LEARNING OBJECTIVES
- Understand importance of preterm birth
- Identify who is at risk and review prevention options
- Understand prompt management of initial presentation
- Review management of preterm premature rupture of membranes
- Management of preterm labor.
MAJOR CAUSES OF PRETERM BIRTH1
- Preterm premature rupture of membranes (PPROM): 20–30%.
- Iatrogenic:
- Maternal indications (preeclampsia, diabetes, prior classical cesarean delivery)
- Fetal indications (nonreassuring fetal testing, intrauterine fetal growth restriction): 20%.
- Spontaneous (unexplained preterm labor: 25–30%.
- Infection/inflammation: 20–25%.
The major causes of preterm birth (PTB) have been shown in Figure 1.
LATEST INTERNATIONAL GUIDELINES
There are several International guidelines such as the European Association of Perinatal Medicine 2017, Western Australian PTB prevention key initiative 2017, French clinical practice guidelines 2016, NICE guideline 2015, FIGO 2015, StratOG by RCOG 2014, ACOG 2012, SOGC 2008.
All the guidelines have uniformly stressed upon the use of progesterone as an alternative to cervical cerclage in women with the one who has delivered early or who has lost her pregnancy in the middle of pregnancy and a short cervix (<25 mm) on ultrasound at 20–37 weeks’ gestation.
ACOG guideline 2012 recommends daily progesterone supplementation in a woman with history of prior PTB, woman without history of prior PTB but at risk due to short cervix (≤20 mm at ≤24 weeks).
PREVENTION
Emphasis on cervical length (CL) screening has been done based on prior studies. Incidence of birth <35 weeks is 30% in women with CL 20–24 mm, 50% with CL 10–19 mm, and 90% with CL <10 mm. The incidence of birth <35 weeks is only 16% in women with CL >25 mm.2
For short cervix <20 mm with no prior PTB, vaginal progesterone/oral/injectable can be given in any form as follows after identification until 36 weeks: dose of 200 mg suppositories, tablets either oral or vaginally, weekly injections of 17-alpha hydroxyprogesterone caproate. Recent introduction of oral sustained-release seems to be effective, but randomized trials are not done.
TERMINOLOGIES
When preterm labor has been diagnosed?
Diagnosis is when there is a positive evidence of preterm labor.
When preterm labor is established?
If the cervix is dilated more than 4 cm with uterine frequent contraction.
When rupture of membranes occurs preterm?
If there is amniotic fluid leak before 37 weeks of pregnancy.
The following points should be assessed:
If the pregnancy is less than 28 weeks, transfer the women to a tertiary level where the neonatal intensive care unit (NICU) facility to present.
CONTRAINDICATIONS TO STOP LABOR
If there is a harm by continuation of her pregnancy:
- When pregnancy is nonviable
- Bleeding from uterus
- Infection is suspected
- Fetal distress
- Rupture of membranes—frank leak of fluid.
INDICATED PRETERM BIRTH3
Placental/Obstetric Issues
- Previa alone
- Preterm premature rupture of membranes.
Maternal Issues
- Chronic hypertension (HTN)
- Gestational HTN
- Preeclampsia + severe features.
Fetal Issues
- Intrauterine growth restriction (IUGR) alone
- Multiple pregnancy with IUGR
- Severe oligohydramnios.
DIAGNOSIS
Only 30–60% of women presenting with preterm labor will lead to a PTB. Five main areas of concern that make a difference in survival of infant and they are: (i) transfer to hospital with NICU capabilities, (ii) tocolytics, (iii) antibiotic prophylaxis, (iv) administration of steroids, and (v) magnesium for neuroprotection.4,5
Are the membranes ruptured?
The following are observed: pooling of fluid in posterior fornix, ultrasound for amniotic fluid index if unsure.
Is an infection present?
Total count and C-reactive proteins (CRPs) can be done.
Is the patient in labor?
Regular contractions are present or not. If there is contractions, check the cervical dilation.
Diagnosing preterm prelabor rupture of membranes:
A genital examination by a speculum has to be done. If the fluid is pooled in posterior fornix, there is no need to do more tests.4
Fetal Fibronectin—24+0 to 33+6 Weeks
Negative predictive value 99% for delivery within 14 days. Positive predictive value 13–30% for delivery in 7–10 days. Can only be done if nothing in vagina in past 24 hours. False positives are seen with amniotic fluid or blood or vaginal infection. Fetal fibronectin (fFN) if available can be offered, which tells that the delivery can occur within 48 hours.
Nonstress Test along with Tocodynamometer for Uterine Contractions Monitoring
Preterm Premature Rupture of Membranes6
Preterm premature rupture of membranes prior to 37 weeks and prior to onset of contractions >50% will give birth within 1 week of rupture, 70–80% in 2–5 weeks after intra-amniotic infection in 15–25%, more likely when more preterm.
PPROM—management 24–33+6 weeks: Admission, expectant management unless, nonreassuring fetal status, overt infection, abruption, onset of labor. Single course steroids should be considered. Tocolysis is not recommended in PPROM.
PPROM—other management: Antibiotics, if imminent risk of delivery, magnesium sulfate (MgSO4) for neuroprotection under 32 weeks, delivery by 34 weeks for all PPROM at earlier gestational ages.
Prognosis: Among the preterm labor, 30% resolves spontaneously, 50% of patient hospitalized for preterm labor birth at term, intervention will benefit baby.
Steroids
Single Course 24–34 Weeks at Risk for Delivery in 7 Days
Betamethasone 12 mg intramuscularly (IM) q 24 hours × 2 doses, dexamethasone 6 mg IM q 12 hours × 4 doses. It improves neonatal outcomes. It decreases—mortality, incidence and severity of respiratory distress syndrome (RDS), intraventricular hemorrhage, necrotizing enterocolitis.
Cochrane review 2012: Repeat single course >7 days after initial course.
Rescue steroids: Further reduces RDS without adverse outcomes, should be reserved for imminent delivery. There is no evidence for multiple repeat courses.7
Magnesium Sulfate Neuroprophylaxis
Administer when birth is anticipated <32 weeks. MgSO4 reduces severity and risk of cerebral palsy when given for neuroprotection in three meta-analysis. Initially 4 g loading dose then 1 g/hour infusion. Toxicity to be monitored, to 5be done. This has to be once in 4 hours for pulse, blood pressure (BP), respiration and deep tendon patellar reflexes done. If there is less urine output, reduce MgSO4 dose.
Tocolytics
Used to allow time to give steroids and magnesium, arrange transport if needed.
Contraindications for the same are: previability, IUFD, lethal anomaly, nonreassuring fetal status, chorioamnionitis, preeclampsia with severe features, eclampsia, hemodynamic instability of mother, PPROM, maternal contraindications.
Tocolytic reduce birth within 48 hours but do not improve neonatal outcomes, no evidence for maintenance therapy outside 48–72 hours while inpatient and many risks. Magnesium should no longer be given for tocolysis. When using for neuroprotection, watch interactions with tocolytics.
For tocolysis ideally nifedipine to be started. Atosiban is an alternative. Do not give two drugs together. Dose of nifedipine is 20 mg stat orally and later 10 mg three times a day. Watch for fall of BP.
Indomethacin
Usually used under 32 weeks, after this concern for premature closure of ductus arteriosus. Loading dose 50–100 mg PO, then 25 mg PO q 4–6 hours. This can be used with MgSO4.
NICE Guidelines 20158
Consider nifedipine for tocolysis for women who have intact membranes and are in suspected preterm labor. When nifedipine is contraindicated, atosiban can be used.
Atosiban
The recent drug is atosiban which is an oxytocin receptor antagonist. It is a synthetic peptide.
The action is by a competitive antagonist of oxytocin at uterine oxytocin receptors.
Atosiban Regimen
Preparation of intravenous (IV) infusion of atosiban. Each 0.9 mL vial of atosiban injection contains 6.75 mg. Each 5 mL vial of atosiban solution for infusion contains 37.5 mg (7.5 mg/mL).
Loading dose: Injection Tosiban (37.5 mg/5 mL) 1.5 vials (7.5 mL) in 92.5 mL NS at 12 drops per minute IV infusion for 3 hours (of this 7.5 mL, 0.9 mL may be given over half a minute as an IV bolus starting the 3-hour infusion).6
Maintenance dose: Injection Tosiban (37.5 mg/5 mL) 1.5 vials (7.5 mL) in 92.5 mL NS at 4 drops per minute IV infusion for 9 hours. Repeat maintenance dose up to five times—45 hours. Loading + one maintenance dose of 3 + 9 = 11 hours. This regimen is expensive but very effective.
Antibiotic in Preterm Labor
Empirical therapy: There was a reduction in maternal infection (relative risk 0.74, 95% CI 0.64–0.87), but no statistically significant differences in mean gestational age at delivery, frequency of PTB, and neonatal outcomes including mortality. In addition, no differences were noted in a subgroup analysis between the types of antibiotics.
WHO Recommendation on the Prophylactic Antibiotic of Choice in those Pregnant Women with Preterm Prelabor Rupture of Membranes
Erythromycin is recommended as the antibiotic of choice for prophylaxis. Conditional recommendation based on moderate-quality evidence. The use of a combination of amoxicillin and clavulanic acid (“co-amoxiclav”) is not recommended.
Analysis of 17 controlled trials which was a meta-analysis of antibiotics in patients at risk of premature birth because of abnormal vaginal flora, previous PTB, or positive fFN, found that there was no association between antibiotic treatment and reduction in PTB irrespective of the criteria used to assess risk, the antimicrobial agent administered, or gestational age at the time of treatment.9
A new antibiotic regimen treats and prevents intra-amniotic inflammation/infection in patients with preterm PROM10,11 (Joon-Ho et al. Published online: 02 December 2015).
Study design—from 1993–2003, ampicillin and/or cephalosporins or a combination was used (“regimen 1”). A new regimen (ceftriaxone, clarithromycin and metronidazole) was used from 2003–2012 (“regimen 2”).
Results
- With the regimens studied there was significance drop in infection with regimen 2, from 68.8 to 52.1% and from 75 to 54.2%, respectively.
- Intra-amniotic inflammation/infection was eradicated in 33.3% of patients who received regimen 2, but in none who received regimen 1.
Erythromycin is offered by NICE guidelines with PPROM (250 mg) four times a day for a maximum of 10 days or until the woman is in established labor (whichever is sooner).
For women with PPROM who cannot tolerate erythromycin or in whom erythromycin is contraindicated, consider an oral penicillin for a maximum of 710 days or until the woman is in established labor (whichever is sooner) (2015, amended 2019).
RCOG RECOMMENDATION
To diagnosed clinical infection vitals have been monitored along with white blood cell (WBC) and CRP. Fetus should be monitored by cardiotocography (CTG).
Steroids and WBC Count
The WBC count rises following steroid administration and return to normal in 3 days.
C-Reactive Protein
C-reactive protein is the most sensitive marker than total count.12
Identifying Infection in Women with PPROM
Assessment of vitals and tests (CRP 1–3 mg/dL) is normal, WBC count, measurement of fetal heart rate using CTG (2015).
When there is a disparity of tests, observation is continued and repeat tests (2015).
DELIVERY MANAGEMENT
Important considerations for preterm delivery, contact NICU, no vacuums <34 weeks, control head extension. Delayed cord clamping is recommended as there is less need for transfusion, less hypotension, less intraventricular hemorrhage, no difference in death. Cord clamping is done after 30 seconds but not longer than 3 minutes. Ideally baby has to be kept below level of the placenta before the cord is clamped.
Fetal monitoring: Fetus should be monitored by CTG or intermittent auscultation.
Mode of birth: Cesarean section if there is no labor pains with severe preterm, malpresentations and if there is severe maternal problems compromising labor.
Cesarean section or normal delivery has to be discussed well.
SUMMARY
- Preterm birth is a serious public health problem. Progesterone is effective in preventing preterm birth. In prior preterm birth, progestogens, cervical length measurements and possible cerclage are the therapeutic alternatives.
REFERENCES
- Norwitz ER, Caughey AB. Progesterone supplementation and the prevention of preterm birth. Rev Obstet Gynecol. 2011;4(2):60–72.
- Iams JD. Identification of candidates for progesterone: why, who, how, and when? Obstet Gynecol. 2014;123(6):1317–26.
- American College of Obstetricians and Gynecologists ACOG committee opinion no. 560: medically indicated late-preterm and early-term deliveries. Obstet Gynecol. 2013;121(4):908–10.
- Sayres W. Preterm labor. Am Fam Physician. 2010;81:477–84.
- American College of Obstetricians and Gynecologists; Committee on Practice Bulletins—Obstetrics ACOG practice bulletin no. 127: management of preterm labor. Obstet Gynecol. 2012;119(6):1308–17.
- ACOG practice bulletins no. 139: premature rupture of membranes. Obstet Gynecol. 2013;122(4):918–30.
- McKinlay CJ, Crowther CA, Middleton P, et al. Repeat antenatal glucocorticoids for women at risk of preterm birth: a Cochrane systematic review. Am J Obstet Gynecol. 2012;206(3):187–94.
- NICE Preterm labour and birth: NICE guideline [NG25]. (2015). [online] Available from: https://www.nice.org.uk/guidance/ng25 [Last accessed January, 2020].
- Simcox R, Sin WT, Seed PT, et al. Prophylactic antibiotics for the prevention of preterm birth in women at risk: a meta-analysis. Aust N Z J Obstet Gynaecol. 2007;47:368–77.
- Lee J, Romero R, Kim SM, et al. A new antibiotic regimen treats and prevents intra-amniotic inflammation/infection in patients with preterm PROM. J Matern Fetal Neonatal Med. 2016;29(17):2727–37.
- Mercer B. Antibiotics in the management of PPROM and preterm labor. Obstet Gynecol Clin North Am. 2012;39(1):65–76.
- Royal College of Obstetricians and Gynaecologists (RCOG) Care of women with PROM guideline no 73 (Care of women presenting with suspected preterm prelabour rupture of membranes from 24+0 weeks of gestation (Green-top guideline no. 73). 2019.