Preterm delivery : Preterm labour and PPROM

Discussion of PTD

1. Preterm delivery : PTL and PPROM Labour pain and fluid leaking during mid pregnancy

2. LEARNING OBJECTIVES To understand the extent of the problem, its causes and consequences. To be aware of the limitations of our current understanding. To appreciate the problems and potential complications associated with our current management of preterm labour. To grasp the potential for improvements in our management of preterm labour.

3. Case scenario Rawshan is 26 years old pregnant lady in her 31 weeks gestation presented to labour room with history of colicky abdominal pain of few hours duration, back pain with thick vaginal discharge & good fetal movement

4. Definitions In pregnancy, the gestational age of viability is 24wks . Currently, the ‘ grey zone’ for viability is around 23 weeks . Occasional survivors are seen after delivery at 23 weeks, which has become the ‘grey zone’ for viability . In pregnancy, term refers to the gestational period from 37+0 to 41+6 wks. Preterm labour (PTL) is the onset of labour before 37 weeks’ gestation. PTL are those that occur between 24 +0 and 36 +6 weeks gestation . Second trimester or late miscarriage occurs between 12 and 23 weeks gestation . A more practical definition of late miscarriage is one occurring between 17 and 23 weeks.

5. Categories Spontaneous PTL 50% PPROM 25% Delivery for maternal or fetal indications 25% Iatrogenic or medically-indicated deliveries Pre-eclampsia Maternal cardiac or renal conditions or malignancies . Chorioamnionitis APH Fetal growth restriction (FGR)

6. According to etiology, outcome and recurrence risk, it is divided into three gestational periods: Extremely preterm births : 24 +0 to 27 +6 weeks. very preterm births : 28 +0 to 31 +6 weeks. Mildly preterm births : 32 +0 to 36 +6 weeks. Classification of preterm births

7. Teenagers and women with advanced maternal age (Parity or >5) Higher incidence of preterm deliveries in first pregnancies. Socioeconomic factors Marital status Genetic and environmental factors Cigarette smoking, illegal substance (i.e. cocaine) abuse, alcohol Poor nutrition Previous preterm The risk of PTD

8. L abo u r vs PTL Labour at term and prior to it share a common pathway involving: uterine contractility, cervical effacement and dilatation membrane rupture. At term , the activation of this pathway is physiological . spontaneous preterm labor is an enigmatic process that occurs when the normal labor pathway is triggered through various pathologic mechanisms. a variety of pathologies underlie labour remote from term . It has been suggested by some authors that preterm labour be considered a syndrome , in order to emphasize its multifactorial nature.

9. Endocrinology and biochemistry of labour During pregnancy the uterus undergoes marked biochemical and physiological changes while expanding to accommodate the growing fetus and remaining quiescent. The cervix remains rigid and closed to retain the developing fetus within the uterus. Throughout pregnancy ‘pro-pregnancy’ factors inhibit myometrial contractility . ‘pro-pregnancy’ factors : progesterone , relaxin , ( hCG ) prorelaxation prostaglandins (PGs), such as prostacyclin

10. The onset of labour involves the synchronization of myometrial activity through greater expression of gap junctions that connect myometrial cells. Increased myometrial activity results from the activation of a ‘cassette of contraction-associated proteins’ (CAPs), which convert the myometrium from a quiescent to a contractile state. CAPs include : gap junction proteins, oxytocin and prostanoid receptors, enzymes for PG synthesis cell signalling proteins. CAPs Activate fetal membrane PG and cytokine production Cervical remodelling and ripening.

11. Progesterone maintains uterine quiescence Labour as an inflammatory process The roles of oxytocin and prostaglandins

12. Causes of preterm labour Cervical weakness ↔ Ascending Infection Ascending Infection ↔ Cervical weakness Ascending Infection → Decidual Haemorrhage Placental abruption → Decidual Haemorrhage Multiple pregnancy → Uterine distension Multiple pregnancy → Fetal stress and Maternal stress Uterine müllerian anomalies Haematogenous infection Iatrogenic infection Idiopathic

13. Infection Infection of the fetal membranes, chorioamnionitis, is a major cause of preterm birth particularly in deliveries before <32 weeks ’ gestation . It is associated with a threefold increased risk of PTD with intact membranes, and a fourfold increased risk with ruptured membranes. In most cases, infection ascends from the vagina, or transplacental or introduced during invasive procedures. Overall , 33% of all pregnancies delivered after PPROM are complicated by infection . The uterine cavity is normally sterile but the vagina contains commensal bacteria. Depending on the bacterial load and cervical resistance, the bacteria may ascend through the cervix and reach the fetal membranes. This: may activate the decidua, increase prostaglandin release and trigger contractions. Alternatively, it may weaken the membranes, leading to rupture.

14. Abnormal vaginal flora, for example bacterial vaginosis (BV) , affects 16% of pregnant women and is associated with PPROM and PTL, with a greater risk the earlier in gestation <16 weeks is identified. Chorioamnionitis is associated with : drives PTL, fetal brain damage (periventricular leukomalacia (PVL) and intraventricular haemorrhage (IVH)) , since intrauterine infection drives a fetal inflammatory response, involving : a proinflammatory cytokinaemia morphologically , a vasculitis of the umbilical cord and/or the vessels of the chorionic plate.

15. TYVU

16. Mul t ipl e pr egn anc y an d u te rin e distension Overall, 56% of multiple births deliver before 37 weeks and 10–15% before 32 weeks. The risk of PTD rises with fetal number, with triplets delivering on average at 32 weeks and quadruplets delivering at 28 weeks. Multiple pregnancies have an increased risk of pre-eclampsia, FGR and other medical complications of pregnancy. Twins have a six to sevenfold increased risk of cerebral palsy. Polyhydramnios, the presence of too much amniotic fluid. Severe polyhydramnios can be managed with amnio-drainage, alternatively, indomethacin (NSAID), used as it reduces fetal urine production.

17. Uterine müllerian anomalies Unrecognized but are estimated to occur in up to 4% of women of reproductive age. Occur as a consequence of abnormal embryologic fusion and canalization of the müllerian ducts and result in an abnormally formed uterine cavity, range from an arcuate uterus, results in minimal fundal cavity indentation, to complete failure of fusion resulting in uterine didelphys. Associated with adverse pregnancy outcome in up to 25% of women, including first and second trimester miscarriage, PPROM, preterm birth, FGR, breech presentation and caesarean section.

18. Haemorrhage The presence of a subchorionic haematoma in early pregnancy increases the risk of later PPROM, either through an effect of thrombin on membrane strength or through the occurrence of infection in the haematoma. Acute bleeding leads to the release thrombin that directly stimulates myometrial contractions . Risk factors include pre-eclampsia and hypertension, previous abruption, trauma, smoking, cocaine use, multiple pregnancy, polyhydramnios, thrombophilias, advanced maternal age and PPROM. When an abruption involves 50% or more of the placenta it is frequently associated with fetal death.

19. Problems of preterm baby Cerebral palsy: Neurological deficit Learning difficulty Retinopathy Hearing aid RDS Hyperbilirubinaemia

20. Neonatal care unit

21. Clinical features of preterm labour

22. History Dating of pregnancy / LMP, early US Clinical presentation / risk factors: Pain /uterine contraction Vaginal loss Pelvic pressure low backache Generally unwell, may be fever or urinary symptoms

23. Examination General examination : pulse, BP, temperature and state of hydration . Abdominal examination : the presence of uterine tenderness, suggesting abruption or chorioamnionitis . Sterile Speculum examination : pooling of amniotic fluid, blood and/or abnormal discharge. Ask patient to cough/press over the fundus  leaking liquor. A visual assessment of cervical dilatation Vaginal examination: Digital exams should be limited, as they are known to stimulate prostaglandin production and may introduce organisms into the cervical canal. Repeat vaginal examination in 1–4 hours should be considered essential in the absence of specialized tests. The interval between assessments should be guided by the severity of the symptoms.

24. Nevertheless, the diagnosis of preterm labour remains notoriously difficult unless contractions are accompanied by advanced dilatation (>3 cm), ruptured membranes or significant vaginal bleeding . Differential diagnosis of PTL : Urinary tract infection Gastroenteritis Constipation Red degeneration of fibroid Placental abruption

25. Investigations Blood group & Rh Full Blood Count MSU / culture & sensitivity Cervicovaginal swab / microbiology Fetal fibronectin (fFN) TA / TV US : Gestational age, cervical length Cervical length measurement by TVU has been shown to improve diagnostic accuracy. A normal cervix measures approximately 35 mm in length . Significant cervical shortening is often accompanied by dilatation and funnelling of the membranes down the cervical canal . Amniotic fluid volume placental site

26. Fetal fibronectin (fFN) Testing the cervicovaginal fluid levels of fetal fibronectin (fFN), a glycoprotein found in cervicovaginal fluid, amniotic fluid, placental tissue and in the interface between the chorion and decidua. It acts like ‘glue’ at the maternal–fetal interface and its presence in cervicovaginal fluid between 22 and 36 weeks ’ gestation has been shown to be a predictor of PTD. Negative fFN test to be sent home . Those with a positive fFN tes t can be admitted for tocolysis and steroids for fetal lung maturation .

27. How you manage women with symptomatic PTL ?

28. Treatment in symptomatic patient o if cervix not dilate d  support o if membrane ruptured  contraction wait & monitor terminate no contraction

29. Management of symptomatic PTL wo men At tertiary center or intrauterine transfer Communication and support : Ensure: Sympathy , pain relief, reassurance Maternal corticosteroids : The most beneficial treatment in preterm labour is a course of maternal steroids . a single course of maternal steroids (two injections 12–24 hours apart) given between 28 and 34 weeks gestation and received within 7 days of delivery. Maximum benefit from the injection is seen after 48 hours . Courses received less than 48 hours or more than 7 days before delivery still lead to benefit, as may courses given between 24 and 28 weeks. They are not indicated below 24 weeks . Effects within 7 days of delivery: ↓ RDS, ↓ IVH, ↓ necrotizing enterocolitis , improve neonatal outcomes and lung function.

30. 3. Tocolytics : The sole reason for using tocolytics is to delay delivery for 48-hour window to allow : a course of steroids for fetal lung maturation to be completed to facilitate transfer of the undelivered mother to a unit able to provide appropriate neonatal care. In utero transfer . Tocolytics are only used for short pregnancy prolongation (delay delivery) for about 48-hour . The first choice → CCB ( nifedipine ) or an OTR antagonist ( atosiban ). However, recently PG inhibitors and CCB are most likely the best therapy for PTD on the basis of delaying delivery by 48 hours, neonatal mortality, neonatal ( RDS) and maternal side-effects.

31. Types of Tocolysis Beta-sympathomimetics Beta-agonists (ritodrine, salbutamol and terbutaline) are predominantly β2 adreno-receptor agonists), which mediate myometrial relaxation by stimulating cyclic adenyl monophospate (AMP) production. Magnesium sulphate (muscle relaxant) Non-steroidal anti-inflammatory drugs ( Indomethacin for short term use < 30 wks gestation ) Calcium channel blockers (Nifedipine) Oxytocin receptor antagonists ( OTR-A atosiban)

32. 4. Antibiotics Given in case of : Suspected or proved vaginal infection ROM or established chorioamnionitis 10 days Erythromycin +/- Clindamycin or Metronidazole. T he use of prophylactic antibiotics in uncomplicated preterm labour before 37 weeks with intact membranes did not confer any short-term neonatal benefit. 5. Pain killers - Risk of placental retention / manual removal under anesthesia 6. Continuous ( EFM ) . Because preterm infants have less reserve to tolerate the stress of labour 7. Low threshold for CS (abnormal FHR Pattern, preterm breech )

33. 8 . Augment contractions After 24 weeks, if there is no evidence of acute maternal or fetal compromise induction with milder prostaglandins +/- conventional-dose oxytocin ( precaution if history of uterine surgery) can be considered as an alternative to a planned CS. I f there is already clinical evidence of chorioamnionitis : Great care must be exercised. In these cases, delay in ending the pregnancy may lead to worsening infection and consequent morbidity for both mother and baby. Augmenting labour may be the most appropriate management . 9. Emergency cervical cerclage - Difficult if cervical dilatation >3 cm & effacement. - Contraindicated : Bleeding Contractions Infection 10 . In utero transfer

34. How you manage asymptomatic women with known risk factors for preterm birth ?

35. Early dating scan / accurate Genital tract infection: Bacterial vaginosis early treatment of BV prior to 20 weeks gestation may lower the risk of late miscarriage and early birth. Asymptomatic bacteriuria: It carries an increased risk of preterm birth. Short courses of antibiotics based on culture sensitivities reduce the risk of pyelonephritis and early delivery. GBS genital colonization: Preterm infants are more susceptible to early-onset GBS infection, acquired during passage through the birth canal. In women known to be at increased risk of early delivery, testing for GBS antenatally with a combined low vaginal/rectal swab allows consideration of intrapartum prophylaxis. Attempts at antenatal eradication has repeatedly been shown to be of no benefit. Fetal fibronectin : (at ≥ 22 weeks ) Can only be undertaken after 23 weeks, as high levels may be physiological before then. In high-risk asymptomatic women: + test at 24 weeks gestation  nearly half will deliver before 30 weeks gestation. - test  the chance of such an early birth is less than 1 per cent with. This negative predictive value may be its main use, as interventions based upon positive test results have not been shown to be helpful. Tocolytics : no evidence of benefit from prophylactic or maintenance therapy with conventional oral or intravenous tocolytics . Management of high-risk asymptomatic women

36. 7. Progestational agents: Progesterone: support of pregnancy through uterine quiescence. it affects cervical ripening and mucous production . have anti-inflammatory properties. It has a good safety profile when used in pregnancy. U sing IM or intravaginal progesterone have shown some reductions in the incidence of preterm birth. 8. Life style modification : may be helpful smoking cessation// sexual abstinence and/or psychological support: are no clearer. 9. Cervical length (TV/US): Cervical length can be accurately and repeatedly measured by TVUSS. In asymptomatic women with a short cervix, the risk of preterm delivery rises dramatically with further decreases in length. In the presence of a normal cervical length  intervention can usually be deferred. S hort cervix at < 24 weeks  can be managed by cervical cerclage . When significant cervical shortening is found at or beyond 24 weeks : women should be educated as to the signs and symptoms that should provoke hospital attendance. Prophylactic steroids should be considered . vaginal progesterone reduces the risk of preterm delivery in cases where the cervix is short. 10. Cerclage Management of high-risk asymptomatic women, cont..

37. Elective cervical cerclage The procedure is usually performed at 12-14 wks Elective cerclage may be advised solely based on a woman’s past obstetric history. if history of 3 or more late miscarriage or very preterm deliveries . In selective cerclage , surgery is based upon serial transvaginal ultrasound measurements of cervical length . Cervical cerclage can be done under general or regional anaesthesia. Removed at: 37 wks if labour started at any time If membrane ruptured McDonald’s technique , simple & quick ( mersilene suture)

38. ROM

39. Case scenario Manal is 34 years old lady, 29 weeks twin gestation presented with history of generalized mild abdominal pain & no vaginal bleeding, , recurrent dampness, decreased fetal movement, temperature = 37.2 C

40. Differential diagnosis of watery vaginal discharge (gush of fluid) : ROM Urine loss: incontinence and UTIs are both more common in pregnancy Vaginal infection Leukorrhoea : the cervical glands often become overactive during pregnancy

41. Definitions # PROM : It is the leakage of amniotic fluid beyond 37 weeks gestation, prior to the onset of labour (in the absence of uterine contraction) - Incidence: (8 %) # P PROM : It is the leakage of amniotic fluid in the absence of uterine activity in preterm pregnancy ( prior to 37 weeks ) - Incidence: (2 %)

42. Latency Period : it is the time from membrane rupture until delivery from the onset of PPROM: 50% of women deliver within 1 week of PPROM. 75% within 2 weeks of PPROM. The earlier in pregnancy that PPROM occurs the shorter the interval to delivery. Pregnancies complicated by PPROM prior to 23 weeks , pulmonary hypoplasia may develop leading to an increased risk of neonatal death. The presence of amniotic fluid greater than 2 cm on ultrasound is associated with a lower incidence of pulmonary hypoplasia .

43. Pathophysiology of PROM: it is physiological condition: Apoptosis & Braxton Hicks contraction → ↑ stretching of the membranes → thinning focally & biochemical changes → membrane prolapse & rupture

44. Significant perinatal morbidity Preterm delivery RDS (respiratory distress syndrome) Risk of chorioamnionitis, neonatal sepsis Cord prolapse, compression Abruptio placentae Operative delivery Fetal death

45. What are the clinical features of PROM / PPROM ?

46. History The most reliable diagnostic feature of PPROM from the history is the report of a ‘gush of fluid’ vaginally , usually followed by a more-or-less continuous dribble . The presence of any vaginal discharge should be ascertained. Fetal movements may be ↓ in strength or frequency after PPROM . occasionally uterine irritability or contractions may be reported . Examiantion General examination: Infection may lead to an increased pulse and temperature and a flushed appearance. . Abdominal examination: may reveal a clinical suspicion of oligohydramnios uterine tenderness if chorioamnionitis is present . Sterile Speculum examination: For definitive diagnosis of PPROM . It is done preferably after the patient has been resting supine for 20–30 minutes. A pool of amniotic fluid in the posterior vagina is diagnostic . Cough or fundal pressure  leakage of liquor. It is also important at this point to visualize the cervix . Fluid may be seen trickling through the external os and dilatation can be assessed. Vaginal examination: Digital vaginal examinations should be avoided if possible in PPROM, as they are associated with a significant reduction in the latent interval before labour. This reduction is most dramatic at the earliest gestations . Frequent vaginal examination should be avoided

47. If a pregnant woman provides a clinical history highly suspicious for PPROM , but diagnosis is not confirmed by initial speculum exam, the woman can be placed in a semi-upright position and reexamined after 1 hour to allow for vaginal poring. As a last resort, if results are still equivocal, amniocentesis with injection of indigo carmine dye may be performed. A tampon is placed and if any dye leaked from the cervix, a blue staining would be noted on the tampon, confirming the diagnosis of PPROM.

48. What in v estigati o ns wo u l d b e most helpful and why? Bed side tests : Nitrazine test : Amniotic fluid is alkaline, whereas the vaginal secretions are usually acidic. An elevated pH turns a nitrazine stick black. Some units use nitrazine sticks to define the presence of amniotic fluid. false positives occur with: blood, semen urine. However , the predictive value of a negative test is very high . Ferning test : microscopic dry smear of liquor False positive: Cervical mucus Genital tract swabs (specialized tests) HVS (high vaginal swab) Screening for GBS ( group B streptococcus) Lower genital tract swabs are routinely taken, but cultures do not correlate well with the risk of chorioamnionitis.

49. Maternal well-being : Conservative management includes intensive clinical surveillance for signs of chorioamnionitis: Regular recording of maternal temperature, heart rate or PR, blood pressure serial white cell counts and C-reactive proteins as early markers of infection Fetal well- being : Serial antepartum CTG is important after PPROM , as a gradually increasing baseline heart rate or fetal tachycardia can be the first sign of intrauterine infection . US : Amniotic fluid volume, placental location, presentation & congenital abnormality of the fetus , estimated fetal weight. Oligohydramnios offers supporting evidence for PPROM having occurred butis not gold standard for the diagnosis. Normal or increased volume does not preclude the diagnosis. Unlike preterm labour, cervical length measurements do not have predictive ability in PPROM. Amniocentesis: A sample of amniotic fluid can be sent for Gram stain, microscopy and culture, to establish whether there is an intrauterine infection ( chorioamnionitis ). There is , however, a risk of stimulating preterm labour by performing an invasive test, and amniocentesis can be technically very difficult when there is little amniotic fluid.

50. Nitrazine test

51. F e rning

52. How you manage women with PPROM ?

53. Treatment of PPROM It balances the risk of prematurity (if delivery is encouraged) versus the risk of maternal and fetal infection (if delivery is delayed ) . Clinical management of PPROM is based on the gestational age and mother- fetal condition : Viability to 34 wks gestational age 34 to 37 wks gestational age

54. PPROM before 34 weeks’ gestation  Conservative management in hospital is followed unless it is contraindicated. Conservative management include: Hospital admission. Close Fetal and maternal surveillance for Chorioamnionitis / abruption/PTL/prolapse/non-reassuring fetal status ( either with a nonstress test or biophysical profile). Antenatal steroids – i.m . betamethasone , 12 mg / 24 hours → 2 days Or i.m . dexamethasone , 6 mg / 12 hours → 2 days There appears to be no increased risk of maternal infectious morbidity from steroids administration. leukocytosis occurs after administration of steroid and may not be representative of infection. 1. Viability to 34 wks gestational age

55. 1. Viability to 34 wks gestational age, cont.. 4. Latency antibiotics . Administration of latency antibiotics: improves neonatal outcomes. ↓ RDS, NEC, neonatal sepsis , bronchopulmonary dysplasia, and pneumonia ↑ latency interval. Latency antibiotics along with antepartum steroids likely reduce perinatal mortality. A typical antibiotic regimen includes 48 hours of intravenous ampicillin and erythromycin, followed by 5 days of oral ampicillin and erythromycin. Ampicillin and amoxicillin cover GBS and provide gram-negative and some anaerobic coverage. Erythromycin offers coverage of genital mycoplasma along with some coverage of gram-positive cocci. Azithromycin , which has a better side effect profile than erythromycin , may be used as an alternate macrolide. Amoxicillin-clavulanic acid should be avoided because of a possible increased risk of NEC. 5. If there is cervical cerclage → removed PPROM at less than 23 weeks or greater than or equal to 32 weeks  cerclage should be removed immediately. For patients greater than or equal to 23 to less than 32 weeks  cerclage should either be removed immediately or after a 48-hr course of steroids.

56. 6 . Magnesium Administration For patients presenting with PPROM prior to 32 weeks, maternal administration of magnesium sulfate may provide neuroprotective benefits for neonates . Pregnant women at risk for preterm delivery between 24 and 31 weeks because of PPROM or advanced preterm labor who were randomized to magnesium sulfate had a significantly lower risk of a child born with cerebral palsy. While protocols and dosing regimens may vary by center , administration of magnesium sulfate for 24 hours , in the absence of maternal contraindications, for patients presenting with PPROM prior to 32 weeks is a reasonable clinical strategy. If a patient with PPROM is not at risk of imminent delivery 24 hours after presentation, magnesium may be discontinued . Induction of labour / at 34 weeks ( if possible ). Immediate induction if ( contraindications for conservative management) : Chorioamnionitis . Active labour Non reassuring fetal heart tracing Significant abruption Cord prolapse 1. Viability to 34 wks gestational age, cont..

57. 2. 34 to 37 wks gestational age PPROM greater than or equal to 34 weeks  delivery is recommended, because the fetal and maternal risks of prolonging pregnancy outweigh fetal benefits of expectant management. However , in remote locations without intensive neonatal care, expectant management may be warranted up until 36 weeks. PROM after 37 weeks ’ gestation and labour has not already begun  Immediate induction of labour is advised by oxytocin (iv) or PG vaginally or within 12 hours.

58. Chorioamnionitis : It is an infection of chorion & amnion with an elevation of temperature ≥ 38 ͦ C (> 100°F) with at least 2 of the followings: Maternal PR ≥ 100 bpm FHR ≥ 160 bpm ↑ CRP, ↑ WBC Uterine tenderness Offensive vaginal discharge

59. If chorioamnionitis is present, antibiotic (Ampicillin or Erythromycin as prophylaxis ) & delivery are indicated If chorioamnionitis is not present antibiotic therapy can significantly delay delivery Tocolysis is contraindicated due to the increased risk of maternal and fetal infection in patients with PPROM. In the majority of cases of PPROM there is time for administration of corticosteroids and in utero transfer before the onset of PTL. Amnio – infusion

60. Prediction of preterm delivery Past obstetric history Ultrasound measurement of cervical length Prevention of preterm delivery Progesterone uterine quiescence and inhibit the production of proinflammatory cytokines and PGs within the uterus Cervical cerclage the cervix shortens (usually <25 mm) in women with a history of cervical surgery or previous preterm birth (ultrasound indicated cerclage); or when the cervix is dilating in the absence of contractions (rescue cerclage). 2019-09-17 15:50:17 -------------------------------------------- In 12-14 week and removed at 3 7 or term