DISCUSSION
Currently there are no reliable clinical or laboratory markers to accurately predict impending neonatal infection in utero i.e. FIRS subsequent to PPROM. This study is amongst the first to show an association between FUPR and FIRS in patients of PPROM. The implications of FUPR in clinical practice are underinvestigated though it is a simple, safe and noninvasive technique of diagnosing fetal condition in utero. Using this easy to perform ultrasound examination to evaluate FUPR in cases of PPROM, we found that neonates with FIRS had lower FUPR antenatally as compared to neonates with no evidence of FIRS. In other words, reduced FUPR is significantly associated with development of FIRS in neonates born to women with PPROM.
Fetal bladder volume can be estimated ultrasonographically and the changes in bladder volume can be expressed as FUPR. In normal pregnancy, FUPR increases with gestational age i.e. from 5ml/hr at 20 weeks of gestation to 51 ml/hr at 40 weeks6. The ability to accurately estimate urinary flow rate non invasively in fetuses can be used for evaluation of fetal well-being. Campbell et al. first estimated human fetal urinary flow rate by calculating changes in fetal bladder volume by means of static ultrasonographic images of the fetal bladder5. The changes in bladder volume were expressed as hourly fetal urinary flow rate. Rabinowitz et al improvised this technique by taking more frequent measurements of fetal bladder volume in real time (every 2 to 5 minutes for 1 hour) and calculating the fetal urinary flow rate from the slope of the serial volume estimates by means of linear regression analysis6. Recent advances in 3D ultrasound have further improved the measurement of fetal organ volume. Few studies have been done in the past where FUPR has been used to evaluate oligohydramnios, polyhydramnios, childhood polyuric and hypercalciuric syndrome, west syndrome and as a marker of fetal well being.
We found a significant correlation between reduced FUPR and development of FIRS where it was found that out of 41 patients with reduced FUPR antenatally, 39 babies had evidence of FIRS while out of 29 patients with normal FUPR, only 5 babies had features suggestive FIRS. These findings suggest that fetuses with reduced FUPR antenatally have significantly high risk of developing FIRS which justifies our hypothesis that FUPR may be an early sign of fetal infection in cases of PPROM. Besides, we found that IL-6 levels were also markedly raised in fetuses with decreased FUPR. However very limited studies have been done in literature where FUPR has been correlated with IL- 6 levels. On searching the literature, we could find only one study which was conducted by Avitan et al in women with PPROM where they did not find any correlation between mean fetal IL-6 levels and FUPR7. However, they did not quote value of IL-6 levels in either group.
In our study the mean IL-6 levels in the FIRS group was significantly higher as compared to the Non FIRS group (77.37±74.51pg/ml vs 5.75±2.80 pg/ml). All the 16 patients with histopathological evidence of FIRS had elevated IL-6 levels also. Similar findings were also found in the study by Naccasha et al, where out 15 infants whose umbilical cords had evidence of funisitis, 93% (14 of 15) had elevated IL-6 concentrations8. Another study by Mittendorf et al found that the median level of IL-6 in the newborns with funistis was 249 pg/ml while the median IL-6 levels in the newborns without funistis was <10pg/ml9. They concluded that histological funisitis is an end-stage pathologic condition that is preceded by ever-increasing levels of IL-6 in the umbilical cord vessels.
Chorioamnionitis is the most common maternal complication after PPROM. The prevalence of chorioamnionitis in cases of PPROM in our study was 60% (42/70). Studies have shown that chorioamnionitis (clinical and histologic combined), complicates as many as 40–70% of preterm births with premature membrane rupture or spontaneous labor10. On comparing FUPR with chorioamnionitis, we found that reduced FUPR is associated with an increased risk of chorioamnionitis. Our findings were similar to that of Avitan et al, where they found that the mean FUPR was significantly lower in women with clinical chorioamnionitis compared to women without signs of clinical chorioamnionitis (89.4 ± 0.6% vs 112.7 ± 25.2%)9. This was in contrast to study by Nguyen et al where the found that the presence of histologic or clinical chorioamnionitis does not appear to affect FUPR in women with PROM11. We further correlated FIRS with chorioamnionitis and found that FIRS is strongly associated with the presence of chorioamnionitis as majority of the newborns who had FIRS had associated evidence of chorioamnionitis in their mothers also. There might be possibility that chorioamnionitis precedes development of FIRS.
FIRS is associated with higher rates of adverse neonatal outcomes. Overall severe neonatal morbidity, risk of early onset sepsis, duration of NICU stay was significantly higher in the FIRS group as compared to the Non FIRS group. The occurrence of respiratory distress syndrome (RDS) and necrotising enterocolitis (NEC) in our study cohort was significantly higher in FIRS group (34.1% and 6.82%) as compared to the Non FIRS group (15.38% and 3.85%) suggesting FIRS as a risk factor for development of severe neonatal morbidity. Similar observations were seen by Gomez et al and Ozalkaya et al in their studies3,12. However, Zhiwei et al, Lahra et al and Watterberg et al observed significant reduction of RDS with FIRS13-15.
On correlating FUPR with neonatal outcomes, it was found that 58.54% babies with decreased FUPR antenatally had evidence of neonatal sepsis as compared to only 34.48% babies developing sepsis with normal FUPR antenatally suggesting that reduced FUPR measured antenatally is significantly associated with the risk of developing neonatal sepsis. The occurrence of RDS, NEC was significantly high in neonates with reducued FUPR as compared to normal FUPR. Only one study had been conducted so far by Avitan et al where they evaluated the association between FUPR and adverse neonatal outcome in patients with PPROM7. They found that the lower FUPR values were associated with clinical chorioamnionitis, longer NICU stay, NEC, IVH and blood transfusion and hence can be used as early sentinel sign.
We also found that chances of developing severe neonatal morbidity were significantly high when both biochemical and histological markers of FIRS were present as compared to when only biochemical marker was elevated. However, in the absence of both, the chances of fetal morbidity was very low even in the settings of prolonged PPROM. We also correlated cord histopathology with placental histopathology and found that all 16 patients (45.71%) with evidence of funisitis on cord histopathology had evidence of chorioamnionitis on placental histopathology suggesting that funisitis is always associated with chorioamnionitis.
Limitations of our study include small sample size of the study, however despite a small sample size, the detected association found in our study was significant. We did not measure neonatal creatinine levels and neonatal urine production in first 24 hour to correlate with reduced fetal urine production rate. Simultaneous measurement of fetal renal blood flow by renal doppler if included in our study would have enabled us to quantify renal blood flow more accurately.
Strengths of this study is its multidisciplinary approach. No study has been done to find association between fetal urine production rate and fetal inflammatory response syndrome. Both the interleukin-6 levels and placental histopathology was used to define FIRS in our study. Very few studies in literature have used both the parameters to define FIRS in their study.