Although AI may provide enough time for antenatal steroids to improve fetal maturation, the results of our meta-analysis of observational studies suggest that these benefits may come with a price. Our study suggests that AI used as a tocolytic agent is associated with PVL in premature infants. The results also suggest that exposure of AI within 72 hours prior to delivery is associated with NEC in premature infants. AI does not appear to be associated with PDA, RDS, BPD, IVH and mortality in premature infants.
Although meta-analysis on randomized studies is a gold standard, the recent meta-analysis of randomized studies evaluating the effect of AI on neonatal outcomes cited several limitations and was inconclusive because of small pooled numbers and lack of clear definitions used for each neonatal outcome.43, 44
Moreover, the neonates studied with randomized studies usually were >35 weeks’ gestation when the neonatal adverse outcomes of interest are rare. The observational studies performed to date involved premature infants <35 weeks’ gestation to study neonatal effects secondary to AI usage, but have shown conflicting results.22–41
Some of these studies were insufficiently powered to evaluate the association of AI usage with individual adverse neonatal outcomes. For these reasons, we chose to analyze observational studies.
Compared to Loe’s published meta-analysis on observational studies44
, we used strict diagnostic criteria for each neonatal outcome in order to determine true association between exposure to AI and neonatal outcome. In addition, we conducted sensitivity analysis to evaluate the effect of possible confounding variables, such as antenatal steroids, gestational age of the infant, use of indomethacin as first choice tocolytic agent and timing of antenatal indomethacin prior to delivery. Another notable difference is that we evaluated the effect of antenatal indomethacin on PVL and RDS in addition to the neonatal outcomes reported by Loe. We did not include the effects of AI on pulmonary hypertension and renal insufficiency because there are no uniform criteria available for these diagnoses in premature infants. There is increased risk of ductal constriction and secondary pulmonary hypertension after 32 weeks’ gestation and, therefore, use of AI is limited < 32 weeks’ gestation.54
In addition, fetal echocardiography is recommended to detect any evidence of ductal constriction if indomethacin is continued for more than 72 hours. 54
All the studies reporting on renal insufficiency employed differing criteria.49–51
The current literature suggests that AI may be associated with renal insufficiency in premature infants.
Recent exposure to AI was associated with NEC which can be explained based on its effect on mesenteric blood flow10
. A possible increased risk of NEC (OR 2.43, 95% CI 0.73–8.03) was also suggested by the meta-analysis of randomized clinical trials but failed to reach statistical significance because of small sample size.44
Antenatal indomethacin was associated with an increased risk of PVL that can be explained by its known effect on cerebral blood flow.12
The trend for an increased risk of RDS with recent exposure to antenatal indomethacin can be explained by its known inhibitory effect on surfactant production.16
The trend for a protective effect on RDS when including studies that controlled for antenatal steroid exposure and gestation at birth suggest that the inhibitory effect on surfactant production may be an acute effect and is probably mitigated by the use of antenatal steroids.
Similar to Loe44
, we found no effect of antenatal indomethacin on PDA, BPD, IVH and mortality. The inclusion of studies that met established diagnostic criteria for neonatal outcomes in our meta-analysis may explain differences in effect size for individual neonatal outcomes between the two meta-analysis of observational studies. For example, compared to Loe44
, we did not include Ojala et al., Abbasi et al., and Vermillion et al. in our meta-analysis for BPD because these studies did not define BPD.25, 32, 35
Moreover, we included five additional studies, two of which were not included in the published meta-analysis and three of which were reported after the published meta-analysis.33, 36–38, 42
Also, we did not include a study that reported neonatal outcomes secondary to the use of postnatal indomethacin and was inadvertently included in Loe’s meta-analysis of AI. 44, 55
A limitation of meta-analysis involving observational studies is that it is difficult to control for the confounding factors and selection bias often associated with observational studies. However, the majority of studies matched on two of the most important confounding factors, GA and antenatal steroid exposure. We conducted sensitivity analysis to control for confounding variables that could affect the neonatal outcomes. Although there are statistical reasons to control for confounding variables in individual observational studies, adjusting for gestation at birth in studies using AI tocolysis could lead to an underestimate of benefit associated with postponing preterm delivery. It is more appropriate to adjust for gestation at onset of preterm labor. However, the information on the age at onset of preterm labor is not reported for most observational studies involving AI. It is unlikely that the results would have differed if the findings were adjusted for gestation at the onset of labor since majority of observational studies included in this meta-analysis used AI for recalcitrant labor. In the face of recalcitrant labor, prolongation of pregnancy for a few hours to days allows time to administer antenatal steroids, a confounding variable, which was adjusted in most of the observational studies included in this analysis.
The other limitation of our meta-analysis is that the results mainly reflect the effect of AI when used for recalcitrant labor. A potential cause for recalcitrant labor could be overt or silent chorioamnionitis56
which has recently been associated with PVL, NEC and BPD.57, 58
Most observational studies did not provide information on silent chorioamnionitis. Whether the adverse neonatal effects are secondary to recent exposure to AI or to underlying silent chorioamnionitis, a marker of recalcitrant labor, remains to be answered. In addition, the few studies using indomethacin as the first agent for tocolysis prevented the performance of a sensitivity analysis evaluating the risk of PVL and BPD after its exposure.
Another limitation is that we were not able to evaluate the independent risk of a spontaneous intestinal perforation after exposure to AI. Most observational studies included in this meta-analysis did not elaborate on their definition of NEC so that a spontaneous intestinal perforation was not differentiated from an intestinal perforation that accompanied NEC.
Since not every computer assisted search will be exhaustive, there is a possibility of missing important publications. However we did not find publication bias for any of the neonatal outcomes studied in this meta-analysis. Despite all these limitations, meta-analysis can improve the conclusions of multiple small studies, especially if individual studies are not powered sufficiently to independently study neonatal outcomes and provide meaningful conclusions. In this context, the findings of this meta-analysis allow investigators to derive more accurate conclusions than those from individual studies or non-quantitative systematic reviews. We conclude that AI used for recalcitrant labor may be associated with PVL and NEC in premature infants and recommend that AI be used judiciously as a tocolytic agent. There is a need to conduct well designed randomized trials to confirm the findings of our meta-analysis.