الفهرس 
Acknowledgements
Progesterone in PregnancyOnly 14 pages are availabe for public view
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Abstract
Many studies in literature proved the positive correlation between the PP and preterm uterine contractility and also reported that large proportion of women who have PP associated with vaginal bleeding will have subclinical uterine contractions before the onset of evident vaginal bleeding. There are many tocolytic drugs may have a role in conservative management of PP; these drugs can prolong the pregnancy and result in an increase in birth weight of the babies without causing any adverse effect on the mother and fetus.
Progesterone is essential for continuation of pregnancy and helps in maintenance of pregnancy. A significant reduction in recurrent preterm birth before 37 weeks was reported, in many studies, in women who received 17-α hydroxyprogesterone caproate. The 17OHP-C has the ability to establish uterine quiescence and maintains cervical length, as well as it has immunosuppressive activity and can block the effect of oxytocin and reduce calcium flux which inhibits the smooth muscle.Aim of the study In the light of above evidences; we aimed, in this study, to test the hypothesis that 17OHP-C has may decrease the subclinical uterine contractions and vaginal bleeding associated with PP which subsequently decrease preterm delivery.Methodology
The current study was registered open, parallel, randomized clinical trial (NCT03130504) compassing the effect of intramuscular 17OHP-C therapy in reducing/ preventing preterm delivery (PTD) in patients with placenta previa. The ethical review board of Assiut Faculty of Medicine approved the study. The study participants were recruited from the Obstetric Outpatient Clinic, Woman’s Health Hospital, Assiut University, Egypt from 1st of April 2016 to 30th March 2017. Women who met the selection criteria of the study were invited to participate and only those who signed the informed consent were recruited
Eligible participants
We included in our study women aged 20-35 years, who were pregnant in a singleton baby with estimated gestational age ranging between 24- 28 weeks gestation. All recruited women were had placenta previa, major or minor degree, either with minimal vaginal bleeding or hadn’t any vaginal bleeding.
However; we excluded women with history of previous premature birth, definite rupture of membranes, polyhydramnios, severe attack of bleeding requiring an immediate intervention, fetal heart rates instability or non-reassuring, intrauterine fetal death or major fetal anomalies, abruptio placentae, known bleeding disorders or on anticoagulant therapy, medical disorders as PET, DM, hepato-renal impediment …etc, multiple pregnancy, previous reported side effects in the mother from 17OHP-C like hypersensitivity reactions, cough and dyspnea and lastly; all women had established preterm labor were excluded.RandomizationEligible women who gave their informed consent were randomized to either group I: 17OHP-C group or group II: non 17OHP-C group. Randomization was conducted using a computer generated table of random numbers with allocation concealment. Blinding of patients and participating investigator to the treatment following the randomization was not possible due to the nature of drugs used in the study. Allocation concealment was done using serially-numbered closed opaque envelope. Counseling for participation was done before recruitment and written consents were obtained from eligible women. Once allocation has been done, it could not be changed.
Intervention
The study included 2 groups: group I ”17OHP-C group” where patients had a 17OHP-C intramuscular injection (Cidolut Depot 250 mg, CID, Egypt) every week starting from 24-26 weeks of gestation till completed 37 weeks. group II ”non 17OHP-C group” where they had no intervention.Study outcomes The primary outcome of our study was the number of preterm babies delivered below 37 weeks. Secondary Outcomes included mean gestational age at the time of delivery (weeks), number of vaginal bleeding episodes during the pregnancy, birth weight and number of babies admitted in Neonatal Intensive Care Unit (NICU).
Follow up schedule
The participating women were encouraged to continue to follow up at Assiut University Hospitals’ Outpatient Obstetric Clinic every 2 weeks. At each visit; we asked them about fetal movement, abdominal pain and number and pattern of vaginal bleeding if occurred. Unscheduled ultrasound examinations ± CTG was done for any fetal-maternal indications as attacks of APH, decreased fetal movement, suspected PROM or, PTL. All patients were received corticosteroids following the recruitment (Our hospital protocol).
Sample size calculation
Sample size calculation was based on the primary outcome (the number of preterm babies delivered in placenta previa women before 37 weeks).The previous non randomized study showed that the rate of PTD due to placenta previa could be as high as 45%. Using two sided chi-square (χ2) test with α of 0.05, a total sample size of at least 114patients (57 in each arm) will have 80% power detect a 50 % difference assuming a rate of loss to follow-up of 10%(Epi-info™, CDC, USA).
Statistical analysis The data were collected and entered into a Microsoft Access database and were analyzed using the Statistical Package for Social Science (SPSS Inc., Chicago, version 21). Enumeration data are expressed as percentages (%) and were compared using the chi-square test. Quantitative data are expressed as the mean ± SD and were compared using Student’s t-test. p<.05 was interpreted as statistically significant.
Main resultsOne hundred twenty women were counseled for participation, however; 6 women refused to participate. One hundred fourteen women consented to participate and divided into two groups; group I (17OHP-C group) included 57 PP women and group II (non 17OHP-C group) included 57 PP women (Fig 2, the study flow chart).
Both groups were homogenous in their baseline admission characteristics without statistically significant differences. The mean gestational age at time of recruitment was about 26 weeks and the most prevalent reported uterine scar was the cesarean section (74%). Thirty two PP women had a previous history of placenta previa while 41 women were presenting with manifestation of threatened preterm labour. Lastly; both groups were anemic at the start of the study (mean hemoglobin level was 9 gm/dl) (table 1).The average fetal weight in 17OHP-C group was 920 gm while in Non 17OHP-C group was 880 gm; no statistically significant difference was noticed between groups as regard the fetal weight (p=0.750) (table 2). We found that 95 PP women (83%) had major PP and 19 women (17%) had minor PP. Collectively; no significant statistically difference was detected between the group as regard the placental site (p= 0.837) (table 2) We noted that, the majority of PP women (70 women, 61.5%), in both groups, had not yet any vaginal bleeding at time of admission (24-26 weeks), while the remaining 44 women (38.5%) had history of previous one to three attacks or more than 3 attacks of vaginal bleeding without statistically significant difference between groups (p =0.286) (table 3). At time of termination; we found that 28 PP women (51.9%) in the 17OHP-C group still had not any vaginal bleeding and only 17 (32.7%) women in the Non 17OHP-C group had not any vaginal bleeding. Moreover; number of women in 17OHP-C group who had one to three attacks and more than 3 attacks at time of termination were much less than that reported in the Non 17OHP-C group. So there was statistically significant difference between groups as regard the number of vaginal bleeding attacks at time of termination (p value=0.000) (table 3).As regard the delivery data; we noticed that women in the Non 17OHP-C group were delivered earlier than 17OHP-C group women with statistically significant difference (36.7±0.7 weeks Vs 34.9±1.2 weeks; p= 0.000). Most of PP women (98; 92.5%) were delivered by cesarean section, while much less number of PP women (8; 7.5%) was delivered vaginally. There was no statistically significant difference between both groups as regard route of delivery (p =0.379). As regard number of term babies, the higher number of term babies was reported in the 17OHP-C group than in the Non 17OHP-C group with statistically significant difference (34 Vs 19; P = 0.006) (table 4).
In contrast, a higher number of preterm babies was reported in Non 17OHP-C group than 17OHP-C group with statistically significant difference (33 Vs 20; p=0.004). Fifteen spontaneous preterm babies (75%) in 17OHP-C group were reported while the remaining 5 preterm babies (25%) were delivered due to sever attack of vaginal bleeding needed immediate intervention. Similarly; 25(73.5%) spontaneous preterm babies and 8 preterm babies (24.2) were delivered due to sever attack of vaginal bleeding in Non 17OHP-C group. No statistically significant difference was noticed between groups as regard the cause of preterm delivery. Again; we found that number of early preterm babies (< 34 weeks) in Non 17OHP-C group was higher than that reported in 17OHP-C group (23 Vs 7; respectively), while for late preterm babies (≥34 weeks); the figures were (13 VS 10; respectively). A statistically significant difference was noticed between groups as regard the time of preterm deliveries (table 4).
The mean birth weight in 17OHP-C group (2841±159 gm) was higher that reported by Non 17OHP-C group (2561±168 gm) with statistically significant difference (p value =0.000). Lastly; the number of babies admitted at NICU was much less in 17OHP-C group with statistically significant difference (p value =0.000) (table 4).
There are some interesting points should be discussed in our study. Firstly; we were able to recruit our calculated sample size for achieving sufficient power to detect a clinically significant difference according to our primary outcome. Secondly; the ultrasound examinations were performed by one investigator to decrease interobserver errors. Thirdly, we stress here not only on effect of 17α OH progesterone on preterm birth but only on the frequency and pattern of the vaginal bleeding; which up to our knowledge is scarce in other studies. However, the present work had some limitations. First, the small sample size that was available for the final analysis at the end of the study (106 PP women). Secondly; the heterogenicity of included PP women might affected our results. Thirdly; we did not care about placenta accreta or maternal outcome because it would take us away from our primary outcome but it should be addressed in another study.ConclusionsThe 17α OH progesterone caproate thereby is beneficial in declining the preterm delivery in asymptomatic and symptomatic placenta previa. This effect may be secondary to inhibition of the subclinical uterine contractions before the onset of apparent vaginal ble.