Effects of perinatal indomethacin treatment on preterm infants

Abstract

Indometasiinia käytetään raskauden aikana ennenaikaisten supistusten hoitoon ja vähentämään liiallista lapsiveden määrää. Syntymän jälkeen sitä käytetään keskosilla avoimen valtimotiehyen (PDA) sulkemiseen. Sekä raskauden aikaisen indometasiinialtistuksen että syntymän jälkeisen indometasiinihoidon on raportoitu aiheuttavan välittömiä haittavaikutuksia ennenaikaisesti syntyneillä lapsilla. Tutkimukseen otettiin 332 alle 33 raskausviikolla syntynyttä lasta. Tutkimuksessa verrattiin lyhyen suurempiannoksisen ja pitkän pieniannoksisen indometasiinihoidon haittavaikutuksia ja tehoa PDAn sulkemisessa sekä selvitettiin raskauden aikaisen ja syntymän jälkeisen indometasiinihoidon vaikutusta tutkittavien lasten sairastavuuteen vastasyntyneisyyskaudella. Indometasiinialtistuksen ja muiden vastasyntyneisyyskauden tekijöiden vaikutusta potilaiden munuaisten rakenteeseen ja toimintaan selvitettiin 2-4 vuoden iässä. Tutkimuksessa todettiin, että PDAn sulku onnistui useammin lyhyellä suurempiannoksisella kuin pitkällä pieniannoksisella indometasiinihoidolla. Lyhyen hoidon saaneet lapset tarvitsivat happihoitoa lyhyemmän ajan ja hoidolla oli vähemmän lieviä suolisto- ja munuaissivuvaikutuksia kuin pitkällä hoidolla. Yli kahden vuorokauden kestoinen tai suurehko (yli 149 mg) vuorokautinen tai yhteenlaskettu äidin saama indometasiinihoito lisäsi lievien aivoverenvuotojen ja vaikean suolistotulehduksen vaaraa tutkituilla vastasyntyneillä. Indometasiinille altistuminen sekä ennen syntymää että syntymän jälkeen lisäsi vaikeiden suolisto- ja bakteeri-infektioiden sekä tähystystutkimuksella todettujen ruokatorven ja mahan limakalvovaurioiden riskiä. Indometasiinialtistuksella ei havaittu olevan yhteyttä munuaisten rakenteen tai toiminnan poikkeavuuksiin 2-4 vuoden iässä. Kuitenkin yhteensä 14%:lla tutkituista lapsista todettiin ultraäänitutkimuksella munuaisten rakenteellisia poikkeavuuksia. Niiden vaaraa lisäsi pitkäkestoinen napavaltimokatetrin käyttö ja furosemidilääkitys vastasyntyneisyyskaudella. Yhteenvetona voidaan todeta, että sekä raskauden aikaiseen että syntymän jälkeiseen pitkäkestoiseen indometasiinihoitoon näyttää liittyvän lisääntynyt välittömien haittavaikutuksien riski ennenaikaisesti syntyneillä lapsilla. Sen sijaan indometasiinihoidolla ei ollut pitkäaikaisvaikutuksia munuaisten kasvuun, rakenteeseen tai toimintaan.

Indomethacin, a prostaglandin synthetase inhibitor, is used antenatally as a tocolytic agent and in the treatment of polyhydramnios, and postnatally for pharmacological closure of PDA. Recently, postnatal indomethacin administration during the first 24 hours of life has been shown to reduce the incidence of IVH in infants born prematurely. However, both antenatal and postnatal indomethacin exposure have been associated with significant adverse effects, including GI pathology, bleeding tendency and renal dysfunction during the neonatal period in preterm patients. Few data are available regarding the long-term effects of perinatal indomethacin use on renal macroscopic structure and function in such patients.

The study objective was to establish whether a prolonged low-dose course of indomethacin for symptomatic PDA would produce a more complete closure rate, have fewer side-effects and correlate with a better outcome compared with a short schedule, and to identify the association of perinatal indomethacin exposure with neonatal complications and oesophageal and gastric mucosal lesions in newborn infants of gestational ages In the randomized study, initial PDA closure occurred more often (94%) in the short three-dose (0.2 mg-0.1mg-0.1mg/kg at 12 hours intervals) group (N=31) than in the group (N=30) treated on the long, 7-day schedule (0.1 mg/kg at 24 hours intervals) (67%), but the sustained closure rates after the first course were not different (74% vs 60%). The final closure rate after repeated indomethacin administration was higher (90%) in the short course group compared with the long (63%). Surgical PDA ligations were less frequent in the short course group (7% vs 30%). This group also had a shorter duration of oxygen supplementation, less frequent symptoms of NEC and less marked tendency to urea retention. Other neonatal morbidity and mortality rates were similar in the groups.

Among 240 cases born at less than 33 weeks gestation studied retrospectively, antenatal indomethacin treatment for longer than two days and a daily or cumulative dosage ?150 mg correlated with an increased risk of grade I-II IVH. Combined ante- and postnatal indomethacin exposure, cumulative antenatal exposure ?150 mg and duration of maternal treatment over two days were associated with an increased risk of NEC and combined indomethacin exposure with an increased risk of septicaemia. There was no independent association between indomethacin exposure and pneumothorax, BPD or RDS.

Abnormal findings were equally common in 69 infants with (N=45) and without (N=24) perinatal indomethacin exposure who underwent upper GI tract endoscopy during their neonatal period. A short interval between the last perinatal indomethacin dose and endoscopy correlated with oesophageal and gastric mucosal lesions. Perinatal indomethacin administration also increased the risk of GI symptoms in retrospective analysis of the cases. In addition, a short duration of enteral feeding before gastroscopy was a risk factor associated with oesophageal mucosal lesions. The risk of abnormal gastric mucosal findings was increased in conjunction with ventilator treatment at the time of endoscopy and with increasing gestational age of the patient.

Renal growth and structure, studied by ultrasonography, and function, evaluated by 51Cr-EDTA, blood tests, urineanalysis and blood pressure measurements, were good in 66 preterm-born children with (N=31) and without (N=24) perinatal indomethacin exposure, at the age of 2-4 years. The mean serum cystatin C concentrations were slightly higher in the group without perinatal indomethacin administration, but in all cases the values were within normal limits. Concentrations of plasma creatinine, sodium and potassium, and serum protein were similar between the groups, as were also urine protein/creatinine and calcium/creatinine ratios. None had tubular proteinuria. Abnormal GFR ( In conclusion, a prolonged low-dose indomethacin regimen offers no advantage compared with a short course in the management of a symptomatic PDA in preterm infants. Preterm infants exposed to antenatal indomethacin might run an increased risk of grade I-II IVH and those with both ante- and postnatal exposure an increased risk of NEC and septicaemia. The risk of adverse effects on the infants seems to increase with increasing duration of both antenatal and postnatal indomethacin uses. Recent perinatal or current postnatal indomethacin treatment may also increase the risk of GI symptoms and oesophageal and gastric mucosal lesions in preterm infants. In addition, short duration of enteral feeding is associated with an increased risk of oesophageal, and increasing gestational age and ventilator treatment with gastric mucosal lesions. Perinatal indomethacin exposure would not appear to affect long-term renal growth, macroscopic structure or function in children born prematurely, but duration of UAC use and furosemide treatment seem to be risk factors underlying subsequent renal macroscopic structural abnormalities.