2. Dr. M.Moshfeghi OBS&GYN fellowship of perinatology Shariati.Hospital,TUMS RUYAN INSTITUTE

3. INTRODUCTION 12% of births before 37 weeks and preterm. 20% of preterm are iatrogenic IUGR preeclampsia, placenta previa, 80 % spontaneous, related to preterm labor or PROM

4. PRETERM BIRTH Classification. By gestational age Moderate preterm: 32 to <37 weeks Late preterm: 34 0/7ths to 36 6/7ths weeks Very preterm: 28 to <32 weeks Extremely preterm: <28 weeks

5. Clinical manifestations The clinical manifestations of true labor, contractions and cervical change, are the same whether labor occurs preterm or at term. Menstrual-like cramping Mild, irregular contractions Low back ache Pressure sensation in the vagina (ie, mucus plug, bloody show)

6. challenge of distinguishing true labor (contractions that result in cervical change) from false labor (contractions that do not result in cervical change).

7. The rate of cervical change distinguishes cervical ripening, which occurs over days to weeks, from true labor, which occurs over minutes to hours. Transvaginal ultrasound is the most reliable method for measuring cervical length. In symptomatic and asymptomatic preterm patients, short cervix (<30 mm) is predictive of an increased risk of preterm labor and birth;.

8. Diagnosis generally based upon clinical criteria of regular painful uterine contractions accompanied by cervical change

9. Approach to the patient with suspected preterm labor Initial evaluation

10. Maternal vital signs fetal heart rate and contraction Uterine contractions are evaluated continuously using a contraction monitor, palpation, and the patient’s subjective assessment Examination of the uterus to assess firmness, tenderness, fetal size, and fetal position. Speculum examination.

11. swab for fetal fibronectin (Ffn) we only send the swab if CL 20 to 30 mm A rectovaginal GBS culture should be performed if not done within the previous five weeks; antibiotic prophylaxis depends on the results Screening for gonorrhea and chlamydia is indicated for women risk of these infections; bacterial vaginosis and trichomoniasis is indicated in women symptomatic.

12. Digital cervical examination has limited reproducibility between examiners, TVS to evaluate the cervix in <34 weeks when the diagnosis of labor is uncertain.

13. perform an obstetrical ultrasound examination, confirm the fetal presentation, assess amniotic fluid volume, and estimate fetal weight

14. Cervical dilation and effacement may be assessed by digital examination after placenta previa and PPROM have been excluded after swabs for fFN rectovaginal (GBS) culture TVS examination has been performed.

15. When assessing cervical dilation and effacement in the second trimester, distinguish between patients whose membranes have hour-glassed (prolapsed) through a mildly dilated and effaced cervix (suggestive of cervical insufficiency) from those who are fully dilated and effaced as a result of advanced labor. Ultrasound imaging can distinguish between these two diagnoses.

16. We obtain a urine culture, since asymptomatic bacteriuria is associated with an increased risk of preterm labor and birth

17. We perform drug testing in patients with risk factors for substance abuse, given the link between cocaine use and placental abruption

18. Triage based upon cervical length no data from large randomized trials to help determine the optimal management of symptomatic women with suspected preterm labor and intact membranes.

19. As a general guideline, preterm birth is highly unlikely in symptomatic women if cervix length is >30 mm unless abruption is the cause of their symptoms, and most likely if cervical length <15 to 20 mm

20. Cervical length >30 mm These women are at low risk of preterm birth, regardless of fFN result, so we do not send their swabs for fFN testing.

21. We discharge the patients home after an observational period of four to six hours during which we confirm fetal well-being (eg, reactive nonstress test), R/O of an acute precipitating event (eg, abruption or overt infection), and assure ourselves that the cervix is not progressively dilating or effacing

22. We arrange follow-up in one to two weeks and give the patient instructions to call if she experiences additional signs or symptoms of preterm labor,

23. CL 20 to 30 mm increased risk but most of these women do not deliver preterm. send the swab for fFN testing. If the test is positive (fFN level greater than 50 ng/mL), we actively manage the pregnancy in an attempt to prevent morbidity associated with preterm birth.

24. Cervical length <20 mm at high risk of preterm birth regardless of the fFN result. we do not send swabs for fFN testing we actively manage the patient in an attempt to prevent morbidity associated with preterm birth

25. Management We hospitalize women diagnosed with preterm labor <34 w initiate the following treatments

26. A course of betamethasone betamethasone Tocolytic for up to 48 hours to delay delivery so that betamethasone can achieve its maximum fetal effect betamethasone Antibiotics for GBS chemoprophylaxis, when appropriate Appropriate antibiotics to women with positive urine culture results Magnesium sulfate Magnesium sulfate for pregnancies at 24 to 32 weeks. provides neuroprotection

27. Preterm labor itself is not an indication for antibiotic prophylaxis or treatment in the absence of documented infection or GBS prophylaxis There is no role for progesterone supplementation in the treatment of acute preterm labor

28. Gestational age limits for tocolytic therapy Lower limit not indicated prior to neonatal viability Upper limit Thirty-four weeks attempting to inhibit contractions after a self- limited event

29. Contraindications to tocolysis Women with preterm contractions without cervical change, especially those with a cervical dilation of <2 cm, generally should not be treated with tocolytics

30. Established contraindications to labor inhibition : Intrauterine fetal demise Lethal fetal anomaly Nonreassuring fetal status Severe preeclampsia or eclampsia Maternal hemorrhage with hemodynamic instability Intraamniotic infection Maternal contraindications to the tocolytic drug

31. fetal pulmonary maturity is not an absolute contraindication to tocolysis, as there are nonpulmonary morbidities associated with preterm birth. As an example, a 30-week fetus with a mature amniotic fluid fetal lung maturity test is still at risk for intraventricular hemorrhage, sepsis, hyperbilirubinemia, and other morbidities unrelated to respiratory distress syndrome.

32. Inhibition of preterm is less likely to be successful when cervical dilation is greater than 3 cm. Tocolysis can still be considered in these cases, especially when the goal is to administer antenatal corticosteroids or safely transport the mother to a tertiary care center

33. TOCOLYTIC OPTIONS 24 to 32 weeks indomethacin indomethacin as first-line. 32 to 34 weeks nifedipine nifedipine for initial treatment for adverse fetal effects with indomethacin use at this gestational age.

34. 32 to 34 weeks For second-line therapy we suggest a beta-adrenergic receptor agonist

35. Maternal side effects with indomethacinindomethacin nausea, esophageal reflux, gastritis, and emesis, Platelet dysfunction

36. indomethacin indomethacin and other COX inhibitors Fetal side effects constriction of the ductus arteriosus oligohydramnios. in which the duration of indomethacin exposureindomethacin exceeded 48 hours

37. Oligohydramnios use of indomethacin or ibuprofen for greater than 72 hindomethacin ibuprofen

38. Neonatal effects associated with in utero indomethacin exposureindomethacin bronchopulmonary dysplasia, necrotizing enterocolitis, patent ductus arteriosus, periventricular leukomalacia, intraventricular hemorrhage

39. Contraindications Maternal contraindications to COX inhibitors include platelet dysfunction or bleeding disorder, hepatic dysfunction, gastrointestinal ulcerative disease, renal dysfunction, and asthma

40. Dose The dose of indomethacin for labor inhibitionindomethacin 50 to 100 mg loading dose (may be given per rectum), followed by 25 mg orally every four to six hours

41. Monitoring If indomethacin longer than 48 hours, sonographic evaluation for oligohydramnios and narrowing of the fetal ductus arteriosus isindomethacin warranted at least weekly Evidence of oligohydramnios or ductal constriction should prompt discontinuation of this therapy.

42. Calcium channel blockers Efficacy no large randomized trials directly comparing the efficacy of calcium channel blockers with placebo for treatment of preterm labor.

43. Maternal side effects Nifedipine is a peripheral vasodilator,Nifedipine nausea, flushing, headache, dizziness, and palpitations.

44. Fetal side effects blood sampling has not shown any clear evidence of fetal hypoxia or acidosis when these agents were used

45. Contraindications Calcium channel blockers hypotension, or preload-dependent cardiac lesions with caution in women with left ventricular dysfunction or congestive heart failure The concomitant use of a calcium-channel blocker and magnesium sulfate result in respiratory depressionmagnesium sulfate

46. Dose initial loading dose 20 mg orally, followed by 20 mg orally in 90 minutes. If contractions persist, 20 mg can be given orally every 3 to 8 hours for up to 72 hours, with a maximum dose of 180 mg/day. (ACOG) suggests a 30 mg loading dose and then 10 to 20 mg every four to six hours

47. Beta-adrenergic receptor agonists ritodrine and terbutalineterbutaline Salbutamol have also been evaluated, but data are sparse ritodrine is the only drug approved by (FDA) for the treatment of preterm labor,

48. Target cells become desensitized to the effect of beta-adrenergic receptor agonists, thereby decreasing efficacy with prolonged use.

49. Maternal side effects causes peripheral vasodilation, diastolic hypotension, and bronchial relaxation. tachycardia, palpitations, and lower blood pressure. Pulmonary edema metabolic effects, including hypokalemia Hyperglycemia lipolysis Myocardial ischemia is a rare complication.

50. Contraindications cardiac disease hyperthyroidism poorly controlled poorly controlled diabetes mellitus In diabetic women, hourly blood glucose monitoring and an intravenous insulin drip are usually required to maintain euglycemia.

51. FDA oral terbutaline should not be used for prevention or any treatment of preterm laborterbutaline The FDA injectable terbutaline should not be used in pregnant women for prevention or prolonged treatment (beyond 48 to 72 hours) of preterm labor in either the hospital or outpatient settingterbutaline

52. terbutaline is the most commonly used beta-adrenergic receptor agonist for labor inhibition. subcutaneously by intermittent injection. The dose is variable: 0.25 mg can be administered 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 every three to four hours until the uterus is quiescent for 24 hours. It can also be administered as a continuous intravenous infusion. We suggest the infusion be started at 2.5 to 5 mcg/min; this can be increased by 2.5 to 5 mcg/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. 48 to 72 hours

53. Monitoring During beta-adrenergic agonist fluid intake, urine output, and maternal symptoms,. We suggest the drug be withheld if the maternal heart rate exceeds 120 beats/min. Glucose and potassium monitored every four to six hours during parenteral drug administration, since hyperglycemia and hypokalemia commonly occur. Significant hypokalemia should be treated to minimize risk of arrhythmias. Significant hyperglycemia can be treated with insulin.

54. Oxytocin receptor antagonists atosiban should be more effective at later gestational ages as effective as beta-adrenergic receptor agonists FDA declined to approve the use of atosiban for tocolysis because of concerns about the drug's safety when used in fetuses less than 28 weeks of gestation

55. Dose Atosiban is administered intravenously beginning with a bolus of 6.75 mg followed by a 300 mcg/min infusion for three hours, and then 100 mcg/min for up to 45 hours

56. Magnesium sulfate magnesium sulfate magnesium sulfate was neither more nor less effective than other s decrease in baseline FHR and fetal heart rate variability. biophysical profile score and nonstress test reactivity are not significantly altered.

57. Neuroprotective effects The minimum duration of administration that results in neuroprotection is not known, but is less than 24 hours.

58. Contraindications Magnesium sulfate myasthenia gravis. women with known myocardial compromise or cardiac conduction defects

59. Dose Magnesium sulfate 6 g intravenous load over 20 minutes, followed by a continuous infusion of 2 g/hour 1 g per hour no maintenance dose if the serum creatinine is greater than 2.5 mg/dL

60. If the first tocolytic not successfully inhibit preterm labor, discontinuing it beginning therapy with a second agent avoiding multiple tocolytics concurrently in patients who fail therapy with a single agent

61. 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

62. Progesterone supplementation no evidence that progesterone supplementation is effective in women with acute preterm labor,

63. Bedrest, hydration, and sedation There is no high quality evidence of the efficacy of bedrest, hydration, or sedation for prevention or treatment of preterm labor in singleton pregnancy

64. ineffectiveness of bedrest on preterm birth Women at risk of preterm birth Women with twin pregnancies Women with arrested preterm labor in index pregnancy

68. MANAGEMENT AFTER CESSATION OF CONTRACTIONS

69. If a second episode of acute preterm labor occurs, the indications for retreatment are the same as for a primary episode. corticosteroids is generally not repeated, except for one course of salvage (rescue)

70. PREVENTION with proven efficacy for prevention Smoking cessation Progesterone supplementation (in asymptomatic women with previous preterm birth or in asymptomatic women with no history of preterm birth but a short cervix in the current pregnancy) Reduction of multiple gestation by limiting the number of embryo transfers in ART Cerclage (in women with previous preterm birth and a short cervix in current pregnancy)

71. Management of pregnant women after inhibition of acute preterm labor The optimal management of pregnancies after resolution of an acute episode of preterm labor (PTL) is unknown.

72. PHYSICAL ACTIVITY Is hospitalization useful? — We suggest outpatient management for stable patients Unstable patient Advanced cervical dilatation, vaginal bleeding, nonreassuring fetal status, a long travel time to a hospital with appropriate levels of obstetric and neonatal care services

73. Is bed rest indicated? no evidence that bed rest is effective for prevention of spontaneous preterm birth in singletons or twins Bed rest has potential harms

74. Should exercise and work be avoided? Most trials of exercise in pregnancy have excluded women at risk for PTL or who develop PTL during the trial; therefore, it is difficult to assess the effect of exercise on these women.

75. reasonable to suggest modification of activities avoid working more than 40 hours per week, night work, prolonged standing (more than a total of eight hours or more than four continuous hours per 24-hour period),

76. Should sexual activity be avoided? Both prostaglandins in semen and orgasm can contribute to increases in myometrial activity discuss with patients that contractions may occur with greater frequency and intensity aft er intercourse We suggest patients avoid demanding physical activity and sexual intercourse,

77. Should travel be avoided? While it is unlikely that travel will cause PTL or preterm birth, women who wish to travel need to consider the risk of pregnancy complications away from their usual source of medical care,

78. MONITORING Fetal fibronectin testing Home uterine activity monitoring ACOG Fetal fibronectin testing and home uterine activity monitoring are not useful for monitoring women with an episode of arrested preterm labor

79. MEDICATION Maintenance tocolysis does not support the use of maintenance tocolytic for prevention Maintenance tocolysis may have a role in providing symptomatic relief with respect to intensity and frequency of contractions

80. Progesterone supplementation In the absence of another indication for progesterone supplementation (eg, prior spontaneous preterm birth, sonographic short cervix), we recommend not using progesterone as an adjunct to tocolysis nor as part of maintenance therapy after an arrested episode of PTL

81. Repeated courses of antenatal corticosteroids do not prevent PTL. We do not recommend routine weekly courses of antenatal corticosteroid therapy

82. Antibiotic prophylaxis There is no proven benefit to use of prophylactic broad-spectrum antibiotics to delay delivery in the setting of PTL with intact membranes

83. FOLLOW-UP singleton and twin scheduled on a weekly basis to review signs and symptoms of PTL and to evaluate whether there has been further cervical change. Typically, this evaluation is performed by digital examination and/or sterile speculum inspection of the cervix

84. After acute labor inhibition, do not routinely recommend a specific strategy of antenatal fetal assessment or serial ultrasound examinations for fetal growth assessment.

85. Efforts to delay delivery largely unsuccessful. SO, much attention focused on prevention

86. Risk factors for preterm birth

88. Supplemental progesterone in women with a history of prior preterm birth or a short cervix on ultrasound examination. It may be effective after an episode of arrested preterm labor, but the evidence is less robust. There is no evidence that progesterone supplementation is beneficial in other settings multiple gestation, PROM.

89. We suggest intramuscular injections of 17-alpha- hydroxyprogesterone caproate rather than vaginal progesteronehydroxyprogesterone caproate beginning (16 to 20 weeks) and continuing through the 36 th week. 250 mg weekly

90. Routine progesterone to preventing preterm birth in multiple gestations. NO twin pregnancies and a previous spontaneous preterm birth, the author prescribes 17-alpha- hydroxyprogesterone caproate. hydroxyprogesterone caproate twin pregnancies and a short cervix in the current pregnancy, the author prescribes vaginal progesterone.

91. Routine progesterone supplementation in the setting of PROM NO after an arrested preterm labor NO. women with a positive fetal fibronectin test. unclear The effect in women with a cerclage is unclear

92. Recommendations for progesterone supplementation to prevent preterm birth Singleton pregnancy, prior spontaneous singleton preterm birth, normal cervical length yes 250 mg intramuscularly weekly between 16 and 20 weeks continuing through 36 weeks or until delivery and monitor cervical length. Short (<25 mm) cervix → perform cerclage

93. Progesterone supplementation indicated? Singleton pregnancy, prior spontaneous twin preterm birth, normal cervical length Possibly 250 mg between 16 and 20 weeks continuing through 36 weeks or until delivery and monitor cervical length. Short (<25 mm) cervix → perform cerclage

94. Progesterone supplementation indicated? Singleton pregnancy, no prior spontaneous preterm birth, short cervix (≤20 mm) Yes Progesterone suppository 90 to 200 mg vaginally each night from time of diagnosis through 36 weeks of gestation..

95. Progesterone supplementation indicated? Multiple pregnancy (twins or triplets) without prior preterm birth, normal cervical length No No progesterone, no cerclage

96. Progesterone supplementation indicated? Twins, short cervix Possibly Vaginal progesterone, no cerclage

97. Progesterone supplementation indicated? Preterm premature rupture of membranes No Positive fetal fibronectin test No Undelivered after an episode of preterm labor Unclear –

98. Uterine anomaly or ART There are no data on the effectiveness of progesterone t for prevention of preterm birth in women with uterine malformations or who conceive with ART

99. . Standard contraindications to progesterone administration hormone-sensitive cancer, liver disease, or uncontrolled hypertension.

100. Placement of a pessary has also been reported to be useful for reducing the risk of preterm birth in women with a short cervix.