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Emerging Concepts in Preterm Labour
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What is preterm birth? Preterm birth – birth that occurs from 20+0 to 36+6 weeks of gestation 70-80% spontaneous, resulting from preterm labor (40-50%) or PPROM (20 – 30%), rarely, cervical insufficiency results in spontaneous PTB 20-30% iatrogenic - issues that jeopardize the health of the mother or fetus like preeclampsia, placenta previa, abruptio placentae, fetal growth restriction, multiple gestation Regular uterine contractions accompanied by a change in cervical dilation, effacement or both, Initial presentation with regular contractions and cervical dilation of at least 2 cm Practice Bulletin No. 171: Management of Preterm Labor, ACOG, October 2016 - Volume 128 - Issue 4 - p e155-e164 doi: 10.1097/AOG.0000000000001711
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Effects of preterm birth Leading cause of neonatal mortality and the most common reason for antenatal hospitalization Occurs in 5-18% of pregnancies worldwide Less than 10% of women with the clinical diagnosis of preterm labor actually give birth within 7 days of presentation Practice Bulletin No. 171: Management of Preterm Labor, ACOG, October 2016 - Volume 128 - Issue 4 - p e155-e164 doi: 10.1097/AOG.0000000000001711
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Risk factors History of spontaneous preterm birth - recurrent sPTB – 15-30% Women who were born preterm are at modestly increased risk of having a sPTB compared with women who were born at term Short interpregnancy interval <18 months History of surgical uterine evacuation had a small but statistically significant increase in risk for PTB – as opposed to medical termination of pregnancy Epigenetics - Genetic polymorphisms appear to contribute to length of gestation and a woman's likelihood of sPTB
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Risk factors Chronic maternal medical disorders - hypertension, renal insufficiency, type 1 diabetes mellitus, depression and exposure to SSRIs History of delivery of an infant who subsequently died from sudden infant death syndrome appears to be a risk factor for PTB in the following pregnancy Pregnancies conceived by assisted reproduction and Multifetal gestation Infections – asymptomatic bacteriria, periodontal disease, genital infection, BV
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Risk factors Early pregnancy bleeding - Decidual hemorrhage results in release of tissue factor can trigger local thrombin formation - decidual thrombin leads to increased expression of sFlt-1 increasing PTB due to preeclampsia, abruption or fetal growth restriction Short cervix, dilated cervix >1cm at 24 weeks Smoking, substance abuse, higher BMI, shorter height, sub-optimal prenatal care – increase the risk of PTB Physical activity, exercise and coitus – not significant
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Risk factors Higher for non-Hispanic Black and Indigenous women than for White, Asian, or Hispanic women Rate of PTB is higher at the extremes of maternal age Cold knife conization and LEEP for CIN - increased risks for late miscarriage and PTB - loss of tensile strength from loss of cervical stroma Uterine malformations – Congenital or acquired like submucosal fibroid Identification of modifiable and nonmodifiable risk factors for PTB before conception or early in pregnancy will lead to interventions that help prevent it However, two-thirds of PTBs occur among women with no risk factors
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Pathogenesis Premature activation of the fetal hypothalamic-pituitary-adrenal axis in response to maternal or fetal stress Exaggerated inflammatory response/infection or an altered genital tract microbiome Decidual hemorrhage (placental abruption) Pathological uterine distension
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Predicting risk for preterm birth Risk scoring systems — quantitative method using epidemiologic, historical and clinical risk factors – low positive predictive value Cervicovaginal fetal fibronectin (fFN) ≥50 ng/mL can be a useful biomarker for predicting PTB within 7 to 14 days in women with contractions and mild cervical dilation and effacement Short cervix before 24 weeks of gestation (<25 mm) is predictive of an increased risk for preterm birth Rectovaginal group B streptococcal culture, Urine culture for asymptomatic bacteriuria
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Diagnosing preterm labour Suspected preterm labour and she is 30+0 weeks pregnant or more, consider transvaginal ultrasound measurement of cervical length as a diagnostic test to determine likelihood of birth within 48 hours - cervical length is more than 15 mm – unlikely PTL Consider fetal fibronectin testing as a diagnostic test to determine likelihood of birth within 48 hours for women who are 30+0 weeks pregnant or more if transvaginal ultrasound measurement of cervical length is not available Do not use transvaginal ultrasound measurement of cervical length and fetal fibronectin testing in combination Suspected PTL in <29 weeks, fFN positive or Cervical length < 15 mm - treat Preterm labour and birth NICE guideline [NG25]Published: 20 November 2015 Last updated: 02 August 2019
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Antenatal steroids gtg 74, feb 2022 Corticosteroids should be offered to women between 24+0 and 34+6weeks gestation in whom imminent preterm birth is anticipated Antenatal corticosteroid use reduces neonatal death when the first dose is given within the 48 hours prior to birth, benefits are also seen when the first dose is given within 24 hours of birth Women with twins and triplets should be offered targeted antenatal corticosteroids for early birth in line with recommendations for singletons Consider the balance of risks and benefits of corticosteroids in women in whom imminent preterm birth is anticipated from 35+0to 36+6weeks’gestation Rescue Course if treatment more than 7 days ago – Likely to reduce birthweight head circumference and neonatal blood pressure
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Antenatal steroid agent of choice 24mg dexamethasone phosphate is given intramuscularly in two divided doses of 12 mg 24 hours apart or four divided doses of 6 mg 12 hours apart 24 mg betamethasone sodium phosphate/acetate mix given intramuscularly in two divided doses of12 mg 24 hours apart Betamethasone phosphate, the preparation widely available has different pharmacokinetics from betamethasone sodium phosphate/acetate mix and there is little evidence to guide the effective dosage regimen for this formulation – Good practice point GTG 74, Feb 2022
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Magnesium sulphate for neuroprotection Offer intravenous magnesium sulfate for neuroprotection of the baby to women between 24+0 and 29+6 weeks of pregnancy who are in established preterm labour having a planned preterm birth within 24 hours Discuss between 23 – 23+6 weeks and consider between 30 – 30+6 weeks 4 g intravenous bolus of magnesium sulfate over 15 minutes, followed by an intravenous infusion of 1 g per hour until the birth or for 24 hours Monitor for clinical signs of magnesium toxicity at least every 4 hours Preterm labour and birth NICE guideline [NG25]Published: 20 November 2015 Last updated: 02 August 2019
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tocolytics Consider nifedipine for tocolysis for women between 24+0 and 25+6 weeks of pregnancy who have intact membranes and are in suspected preterm labour Offer Nifedipine between 26+0 and 33+6 Do not offer beta mimetics, no role for transdermal nitroglycerine patch Preterm labour and birth NICE guideline [NG25]Published: 20 November 2015 Last updated: 02 August 2019
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Nice in its 2019 update History of spontaneous preterm birth (up to 34+0 weeks of pregnancy) or mid-trimester loss (from 16+0 weeks of pregnancy onwards) and Transvaginal ultrasound scan between 16+0 and 24+0 weeks of pregnancy shows a cervical length of 25 mm or less Offer a choice of prophylactic vaginal progesterone or prophylactic cervical cerclage to women who have both Consider prophylactic vaginal progesterone for women who have either Vaginal progesterone from 16-24 weeks till 34 weeks Prophylactic cervical cerclage if transvaginal ultrasound scan between 16+0 and 24+0 weeks of pregnancy show a cervical length of 25 mm or less with PPROM in a previous pregnancy or a history of cervical trauma
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Screening for cervical length FIGO recommends sonographic cervical length screening in all women 19+0 to 23+6 weeks of gestation using TVUS ACOG - cervical length screening with serial endovaginal ultrasonography is indicated for individuals with a singleton pregnancy and a prior spontaneous preterm birth 18-22+6 weeks Society for Maternal-Fetal Medicine - TVUS cervical length screening between 16 and 24 weeks of gestation for women with a singleton pregnancy and history of prior spontaneous preterm birth
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“rescue” cerclage Consider 'rescue' cervical cerclage for women between 16+0 and 27+6 weeks of pregnancy with a dilated cervix and exposed, unruptured fetal membranes Do not offer if signs of infection, active vaginal bleeding, uterine contractions Occlusive cerclage - occlusion of the external os could be performed to retain the cervical mucus plug thereby preventing infection - no significant additional effect - Randomised trial of cervical cerclage, with and without occlusion, for the prevention of preterm birth in women suspected for cervical insufficiency, BJOG 2013 Preterm labour and birth NICE guideline [NG25]Published: 20 November 2015 Last updated: 02 August 2019
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progesterone 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death Blackwell SC,et al. 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial. Am J Perinatol. 2020 Jan;37(2):127-136. doi: 10.1055/s-0039-3400227. Epub 2019 Oct 25. PMID: 31652479. Norman JE et al OPPTIMUM study group. Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. Lancet. 2016 May 21;387(10033):2106-2116. doi: 10.1016/S0140-6736(16)00350-0. Epub 2016 Feb 24. Erratum in: Lancet. 2019 Jan 19;393(10168):228. Erratum in: Lancet. 2019 Apr 20;393(10181):1596. PMID: 26921136; PMCID: PMC5406617. Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age
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pessary Cervical pessary to prevent preterm birth in asymptomatic high-risk women: a systematic review and meta-analysis. AU Conde-Agudelo A, Romero R, Nicolaides KH, SO, Am J Obstet Gynecol. 2020 Current evidence does not support the use of cervical pessary to prevent preterm birth or to improve perinatal outcomes in singleton or twin gestations with a short cervix and in unselected twin gestations STOPPIT-2 study aims to determine the clinical utility of the Arabin cervical pessary in preventing preterm birth in women with a twin pregnancy and a short cervix Norman JE, et al. Open randomised trial of the (Arabin) pessary to prevent preterm birth in twin pregnancy with health economics and acceptability: STOPPIT-2-a study protocol. BMJ Open. 2018 Dec 6;8(12):e026430. doi: 10.1136/bmjopen-2018-026430. PMID: 30530477; PMCID: PMC6286620.
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Intrapartum care Monitoring FHR during labour – intermittent auscultation vs CTG based on risk factors Do not carry out fetal blood sampling, fetal scalp electrode if the woman is less than 34+0 weeks Wait at least 30 seconds, but no longer than 3 minutes, before clamping the cord of preterm babies if the mother and baby are stable Consider caesarean section for women presenting in suspected, diagnosed or established preterm labour between 26+0 and 36+6 weeks of pregnancy with breech presentation Preterm labour and birth NICE guideline [NG25]Published: 20 November 2015 Last updated: 02 August 2019
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Interventions to reduce recurrent preterm birth In women with a history of PTB in whom the diagnosis of cervical insufficiency is uncertain, sonographic evidence of a short cervix in the mid trimester will benefit from USG indicated cerclage To reduce recurrent indicated PTB - administration of low-dose aspirin to women with a history of early delivery because of preeclampsia with severe features can reduce their risk for recurrent preeclampsia and PTB Septal resection and myomectomy before pregnancy may be indicated in women with pregnancy loss or early PTB Prevention and reduction of multifetal gestations in ART pregnancy
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Diagnosing pprom Speculum examination to look for pooling of amniotic fluid If pooling of amniotic fluid is observed, do not perform any diagnostic test, offer care If pooling of amniotic fluid is not observed, perform an insulin-like growth factor binding protein‑1 test or placental alpha-microglobulin‑1 test of vaginal fluid If the results of the insulin-like growth factor binding protein‑1 or placental alpha-microglobulin‑1 test are negative, do not offer antenatal prophylactic antibiotics - unlikely that she has P‑PROM No role for nitrazine test Preterm labour and birth NICE guideline [NG25]Published: 20 November 2015 Last updated: 02 August 2019
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pprom PPROM refers to rupture of fetal membranes prior to onset of labor in pregnancies <37+0 weeks Occurs in 3% of pregnancies and is responsible for one-third of preterm births Cessation of fluid leakage is rare, except in patients with PPROM related to amniocentesis Majority of pregnancies with PPROM deliver within one week of membrane rupture USG evidence of oligohydramnios – presumptive diagnosis
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Managing PPROM Women whose pregnancy is complicated by PPROM after 24+0 weeks’ gestation and who have no contraindications to continuing the pregnancy should be offered expectant management until 37+0 weeks Combination of clinical assessment (lower abdominal pain, abnormal vaginal discharge, fever, malaise and reduced fetal movements), maternal blood tests (C-reactive protein and white cell count) and fetal heart rate should be used to diagnose chorioamnionitis Thomson AJ, on behalf of the Royal College of Obstetricians and Gynaecologists. Care of Women Presenting with Suspected Preterm Prelabour Rupture of Membranes from 24+0 Weeks of Gestation. BJOG 2019;126:e152–166, GTG 73
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Antibiotics for pprom Oral erythromycin 250 mg 4 times a day for a maximum of 10 days or until the woman is in established labour – if woman does not tolerate, consider an oral penicillin Do not use Co-Amoxiclav Erythromycin for women with pPROM is associated with a range of health benefits for the neonate, and thus a probable reduction in childhood disability. However, co-amoxiclav cannot be routinely recommended for pPROM because of its association with neonatal necrotizing enterocolitis - Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial Preterm labour and birth NICE guideline [NG25]Published: 20 November 2015 Last updated: 02 August 2019