Laleh Eslamian MD, Prof of Obstet& Gynecol, Perinatologist, TUMS

- 130  10 6 birth annually in the world. - 4  10 6 die in the 1 st 4 weeks of life. - Main causes of neonatal death: PTB, severe infection & asphyxia. - PTB is responsible for about half of neonatal deaths.

 Iran, Health ministry data: 1,247,315 birth in 1392 in hospitals,1, total.  7.7% < 37w :  7.7% < 2500g  Iatrogenic PTB rate ? (20% in USA)  12% of births in Iran occurred <37 weeks in 2011 ( according to WHO data).

 In theory, identification of risk factors for preterm delivery before conception or in early pregnancy provides an opportunity for intervention to prevent this complication.  However, many preterm births occur among women with no risk factors and there are few interventions that have been proven to prolong pregnancy in women at risk.

 The risk of PTB is highest when: 1)The previous PTB was in the pregnancy prior to the current pregnancy (ie, no intervening term pregnancies) (15-30%) 2)There is a history of multiple PTBs (60%: 2)

 Whether PTB of twins is associated with an increased risk of PTB in a subsequent singleton pregnancy is unclear.  Data are conflicting, but the bulk of evidence suggests that a prior preterm twin birth is associated with an increased risk of preterm birth in a subsequent singleton pregnancy.

 The overall risk of spontaneous preterm birth in twin pregnancy is significantly higher in multiparous women whose previous singleton delivery occurred preterm:  67.3 versus 20.9% if the previous singleton delivery was at term (OR 7.8; 95% CI 5.5– 11.2).

 Hx of abortion  Short inter pregnancy interval  Assisted reproduction  Multiple gestation (reduction)  Vaginal bleeding  Infection (asymptomatic bacteriuria, periodontal disease, bacterial vaginosis…)  Genetic factors (maternal not paternal)  Maternal age and race  Life style (physical activity and work, stress, weight and weight changes, smoking, substance abuse)  Cervical & uterine factors (CL: 16-28w)  Chronic maternal medical disorders, autoimmune disease, anemia, chronic infection.  Fetal: FGR, anomalies, male gender  Hx of SIDS  Biomarkers ( fibronectin & 30 others)

 What should be done for prevention of PTB in primiparas?

 Cervical shortening (effacement) is one of the first steps in the parturition process, preceding labor by several weeks.  As CL decreases in the 2 nd trimester, the risk of spontaneous PTB increases, especially when effacement occurs early in the 2 nd trimester.  Because effacement begins at the internal cervical os and progresses caudally, it is often detected on ultrasound exam before it can be appreciated on physical exam.  The cause of preterm cervical shortening is often unclear.

 Routine US screening for short cervix in singleton pregnancies is suggested.  The protocol for initiating CL measurement is based on prior OB Hx.  CL measurement is not a sensitive screening test for prediction of PTB in multiple gestations with short cervix.

Normally, cervical length: stable between 14-28w  15 mm – 2nd centile  20 mm – 5th centile  25 mm – 10th centile  35 mm – 50th centile *****  45 mm – 90th centile

1) After 28 – 32w, a gradual decline in cervical length is normal. 2) The median cervical length is:  40 mm< 22w  w  30 mm> 32 w 3) Cervical length is not significantly affected by parity, race/ethnicity, or maternal height.

TVS: The most reproducible technique for CL assessment. No management should be done on TAS results.

Procedure of CL measurement: - GA (14 – 24 w ) - Empty the bladder,dorsal lithotomy position - Apply gel on probe and on the covering condom. - Place the transducer in anterior fornix. - Avoid pressure on the anterior lip. - Enlarge the image to fill at least one half of the screen - Locate int.os below the lower edge of mat. empty bladder. - Place calipers between int. and ext. os - Anterior & posterior lips of cervix should be equal. - Measure 3 times: record the “shortest best”. - Minimum of 3 minutes is needed to see funneling after pushing. - Record absence or presence of funneling & CL.

Dx of short cervix when cervical length on -28 w:  ≤20 mm in women with no prior preterm delivery  <25 mm in women with a prior preterm delivery

The following strategies have no benefit in reducing recurrences: Bed rest (adverse effects: DVT, muscle atrophy & stress)  mimetics (prophylactically) Life style interventions :↓ manual labor ↑ Prenatal visits Psychosocial supports Diet supple: Fe, FA, Ca, Zn, Mg, fish oil

These 2 strategies have proved to have benefit in reducing recurrence: 1) Cervical cerclage 2) Progesterone

In cases with previous PTB:↓ 25% in PTB<34 w ( 2 protocols) 1-Cerclage soon after 11 – 13 w (normal scan) 2- CL measurement q2 w (14 – 24 w ) → cerclage when CL < 25mm Similar results for PTB but cerclage rate is reduced 50% in the 2 nd.

 Progesterone supplementation reduces the risk of preterm birth by about one-third: 1) in women with a singleton pregnancy who have had a previous spontaneous singleton preterm birth and 2) in women with a short cervix on ultrasound examination in the current pregnancy.

 Meta-analyses of randomized trials have concluded that progesterone supplementation is protective against recurrent preterm birth and improves neonatal outcome. (2013 meta-analysis including 36 trials, comparing the benefits of progesterone supplementation with placebo)   Birth <34 weeks (relative risk [RR] 0.31, 95% CI )   Birth <37 weeks (RR 0.55, 95% CI )   Neonatal death (RR 0.45, 95% CI )   Use of assisted ventilation (RR 0.40, 95% CI )   Necrotizing enterocolitis (RR 0.30, 95% CI )  Reductions in intraventricular hemorrhage, neonatal sepsis, and retinopathy of prematurity were not statistically significant.

 Tx interventions is based upon both cervical length and prior pregnancy history.  The change in cervical length on subsequent US exams also appears to impact the risk of PTB in women diagnosed with a short cervix (<25 mm).

For women with a singleton pregnancy who have had a previous spontaneous singleton preterm birth:  Progesterone Tx is suggested.  im injections of hydroxyprogesterone caproate rather than vaginal progesterone.  -20 and continuing to 36th w.  17-OHC 250 mg weekly.

 Women with a singleton pregnancy who have had a prior spontaneous twin birth:  Progesterone Tx is suggested.  im injections of hydroxyprogesterone caproate rather than vaginal progesterone.  -20 and continuing to 36th w.  17-OHC 250 mg weekly.

 Women with midtrimester cervical shortening (≤20 mm <24 w) and no prior spontaneous singleton preterm birth:  vaginal progesterone Tx through the 36 th w.  Reasonable options include a vaginal suppository (100 or 200 mg), gel (90 mg), or tablet (100 mg micronized progesterone).

 Routine progesterone supplementation does not appear to be useful for preventing preterm birth in unselected multiple gestations.  For women with twin pregnancies and a previous spontaneous preterm birth: hydroxyprogesterone caproate.  For women with twin pregnancies and a short cervix in the current pregnancy: vaginal progesterone.

 Routine progesterone supplementation does not appear to be useful for preventing preterm birth in the setting of: 1) PPROM 2) After an episode of arrested preterm labor.  There is no information on efficacy in women with a positive fetal fibronectin test.  The effect in women with a cerclage is unclear.

 A synthetic progestogen with minimal to no androgenic activity.  It is typically administered im.  Doses have ranged from 25 mg every 5 days to 1000 mg/ w, beginning as early as 16w.  We use 250 mg dose/w.  Standard contraindications to progesterone administration include hormone-sensitive cancer, liver disease, or uncontrolled hypertension.  FDA approved.  Hypospadias in male offsprings. (when<11w)  GDM: 3 fold in one study.

 Natural progesterone is typically administered vaginally.  The advantage of vaginal progesterone is its high uterine bioavailability since uterine exposure occurs before the first pass through the liver.  It also has few systemic side effects, but vaginal irritation can be bothersome and the drug needs to be administered daily.  Doses of 90 to 400 mg have been effective, beginning as early as 18 w.  Other options include a 100 mg micronized progesterone vaginal tablet or an 8 vaginal gel containing 90 mg micronized progesterone per dose.  Not FDA approved.

 An oral micronized preparation of natural progesterone also exists.  Daily doses of 900 to 1600 mg have been given.  Reported side effects include sleepiness, fatigue and headache.

 Use of a pessary to prolong pregnancy in women with a short cervical length may be an effective, inexpensive, and easy to implement intervention.  In 2012, a multicenter trial randomly assigned 385 pregnant women with cervical length ≤25 mm at 20 to 23 w to use of a cervical pessary or expectant management. The majority of these patients (89%) had no history of previous PTB, and none were treated with progesterone or cerclage. The pessary group had a lower rate of spontaneous PTB than the expectant management group:  Delivery <28 w 2% vs 8%,OR: 0.23, (95% CI )  Delivery <34 w 6% vs 27%; OR: 0.18, (95% CI )  A subsequent RCT published in 2013 found that use of a pessary did not reduce the rate of preterm delivery <34 w compared with no Tx.