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.