PRETERM LABOR

Definition, prevalence, risk factors

Prevention in patients at high risk

I. Definition, prevalence, risk factors

1. Defined as uterine contractions + cervical change prior to 38 weeks gestation
2. Occurs in 7% of pregnancies nationally
3. No change in rates of preterm birth or low birth weight between 1950's and 1990's despite development of multiple treatments
4. Risk factors

1. Previous preterm labor
2. Multiple gestation
3. Uterine anomalies: malformations, fibroids, cervical incompetence
4. Lower genital tract infection e.g. GC, chlamydia, BV, trich, group B Strep
5. Chorioamnionitis
6. Polyhydramnios
7. Certain illicit drugs (e.g. cocaine, amphetamine)
8. Tobacco use
9. Inadequate weight gain in pregnancy
10. Poverty
11. Age < 19 or > 40
12. African-American > white > Hispanic
13. Periodontitis (Mod-severe periodontal disease was independently associated with RR 2.6 (sig.) for delivery at < 37wks  in a prospective study of 1,020 pts; (Obs. Gyn. 107:29, 2006--JW)
14. Short cervix in 2nd trimester by ultrasound (Obs. Gyn. 95:222, 2000--AFP)
15. Diabetes
16. Hypertension
17. Anemia
18. Collagen vascular disease

II. Prevention in patients at high risk

1. Cervicitis screening at intake & again at 24-28 weeks
2. Cerclage in pts at high risk
   1. Thought to protect against very early preterm birth (due to "incompetent cervix")
   2. In a study of 47,123 pts screened for unusually short cervix (< 15mm) at 22-24wks on ultrasound, 253 met the selection criteria and were randomized to cerclaga vs. expectant management; the cerclaga group had a nonsig. reduction in incidence of (birth at < 33wks) c/w control group (22% vs. 26%) (Lancet 363:1849, 2004--AFP)
3. Progestins
   1. In a randomized trial in women at high risk for preterm delivery randomized to 17-alpha hydroxyprogesterone (HP) IM Qwk vs. placebo from 16-20wks, HP recipients had significantly reduced incidence of delivery at < 37wks (36.3% vs. 54.9%); ditto for delivery at < 35wks and at < 32wks. (NEJM 348:2379, 2003--UW Pharm. Letter)
   2. In a meta-analysis of 10 randomized studies in women with risk factors for preterm birth (summary doesn't list them all but included prior preterm birth and/or multiple spontaneous abortions), progestins were associated with sig. reduced incidence of birth at < 37wks (26.2% vs. 35.9%) and perinatal mortality (14.8% vs. 17.1%)(Obs. Gyn. 105:273, 2005--JW)
4. Approaches not shown to reduce incidence of preterm birth
   1. Patient education for early detection
   2. Nurse telephone contact with pt (& some evidence of increased utilization or resources--NEM 338:15, 1998--JW)
   3. Home uterine activity monitoring
   4. Repetitive cervical exams
   5. Activity restriction
   6. Antibiotics in patients with positive fetal fibronectin test in cervicovaginal secretions
      1. In a study in 100 such women, randomized to metronidazole 400mg TID vs. placebo x 1wk during 2nd trimester, there was no sig. diff. in risk of delivery before 37wks but metronidazole group had sig. greater risk of delivery before 30wks (21% vs. 11%) ("PREMET" Trial; BJOG 113:65, 2006--JW) 

III. Diagnosis:

1. If can't pick up ctx on monitor b/c early gestation or obese pt, try palpating uterus!
2. Any cervical change can be significant if occurs over hours
3. Often, presumptive dx is made & tx initiated without documenting cervical change
4. Ultrasound can be helpful to estimate effacement if Px is unclear
5. Predicting preterm delivery
   1. Frequency of uterine contractions as measured by home uterine activity monitoring
      1. Regular monitoring starting @ 22-24wks was a poor predictor of preterm delivery in one observational study of 306 women with risk factors for preterm delivery (for instance, threshold of 4 or more ctx/hr ass'd with sensitivity of only 9-28% and pos. predictive value of only 11-25%, depending on gest. age) (NEJM 346:250, 2002)
   2. Cervical length measured by transvaginal ultrasound
      1. Preterm birth more likely if < 25%ile for gest. age
      2. Length < 25mm ass'd with sensitivity of 47-82% and specificity of 75-89% for preterm birth depending on gest. age at measurement in one observational study of women with risk factors for preterm delivery (NEJM 346:250, 2002)
   3. Fetal fibronectin measurement in cervicovaginal secretions
      1. Fetal fibronectin is a normal constituent of the extracellular matrix at maternal-fetal interface
      2. Normally present at very low levels in cervicovaginal secretions
      3. Presence in cervicovaginal secretions is thought to indicate separation of fetal membranes from the decidua
      4. Highly sensitive, though not highly specific, predictor of preterm delivery in pts with preterm contractions
         1. Negative predictive value 94-99%; pos. predictive value 17-46% in published studies--UW Lab Letter Spring 2000)
         2. Pos. predictive value 30-35%, negative predictive value 89-95% for eventual preterm delivery in one observational study of women with risk factors for preterm delivery (NEJM 346:250, 2002)
      5. Requires a special Dacron swab used to get specimen from posterior fornix or ectocervical part of external os; candida may give false-negative results; semen may give false-positive results; manipulation of the cervix may give false-positive results so do before digital cervical exam.
   4. Salivary estriol--rises 2-3wks prior to onset of labor, whether at term or preterm; most predictive after 30wks
6.  

IV. Workup

1. Urinalysis to r/o cystitis/pyelonephritis
2. Cervical cultures to r/o GC, chlamydia
3. Vaginal wet mount to r/o trich, BV
4. GBS cx
5. Ask re: recent intercourse: causes ctx but doesn?t seem to cause preterm delivery
6. Ultrasound for pts whose ctx are not easily stopped, if not done recently, to r/o polyhydramnios, fetal abnormalities which may cause PTL
7. Attend to FHR tracing; abruption can cause PTL and can be dx?d by fetal distress
8. Amniocentesis: chorioamnionitis can cause PTL; some do amniocentesis for all pts in PTL even if fetal maturity is not at issue. Glu normally 40-60; Glu <10 is >90% spec. & sens. for chorioamnionitis. About 16% of pts with PTL have positive amniotic fluid cx

IV. Treatment

1. Hydration (more than 1 liter IV rarely helpful) & position changes: 80-90% respond
2. Tx UTI, GBS, BV, tich, etc. if present
3. Serial cervical exams
4. Tocolyse to 36-37wks, earlier if more Mg, with its risk to mother, is needed; benefit is limited after 34 weeks
5. Try maximizing one drug before adding another; see notes below re: combining agents
6. Contraindications to tocolysis:

1. Fetal demise or anomalies incompatible with life
2. Fetal distress
3. PROM
4. Preeclampsia
5. Severe bleeding or abruptio placentae
6. Severe IUGR
7. Chorioamnionitis
8. Cervix > 5cm dilated
9. Relative contraindications include chronic HTN, mild IUGR, mild abruption

7. Bedrest traditionally prescribed
8. Steroids to accelerate fetal lung maturity
   1. If anticipate premature delivery in <1wk; repeat if 7 days have lapsed since the first dose
   2. Most benefit if 28-34 weeks
   3. May increase glucose in diabetic moms
   4. May have less benefit (and even some potential for harm by increasing risk for neonatal sepsis) in pts with hypertensive disorders of pregnancy (Obs. Gyn. 93:174, 1999--JW)
   5. Use of repeat courses of antenatal steroids if delivery is not imminent:
      1. Concern is that too much steroids might cause growth restriction, adrenal suppression, and neonatal sepsis.
      2. 982 mothers at < 32wks gestation and at risk for preterm delivery, all of whom, had received an initial course of prenatal corticosteroids > 6d previously randomized to betamethasone (7.8mg BM sodium phosphate + 6mg MB acetate) Qwk vs. placebo until wk 32. The neonates of the active-tx group had sig. lower incidence of Respiratory Distress Syndrome (RR 0.82), sig. less need for oxygen therapy, and sig. fewer days on gentilation. However, babies of the active-tx group had sig. lower weight and head circumference percentiles c/w the placebo group. Lancet 367:1913, 2006--JW)

      3. In a study in 437 women at 25-33wks gestation with intact membranes and preterm labor with clinician assessment of "risk of imminent preterm delivery", all of whom had received at least 2 weeks prior and at < 30wks, randomized to a single repeat course of steroids vs. placebo, there was no sig. diff. in incidence of delivery at < 34wks, but incidence of two or more of neonatal (respiratory distress syndrome, bronchopulmonary dysplasia, severe intraventricular hemorrhage, periventricular leukomalacia, sepsis, necrotizing enterocolitis, or perinatal death) before 34 wks was sig. lower in the repeat-steroid-dose group (OR 0.45), mostly due to less RDS. (Am. J. Obs. Gyn. 200:248, 2009-JW)

      4. In a study in 1,850 women felt to be at high risk for preterm delivery after an initial course of antenatal steroids randomized to (betamethasone vs. placebo Q24h x 2) Q14d until 33wks gestation or delivery, incidence of a combined endpoint of perinatal and neonatal mortality and serious morbidity was not sig. diff. between the treatment groups, though betamethasone group had sig. lower birth weight and head circumference at birth ("Multiple Courses of Antenatal Corticosteroids for Preterm Birth" ("MACS") Trial; Lancet 372:2143, 2008-JW)

   6. Specific agents:

1. Betamethasone 12mg IM Q12h x 2
2. Dexamethasone 4mg IV or IM Q8h x 3

9. Magnesium Sulfate for neuroprotection in preterm birth
   1. In a randomized trial of 1062 women at < 30wks gestation with preterm birth anticipated within 24h, randomized to MgSO4 IV (4g then 1g/h) vs. placebo, over 2y f/u, nonsignificantly lower incidences of mortality and cerebral palsy were seen in children of MgSO4 recipients.  Sig. reductions were seen in prevalence at 2y of substantial gross motor dysfunction (3.4% vs. 6.6%) and (death or substantial gross motor dysfunction) (17% vs. 22.7%) (JAMA 290:2669, 2003--abst)
   2. In a meta-analysis of six trials involving 4,796 women at risk for preterm labor at < 34 weeks gestation randomized to magnesium sulfate vs. placebo, risk for birth to an infant with diagnosed cerebral palsy was sig. reduced (3.9% vs. 5.6%, RR 0.69), as was risk for substantial gross-motor dysfunction at 2y of age (2.6% vs. 4.2%; RR 0.60). The authors recommend max 6g IV bolus then 1-2g hourly x 24 hours. (AJOG 200:595, 2009-JW)
10. Thyrotropin releasing hormone to accelerate fetal lung maturity-not yet available
11. Phenobarbital to mom may decrease risk of intraventricular hemorrhage in baby

VI. Specific drugs for tocolysis

1. Beta-agonsists

1. Shown to be effective in prolonging pregnancy and increasing birthweight, mostly before 33 weeks
2. May increase risk of pulmonary edema if given along with Mg
3. Terbutaline--See also below

1. Works by increasing cAMP
2. Dose limited by pulse (120 us. used as limit): 2.5-5mg PO Q2-4h; 0.25mg SQ Q3h (limit 2-3 doses) or by SQ pump
3. Contraindications: maternal arrhythmia or other cardiac disease, poorly controlled diabetes, thyrotoxicosis
4. Tachyphylaxis occurs after a few days
5. Can cause glucose intolerance in mom
6. May cause non-significant, transient RVH/pulm HTN in baby
7. Possible association with DM in child
8. See below (bottom of page) for a literature review re: its efficacy

4. Ritodrine

1. Another beta-agonist; same side effects/contraindications as terbutaline
2. 10-20mg PO Q2-4h
3. 0.05-0.35 mg/min IV (us. start at 0.1mg/min, incr. by 0.05 mg/min Q20min until side effects occur or ctx stop; then decrease by 0.05mg/min Qh1 to minimum 0.1mg/min as long as ctx absent)
4. 5-10mg IM Q3h
5. May be more effective than Mg, esp. at advanced dilatations

2. Nifedipine

1. Blocks Ca-channels20mg Q6h as starting dose; give 1st dose SL
2. One study showed more effective than ritodrine in delaying delivery > 48h
3. DON'T COMBINE WITH MAGNESIUM b/c of similar mech. & higher risk or hypotension, resp. arrest, etc.

3. NSAIDS

1. Inhibit prostaglandins, affecting mm. fiber gap junctions
2. Studies have shown only slight prolongation of pregnancy (around 48h)--See below
3. Can cause oligohydramnios so monitor amniotic fluid index by u/s if on it > 3d
4. Avoid after 32wks; can cause premature closure of ductus arteriosus, NEC. Prob. ok for 24-48h
5. Indocin 50-100mg PO initial dose then 25-50mg PO Q6h or 50mg PR x1
6. Ibuprofen 600-800mg Q6h

4. Magnesium Sulfate IV--Click on link for dosing guidelines and other info

1. May be slighly less effective than beta agonist threatment but need to discontinue for side effects is less and may more than outweigh the advantage in efficacy
2. For tocolysis, can give PO after 12-24h stable on IV
3. Serum levels correlate poorly with tocolytic effect but level should be < 7mg/dl (nl 1.8-3)
4. Don't combine with calcium-channel blockers
5. May increase risk of pulmonary edema if combined with beta agonists
6. Can combine with NSAIDs

5. Atosiban-A competitive antagonist of oxytocin that also downregulates uterine oxytocin receptors.
   1. In a study in 128 women in preterm labor at 23-3wks gestation randomized to atosiban vs. ritodrine for up to 48h, the incidence of no delivery and no need for alternative therapy at 7d was sig. higher in the atosiban group (60% vs. 35%) (BJOG 113:1228, 2006--JW)

VII. Data on fetal survival to discharge with delivery at:

• 24 weeks: 2%
• 25 weeks: 11%
• 26 weeks: 29%
• 27 weeks: 40%
• 28 weeks: 59%
• 29-30 weeks: 83%
• 31-32 weeks: 90%
• 33-34 weeks: 96%
• 34-36 weeks: 99%

(source: Benedetti lecture 5/95)

VIII. If you have to deliver preterm (tocolytics don't work or are contraindicated):

1. Vaginal delivery ok for vertex presentation
2. Try to minimize birth trauma b/c of high risk for intraventricular hemorrhage in low birth weight babies; note that routine episiotomy doesn't seem to prevent this

The following are summaries of abstracts of papers found with a search of Medline from 1966-present done on 8/1/98 with the following search terms: (labor, premature OR pregnancy OR tocolytic agents OR infant, premature OR "preterm labor" OR "prematurity" OR "premature" OR "preterm") AND (terbutaline or "terbutaline"). Results were edited to exclude all but controlled trials addressing the issue of efficacy of terbutaline in treatment of preterm labor.

Papers comparing terbutaline vs. placebo or no tx:

1. 45 pts with PTL arrested with MgSO4 IV (plus PO indomethacin if necessary) randomized to terb SQ pump, terb PO, or saline placebo SQ. No sig. diff. among groups in mean EGA at delivery or "neonatal outcomes" (abtract doesn’t specify). Note that if PTL recurred during study period, pts were unblinded and tx was changed (Wenstrom KD et al. Am. J. Perinat. 14:87, 1997)

2. 175 pts w/PTL and 200 pts w/preterm ctx but no cervical changes, all at 24-35wks and w/ctx arrested w/IV meds, tx’d with terb PO until 37wks vs. no tx. Abstract doesn’t say whether randomized. No sig. diff. in latency to delivery w/ terb vs. no tx (Brown HL et al. Am. J. Perinat. 14:405, 1997)

3. 200 pts w/PTL at 24-35wks arrested with IV meds randomized to terb 5mg PO Q4h 9continued until 37wks) vs. placebo. No sig. diff. in incidence of delivery 1wk after tx onset, median latency to delivery, mean EGA at delivery, or incidence of recurrent PTL. Among subset of pts (n = 96) presenting at < 32wks, sig. greater latency to delivery w/ terb (Lewis R et al. AJOG 175-4 pt 1-834, 1996)

4. 205 pts with PTL arrested with meds randomized to terb 5mg PO Q4h, MgCl 128mg Q4h, or placebo. All were in a special preterm delivery prevention program that included home uterine activity monitoring. After adjusting for confounding variables (abtract doesn’t state what they were), no sig. differences in % delivering < 37wks, % delivering < 34wks, % of NICU admissions, and mean neonatal length of stay (Rust OA et al. AJOG 175-4 pt. 1: 838, 1996)

5. 184 pts w/PTL at 24-35wks arrested w/IV meds were assigned to bedrest at home and randomized to PO terb 5-10mg Q4-6h (continued until 38wks) vs. no meds. No sig. diff between groups in EGA at delivery, % of pts reaching 37wks, # of readmissions, # of unscheduled hosp. visits, or "neonatal outcomes" (abstract isn’t specific) (How HY et al. AJOG 173:1518, 1995)

6. 112 pts with placenta previa and bleeding at < 35wks studied retrospectively. 85% of pts got IV MgSO4 and/or beta-sympathomimetics within 24h of admission. Compared w/pts who didn’t get tocolytics, latency to delivery was greater (39 vs. 27d; sig.) and birth weight was greater (2.5kg vs. 2.1kg; sig.). Those pts who got long-term maintenance tocolysis w/SQ terb vs. those who got only short-term tocolysis had greater latency to delivery (44 vs. 15d; sig.) No diff. in incidence of recurrent bleeding or need for transfusion (Besinger etal. AJOG 172: 1770, 1995)

7. 55 pts w/PTL at 28-35wks arrested w/IV MgSO4 randomized to terb PO (titrated to maternal HR > 100/min and continued to 37wks) vs. no therapy. No sig. diff. between the 2 groups in latency from tx to delivery, EGA at delivery, % of pts delivering at 37 or more weeks, recurrent PTL, recurrent uterine ctx w/o labor, birth weight, NICU admissions, or neonatal RDS (Parilla BV at al. AJOG 169:965, 1993)

8. 50 pts w/PTL arrested with parenteral meds randomized to MgO 200mg Q3-4h vs. terb 2.5-5mg Q3-4h. No sig. diff in % of pts delivering < 36wks (Ridgway et al. AJOG 163:879, 1990)

9. 54 pts w/PTL at 26-34wks randomized to terb, MgSO4, or placebo. No sig. diff among the 3 groups in rates of delivery within the 48h after tx (about 50% in all groups), gestational age at delivery, birth weight, or neonatal survival (Cotton DB et al. J. Repr. med. 29:92, 1984)

10. 46 pts w/PTL initially arrested with IV ethanol assigned (abst. doesn’t say whether randomized) to terb PO vs. placebo until 38wks. Baseline Bishop score was higher in placebo group. Duration of pregnancy sig. greater in terb group (Brown SM and Tejani NA, Obs. Gyn. 57:22, 1981)

11. 30 pts in PTL randomized to terb (IV x at least 8h then SQ QID + PO x 3d) vs. placebo continued until 37wks). Success rate in arresting PTL beyond the tx period was 80% w/terb vs. 20% w/placebo (sig.) (Ingemarrson I., AJOG 125:520, 1976)

 

 

Papers comparing terbutaline vs. other drugs:

 

1. 65 pts w/PTL at 26-32wks arrested w/IV meds randomized to terb PO vs. indomethacin PO. No sig. diff. in % of pts achieving 34wks or in neonatal outcome (Bivins HA et al. AJOG 169:1065, 1993)

2. 80 pts w/PTL at < 34wks randomized to PO nifedipine vs. IV MgSO4 for initial arrest of labor (ritodrine used as backup). After arrest of labor, nifedipine pts maintained on same; MgSO4 tx w/ PO terb. Tx continued until 35wks. No diff. between success at arresting labor between nifedipine and MgSO4. No diff. between nifedipine and terb groups in rates of recurrent labor and EGA > 34wks at delivery (Glock JL and Morales WJ AJOG 169:960, 1993)

3. 52 pts w/PTL at 20-35wks randomized to nifedipine 30mg PO x 1 vs. terb SQ (abstract doesn’t mention dose). "Success rate" 68% for nifedipine; 71% for terb (abstract doesn’t say what "success" was) (Smith CS and Woodland MB Am. J. Perinat. 10:280, 1993)

4. 98 pts w/PTL at 23-35 wks tx’d with terb PO vs. IV then PO Mg. Delivery at 37wks or more more frequent in Mg group (74% vs. 52%, sig.); also, mean latency between tx and delivery sig. greater for Mg (7.1 vs. 5.0 wks). However, no sig. diff in delays of delivery by 48h or 1wk (Chau AC et al. Obs. Gyn. 80:847, 1992)

5. 30 pts w/PTL at 28-36 wks tx’d with either terb (doesn’t say route) or MgSO4. No sig. diff in rates of delivery in 48h after initiation of tx between the 2 groups. (Jimenez AJF et al. Gineco. Obs. Mexic. 58:265, 1990)

6. 92 pts w/PTL randomized to terb vs. ethanol (abst. doesn’t give route/doses). Terb pts had sig. less cervical dilatation during 1^st 36h of tx; also sig. longer maintenance of pregnancy w/terb (15 vs. 10d). No diff. in % who got beyond 36wks. (Caritis SN et al. AJOG 142:183, 1982)

7. 100 pts w/PTL randomized to ritodrine 120mg/d vs. terbutaline PO 30mg/d. Among pts w/intact membranes, recurrent labor n 5d after start of tx sig. less in terb group (1/19 vs. 12/23); mean prolongation of pregnancy sig. greater in terb group (40d vs. 22d) (Caritis et al. AJOG 150:7, 1984)

8. Pts w/PTL (abstract doesn’t give #) tx’ w/IV ritodrine vs. terb; latency of delivery 26d w/terb vs. 13d w/ritodrine; 60% w/terb and 39% w/ritodrine achieved EGA of 36wks (abstract doesn’t say if sig.) (Kosasa TS et al. Acta Obs. Gyn. Scand. 64:421, 1985)

 

 

Papers comparing terbutaline one route vs. another:

 

1. 32 pts w/ "recurrent" PTL tx’d with either terb SQ or terb PO studied retrospectively. Pts matched for age, race, parity, EGA, and cervical dilation. Doses in both groups titrated to uterine ctx. % of pts reaching "term" greater in SQ group though abstract doesn’t say if stat. sig. (Albert JR et al. J. Repr. Med. 39:614, 1994)

 

 

Papers on terbutaline for preterm ctx w/o PTL:

 

1. 156 pts w/ctx (8/h or more) at 20-37wks, cervical dilation < 2cm and < 80% effaced, and no cervical change over 2h were assigned (abstract doesn’t state whether randomized) to inpt tocolysis vs. d/c to home w/o tx. No sig. diff in mean rates of preterm delivery, mean EGA at delivery, or mean birth weight. n.b. women with previa, abruptio, ROM, chorioamnionitis, multiple gestation, and prior tocolytic tx in the current pregnancy were excluded (Sciscione AC et al. Am. J. Perinat. 15:177, 1998)
2. 179 women w/preterm ctx (> 3/30min) at 20-34 wks, cervix 1cm or less, effacement < 80%, and intact membranes randomized to terb 0.25mg SQ x 1, IV hydration, or observation alone. Terb group had earlier cessation of ctx than other groups (sig.). However, no sig. diff. in mean latency to delivery, % delivering at < 34wks, % delivering at < 37wks, # of repeat L & D visits, or incidence of PTL at < 34wks (pts progressing to PTL were tx’d with IV tocolytics) (Guinn DA et al. Am. J. Obs. Gyn 177:814, 1997)

 

Another paper; abstract not avail. through Medline: Unique Identifier 83063331; Howard TE Jr et. al, A double blind randomized study of terbutaline in premature labor. Military Medicine. 147(4):305-7, 1982 Apr.

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Papers comparing indomethacin vs. placebo:

1. 34 women with PTL at 23-30wks randomized to indomethacin (50mg then 25mg Q6h x 48h) vs. placebo. More pts in the indomethacin group (81% vs. 56%) had successful extension of labor x 48h. Incidence of perinatal mortality or severe neonatal morbidity not sig. diff. (32% in indomethacin group, 15% in placebo group) (Panter KR. Hannah ME. Amankwah KS. Ohlsson A. Jefferies AL. Farine D. The effect of indomethacin tocolysis in preterm labour on perinatal outcome: a randomised placebo-controlled trial. British Journal of Obstetrics & Gynaecology. 106(5):467-73, 1999 May.)

2. 36 pts with PTL randomized to indeomthacin 200-300mg/24h vs. placebo; sig. more pts in indomethacin group had cessation of ctx (83.3% vs. 22.2%) mean duration of pregnancy sig. greater in indomethacin group (36.4 vs. 31.2 wks). (Zuckerman H. Shalev E. Gilad G. Katzuni E. Further study of the inhibition of premature labor by indomethacin. Part II double-blind study. Journal of Perinatal Medicine. 12(1):25-9, 1984.)

3. 30 pts with PTL randomized to indomethacin vs. placebo; sig. more indomethacin pts had cessation of ctx in first 24h; no diff. between indomethacin and placebo groups in gestational age at delivery, birthweight, or neonatal morbidity or mortality. (Niebyl JR. Blake DA. White RD. Kumor KM. Dubin NH. Robinson JC. Egner PG. The inhibition of premature labor with indomethacin. American Journal of Obstetrics & Gynecology. 136(8):1014-9, 1980 Apr 15.)

4. Uncontrolled trial of 29 pts at 26-37wks with PTL; 26 had "significant decrease in uterine activity." Grella P. Zanor P. Premature labor and indomethacin. Prostaglandins. 16(6):1007-17, 1978 Dec.

Papers comparing indomethacin to other NSAIDs:

1. 36 pts with PTL (mean EGA 29-30wks) not responding to MgSO4 randomized to indomethacin vs. sulindac x 48h; no diff. in success at delaying delivery for 48h or 7d. Sulindac group had sig. greater AFI's than indomethacin group. (Carlan SJ. O'Brien WF. O'Leary TD. Mastrogiannis D. Randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor [see comments]. Comment in: Obstet Gynecol 1992 Jun;79(6):1054-5 Obstetrics & Gynecology. 79(2):223-8, 1992 Feb.)

Papers comparing indomethacin to other tocolytics:

1. 65 pts at 26-32wks with PTL and successful cessation of ctx with IV meds randomized to indomethacin vs. terbutaline. All monitored with weekly u/s; indomethacin pts converted to terb at 34wks or w/occurrence of constriction of fetal ductus arteriosis, or oligohydramnios. No diff. in % reaching 34wks or in neonatal outcome. (Bivins HA Jr. Newman RB. Fyfe DA. Campbell BA. Stramm SL. Randomized trial of oral indomethacin and terbutaline sulfate for the long-term suppression of preterm labor. American Journal of Obstetrics & Gynecology. 169(4):1065-70, 1993 Oct.)

2. 49 pts < 32wks with PTL randomized to indomethacin vs. IV MgSO4. No sig. diff. in success at delay of delivery > 48h. Sig. fewer pts in indomethacin group than MgSO4 group needed to stop b/c of maternal side f/x. (Morales WJ. Madhav H. Efficacy and safety of indomethacin compared with magnesium sulfate in the management of preterm labor: a randomized study. American Journal of Obstetrics & Gynecology. 169(1):97-102, 1993 Jul.)

3. 40 pts at 23-34wks with PTL randomized to indomethacin vs. IV ritodrine (followed by PO terb if successful at stopping ctx); no sig. diff. in time to delivery, gestational age at delivery, % reaching 35wks, or % delivering > 7d after presentation (Besinger RE. Niebyl JR. Keyes WG. Johnson TR. Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor. American Journal of Obstetrics & Gynecology. 164(4):981-6; discussion 986-8, 1991 Apr.)

4. 106 pts with PTL at < 32wks randomized to indomethacin x 48h vs. ritodrine IV; no sig. diff. in successful delay of delivery x 48h or 7d (Morales WJ. Smith SG. Angel JL. O'Brien WF. Knuppel RA. Efficacy and safety of indomethacin versus ritodrine in the management of preterm labor: a randomized study. Obstetrics & Gynecology. 74(4):567-72, 1989 Oct.)

5. 60 pts 25-34wks with PTL randomized to indomethacin (100mg PR then 50mg PO Q8h for total 3d) vs. nylidrin (a beta-agonist) 100-150ug/min IV x 3d. Successful arrest ot PTL at 48h was sig. greater in indomethacin group c/w nylidrin group. 70% of indomethacin group reached 37wks, c/w 43% of nylidrin group (sig.) (Kurki T. Eronen M. Lumme R. Ylikorkala O. A randomized double-dummy comparison between indomethacin and nylidrin in threatened preterm labor. Obstetrics & Gynecology. 78(6):1093-7, 1991 Dec.)

Papers comparing indomethacin plus other tocolytics to other tocolytics alone:

1. 44 pts with preterm labor randomized to ritodrine alone vs. ritodrine + indomethacin; "slight but significant" increase in duration of pregnancy after presentation in combined group. (Gamissans O. Canas E. Cararach V. Ribas J. Puerto B. Edo A. A study of indomethacin combined with ritodrine in threatened preterm labor. European Journal of Obstetrics, Gynecology, & Reproductive Biology. 8(3):123-8, 1978 Jun.)