Mid-trimester preterm premature rupture of membranes (PPROM), defined as rupture 
of fetal membranes prior to 28 weeks of gestation, complicates approximately 
0.4%-0.7% of all pregnancies. This condition is associated with a very high 
neonatal mortality rate as well as an increased risk of long- and short-term 
severe neonatal morbidity. The causes of the mid-trimester PPROM are 
multifactorial. Altered membrane morphology including marked swelling and 
disruption of the collagen network which is seen with PPROM can be triggered by 
bacterial products or/and pro-inflammatory cytokines. Activation of matrix 
metalloproteinases (MMP) have been implicated in the mechanism of PPROM. The 
propagation of bacteria is an important contributing factor not only in PPROM, 
but also in adverse neonatal and maternal outcomes after PPROM. Inflammatory 
mediators likely play a causative role in both disruption of fetal membrane 
integrity and activation of uterine contraction. The "classic PPROM" with 
oligo/an-hydramnion is associated with a short latency period and worse neonatal 
outcome compared to similar gestational aged neonates delivered without 
antecedent PPROM. The "high PPROM" syndrome is defined as a defect of the 
chorio-amniotic membranes, which is not located over the internal cervical os. 
It may be associated with either a normal or reduced amount of amniotic fluid. 
It may explain why sensitive biochemical tests such as the Amniosure (PAMG-1) or 
IGFBP-1/alpha fetoprotein test can have a positive result without other signs of 
overt ROM such as fluid leakage with Valsalva. The membrane defect following 
fetoscopy also fulfils the criteria for "high PPROM" syndrome. In some cases, 
the rupture of only one membrane - either the chorionic or amniotic membrane, 
resulting in "pre-PPROM" could precede "classic PPROM" or "high PPROM". The 
diagnosis of PPROM is classically established by identification of nitrazine 
positive, fern positive watery leakage from the cervical canal observed during 
in specula investigation. Other more recent diagnostic tests include the vaginal 
swab assay for placental alpha macroglobulin-1 test or AFP and IGFBP1. In some 
rare cases amniocentesis and infusion of indigo carmine has been used to confirm 
the diagnosis of PPROM. The management of the PPROM requires balancing the 
potential neonatal benefits from prolongation of the pregnancy with the risk of 
intra-amniotic infection and its consequences for the mother and infant. Close 
monitoring for signs of chorioamnionitis (e.g. body temperature, CTG, CRP, 
leucocytes, IL-6, procalcitonine, amniotic fluid examinations) is necessary to 
minimize the risk of neonatal and maternal complications. In addition to delayed 
delivery, broad spectrum antibiotics of penicillin or cephalosporin group and/or 
macrolide and corticosteroids have been show to improve neonatal outcome 
[reducing risk of chorioamnionitis (average risk ratio (RR)=0.66), neonatal 
infections (RR=0.67) and abnormal ultrasound scan of neonatal brain (RR=0.67)]. 
The positive effect of continuous amnioinfusion through the subcutaneously 
implanted perinatal port system with amniotic fluid like hypo-osmotic solution 
in "classic PPROM" less than 28/0 weeks' gestation shows promise but must be 
proved in future prospective randomized studies. Systemic antibiotics 
administration in "pre-PPROM" without infection and hospitalization are also of 
questionable benefit and needs to be further evaluated in well-designed 
randomized prospective studies to evaluate if it is associated with any neonatal 
benefit as well as the relationship to possible adverse effect of antibiotics on 
to fetal development and neurological outcome.