (loss of reflexes being the first manifestation of symptomatic hypermagnesemia), respirations exceed 12 per minute, and the urine output exceeds 100 mL per four hours.

63. Neuroprotective effects of in utero exposure to magnesium sulfate Retreatment — Retreatment with magnesium sulfate is not recommended as there are inadequate data regarding any benefit for women who do not deliver after initial magnesium sulfate therapy.magnesium sulfate

64. Neuroprotective effects of in utero exposure to magnesium sulfate the American College of Obstetricians and Gynecologists (ACOG) encourages physicians electing to use magnesium sulfate for neuroprotection to develop guidelines for its usemagnesium sulfate Up to date: we consider women at high risk of imminent (ie, within 24 hours) spontaneous or indicated preterm birth between 24 and 32 weeks of gestation candidates for magnesium sulfate administration for neuroprotection.magnesium sulfate

65. Neuroprotective effects of in utero exposure to magnesium sulfate If tocolysis is indicated, the most effective agent with the most favorable side effect profile should be chosen: indomethacinindomethacin

66. corticosteroid therapy for reduction of neonatal morbidity and mortality  Antenatal corticosteroid therapy leads to improvement in neonatal lung function by enhancing maturational changes in lung architecture and by inducing lung enzymes involved in respiratory function.

67. corticosteroid therapy for reduction of neonatal morbidity and mortality  ●Antenatal corticosteroid therapy reduces the incidence of respiratory distress syndrome, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and neonatal mortality by approximately 50 percent.  These effects are not limited by gender or race;  efficacy in multiple gestations is unclear, as high-quality data are sparse.

68. corticosteroid therapy for reduction of neonatal morbidity and mortality  GESTATIONAL AGE AT ADMINISTRATION  23 to 34 weeks — recommend administration of antenatal corticosteroids for all pregnant women at 23 to 34 weeks who are at increased risk of preterm delivery within the next seven days.  22 weeks or less —At 22 weeks parents should be informed that antenatal corticosteroids may provide a survival benefit while increasing the risk for survival with severe impairment

69. corticosteroid therapy for reduction of neonatal morbidity and mortality  GESTATIONAL AGE AT ADMINISTRATION  After 34 weeks — The use of antenatal corticosteroids after 34 weeks of gestation is controversial because of inconsistent data about its efficacy and virtually no data about long-term safety.  Limitations of available data are largely related to the low risk for severe respiratory morbidity after 34 weeks of gestation and lack of information on long-term outcomes after exposure to corticosteroids in late gestation

70. corticosteroid therapy for reduction of neonatal morbidity and mortality  GESTATIONAL AGE AT ADMINISTRATION  37 to 39 weeks of gestation — Empiric use of steroids has been recommended prior to cesarean delivery at 37 to 39 weeks of gestation based on two trials  ●The Society for Maternal-Fetal Medicine Specialists recommends a two-dose course of antenatal betamethasone for women at 34 0/7ths to 36 6/7ths weeks of gestation at high risk for preterm birth within seven daysbetamethasone

71. corticosteroid therapy for reduction of neonatal morbidity and mortality  Other approaches  ●The American College of Obstetricians and Gynecologists states administration of betamethasone may be considered in women with a singleton pregnancy at 34 0/7ths to 36 6/7ths weeks of gestation at imminent risk of preterm birth within 7 days, with the following caveatsbetamethasone  Antenatal corticosteroid administration should not be administered to women with chorioamnionitis.  Medically/obstetrically indicated preterm delivery should not be postponed for steroid administration.  Antenatal corticosteroids should not be administered if the patient has already received a course antenatal corticosteroids.  Newborns should be monitored for hypoglycemia.

72. corticosteroid therapy for reduction of neonatal morbidity and mortality  Other approaches  ●The Royal College of Obstetricians and Gynaecologists (RCOG) recommends routine administration of antenatal glucocorticoids for  (1) all women at risk of preterm birth up to and including 34 6/7ths weeks of gestation  (2) all women who must undergo scheduled cesarean delivery before 39 /07ths weeks of gestation

73. corticosteroid therapy for reduction of neonatal morbidity and mortality  recommend administration of antenatal corticosteroids to pregnant woman who are at 23 to 34 weeks of gestation and at increased risk of preterm delivery within the next seven days.  This approach minimizes the need for salvage (rescue, booster) therapy while allowing most patients to receive a course of antenatal corticosteroids prior to preterm delivery.

74. corticosteroid therapy for reduction of neonatal morbidity and mortality  Some clinicians and patients may choose not to use steroids after 34 weeks of gestation, given uncertainly in the balance between benefits and risks after 34 weeks.

75. corticosteroid therapy for reduction of neonatal morbidity and mortality A course of antenatal corticosteroids consists of betamethasone suspension 12 mg intramuscularly every 24 hours for two doses or four doses of 6 mg dexamethasone intramuscularly 12 hours apart.betamethasonedexamethasone the optimal window of after steroid administration: 24 hours to 7 days after the second dose Observational data suggest neonatal benefits begin to accrue within a few hours of corticosteroid administration

76. corticosteroid therapy for reduction of neonatal morbidity and mortality  For women at 34 0/7ths to 36 6/7ths weeks :  who have already received a course of antenatal corticosteroids,  who are expected to deliver vaginally,  whose likelihood of delivery within the next seven days is uncertain, not administering a course of antenatal corticosteroids.

77. corticosteroid therapy for reduction of neonatal morbidity and mortality  a single course of salvage (rescue, booster) therapy only if: 1. the patient is clinically estimated to be at high risk of delivery within the next seven days, 2. more than two weeks have elapsed since the initial course of antenatal corticosteroid therapy, 3.the gestational age at administration of the initial course was <28 weeks of gestation

78. corticosteroid therapy for reduction of neonatal morbidity and mortality For salvage (rescue, booster) therapy use one dose of 12 mg betamethasone and limit treatment to this one additional dose.betamethasone One dose appears to be effective and may minimize complications related to steroid use; however, a two dose course is also reasonable

79. Potential fetal side effects  Fetal heart rate and biophysical parameters – Administration of antenatal corticosteroids may be associated with transient fetal heart rate (FHR) and behavioral changes that typically return to baseline by four to seven days after treatment.  The most consistent FHR finding is a decrease in variability on days two and three after administration.  Reduced fetal breathing and body movements can result in a lower BPP score or NR-NST

80. Potential fetal side effects  FHR and behavioral changes may reflect a direct physiologic response of the brain to corticosteroids or they may be an indirect result of a transient increase in fetal vascular resistance and blood pressure  Whether continued close fetal monitoring or delivery is preferable in this setting depends on assessment of the total clinical scenario and clinical judgment.

81. Potential fetal side effects  Doppler flow studies –  A transient improvement in umbilical artery end-diastolic flow (EDF) after antenatal corticosteroid administration has been described in three studies  The improvement began about eight hours after the first dose of betamethasone and lasted a median of three days (range 1 to 10 days). betamethasone  other studies have not observed effects on fetal blood flow velocity waveform patterns in the umbilical artery, middle cerebral artery, or ductus venosus  However, these observations are based on a small number of events in two studies and need to be confirmed before a change in management of this subgroup of fetuses is considered

82. Potential fetal side effects  However, preterm fetuses with severe early-onset growth restriction and absent or reversed EDF do not have a consistent cardiovascular response to maternal betamethasone administration.betamethasone

83. Potential adverse effects on infants  The safety and effectiveness of steroid administration after 34 weeks is less clear.  In a multifaceted intervention trial (ACT) designed to increase the use of antenatal corticosteroids in low- income and middle-income countries, increased use of steroids increased neonatal and perinatal mortality in the overall population, which was an unexpected and unexplained finding that may have been related, in part, to increased in utero steroid exposure among neonates born at term

84.  Multiple gestation — We use a standard dosing schedule for both singleton and multiple gestations.  In theory, multiple gestations may require higher doses of antenatal corticosteroids to maximize fetal exposure. However, maternal and cord blood betamethasone levels were similar in singleton and multiple gestations in a randomized trial.betamethasone

85.  Hypertension — Betamethasone has low mineralocorticoid activity compared with other corticosteroids and does not aggravate hypertension.Betamethasone  A randomized trial supported both the safety and efficacy of antenatal corticosteroid therapy in pregnancies complicated by severe preeclampsia.

86.  Diabetes — Antenatal corticosteroid therapy should be administered to women with diabetes when indicated; however, hyperglycemia related to corticosteroid administration can be severe in this population if not closely monitored and treated.  The steroid effect on glucose levels begins approximately 12 hours after the first dose and may last for five days.  Women with diabetes generally have been excluded from randomized trials of antenatal corticosteroid therapy because of the adverse effects of steroids on glycemic control, thus efficacy in this population is inferred

87.  Preterm premature rupture of membranes — Antenatal corticosteroid administration improves neonatal outcome in pregnancies complicated by preterm premature rupture of membranes and does not increase the risk of neonatal or maternal infection