Abstract
Background and objectives :the objective of our study was to compare the efficacy & safety of the half dose salbutamol plus progesterone verus salbutamol in the treatment of threatened preterm labor.
Patients and Methods :one hundred fifteen pregnant women with gestational age ( 28 – 36 weeks) presented with threatened preterm labor was conducted in Al-Diwaniya Maternity Teaching Hospital .The patients divided into two groups : the control group include 55 pregnant women with preterm labor received salbutamol infusion (in a dose of 2.5 mg/500 ml 5% dextrose) as a treatment of the preterm labor & 60 patients received progesterone (250mg) I.M with half dose of salbutamol infusion(1.25mg in 500 ml of 5% dextrose which considered as a study group . Both groups were compared time of delivery within 1^st 48 hrs , 48 hrs-one week , and after one week ,development of maternal adverse effects and neonatal follow up.
Results : there was no significant difference between control and study group regarding treatment-delivery interval within 1^st 48 hrs , 48 hrs-one week , and after one week (P=0.6) .
There was no significant difference between control and study group regarding neonatal outcome(P=0.078).
But there was significant reduction in the side effects for patients treated with half dose salbutamol in combination with progesterone.
Conclusion and Recommendation :progesterone had a role in the treatment of preterm labor when used in combination with salbutamol to minimize the potentially life threatening side effects .
Key word: preterm labor ,tocolytics ,progesterone , salbutamol
Introduction:
Preterm labor (PTL) is the single most important cause of perinatal morbidity and mortality , excluding lethal congenital malformations. It is responsible for 75% of all perinatal deaths and for 50%of neurological disabilities in childhood.(1)
Preterm labor refers to the onset of labor after gestation of viability 28 weeks and before 37 completed weeks . The onset of labor may be determined by documented uterine contractions (at least one every 10 minutes) with or without ruptured fetal membranes ,vaginal bleeding and cervical effacement with an estimated length of less than 1 cm or cervical dilatation more than 2 cm. Threatened preterm labor may be diagnosed when there are documented uterine contractions but no evidence of cervical change .(2)
The incidence of PTL about 5% to 10% , with some regions noticing a small increase above the usual incidence over the last 5 years(2). Social and epidemiological factors influence the incidence of PTL . Many studies have shown that PTL is significantly more common in women of young and older age , low body weight (BMI less than 19) low social class , single (unmarried/unsupported) and smokers . each of these factors carries a relative risk of 1.5-2.0.
Both anemia(Hb”9.5 g/dl) and high hemoglobin concentration (”13.5 g/dl) due to failure of plasma volume expansion , are associated with a markedly increased risk of PTL.(3)
Preterm labor may be diagnosed by history of painful uterine contractions, bleeding with or with rupture of amniotic membrane, previous obstetric history of preterm labor in examination may reveal dilatation of the cervix and/or amniotic fluid leak through the cervix .(4)
Digital examination should not be performed if it is through that the membranes had ruptured , as this will increase the risk of infection to the fetus . If the membranes have not ruptured , vaginal examination should performed(5) . Once diagnosis of threatened or actual PTL is established , then parenteral tocolytics therapy should be considered . After a careful clinical appraisal of the maternal and fetal condition , preliminary investigations should be performed . Ultrasonography can be used to ascertain fetal number , estimate fetal weight , check fetal morphology and presentation , measure the volume of amniotic fluid , and identify placental site . It can be used to assess fetal well-being ..(2)
The use of tocolytic therapy between 24 and 34 weeks gestation is not only to facilitate the in utero transfer of the fetus to a tertiary referral center , but also to enable sufficient time to enhance fetal maturity by the concomitant use of maternal corticosteroid therapy . Treatment of PTL after 34 weeks’ gestation has little to recommend it because the additional expense and maternal risks of tocolysis which are not justified in view of minimal neonatal morbidity that is potentially avoided between 34 and 37 weeks’ gestation .(6)
The perfect tocolytic should be safe for mother and fetus , could prolong gestation for enough time to achieve a significant reduction of preterm birth , allowing fetal maturation and therefore diminishing perinatal morbidity .(7.8)
Myometrial cell contractility is modulated by intracellular concentration of calcium , from a variety of different mechanisms binds with calmodulim and leads to activation of calcium dependent myosin light chain kinase (CDMLK) , this is in the turn triggers an ATP-dependent phosphorylation of myosin . This allows interaction with actin filaments and cross bridges from which result in contraction of myometrial cell . Subgroups of tocolytic drugs act at a variety of different levels of this pathway to cause inhibition of contractions . This may be via mechanisms specific to labor (oxytocin-receptor antagonists , cyclo-oxygenase (COX) inhibitors and possibly nitric oxide donors) or due to nonspecific action on cell contractility (B-mimetics , magnesium sulphate and calcium channel blocker) .(9.10)
”-mimitics are effective in delaying delivery in women in preterm labor for 48 hrs(10) . Short term tocolysis with intravenous ritodrine may be helpful to transfer woman in preterm labor to a hospital with better neonatal facilities or to allow time to complete a course of antenatal glucocorticoids.
”-mimitics are associated with maternal side effects of palpitation , tachycardia , arrhythmia , nausea , vomiting , tremor , hyperglycemia , hypokalemia and pulmonary edema(8.11) . fetal sid effect of B-mimitic drug are tachycardia,hyperinsulinemia & hyperglycemia.(11,12)
other drug of tocolytic are Nonsteroidal Anti-inflammatory drug, Magnesium sulphate, Calcium-Channel Blockers ,Oxytocin receptor antagonist (Atosiban)
Progesterone is an essential hormone in the process of reproduction . It is involved in the menstrual cycle , implantation and is essential for pregnancy maintenance. Although the pharmacokinetics and pharmacodynamics of progesterone have been well studied , and since 1935 it has been synthesized and is now available commercially , its use in pathophysiology of pregnancy remains controversial . one of these concerns is the way in which the hormone is administered , with parenteral use proving the best way to obtain optimal plasma levels . Another concern is the paucity on randomized controlled trails and the different dosages and populations studied . As a result , the therapeutic application of progesterone in pregnancy is used for prevention and treatment of threatened miscarriage , recurrent miscarriage , and preterm birth .(13)
Progesertone has been shown to possess a tocolytic action on the myometrium both in vitro and in vivo during the pregnancy .(14.15.16)
At the cellular level , progestins act on receptor proteins in cellular cytoplasm . The resulting progesterone-receptor complex is transported into the cell nucleus , where the synthesis of mRNA is stimulated . Under the direction of mRNA , the cell produces various proteins that are responsible for pharmacologic effects of the progestins .(17)
Progesterone has also been shown in vivo to be concentration dependent . only high-dosage progesterone exerts a tocolytic action in early pregnancy and , according to patient weight , the optimal dose should be between 100 and 200 mg/day . This dosage has also proven effective in maintenance of uterine quiescence during cervical cerclage (during the first trimester of pregnancy) and/or following surgery (e.g. appendectomy) .(18) .
progesterone is implicated in mechanism of human parturition (at term and preterm ) with different outcomes. Adequate progesterone concentrations in myometrium are able to counteract prostaglandin stimulatory activity as well as oxytocin properties that enhance the activity of ”-agonists (19). Progesterone decreases the concentration of myometrial oxytocin . The same is true with respect to the number and properties of gap junctions . Progesterone also inhibits prostaglandin production by amnion-chorion-decidua and has been shown to increase the bending of progesterone in the fetal membranes at term , which may explain the predominant effect of estrogen in promoting prostaglandin production and triggering labor .(20)
Materials and Methods: one hundred fifteen pregnant women enrolled in our study with a gestational age 28-36 weeks , who have threatened preterm labour that attend Al-Diwaniya Maternity and Pediatrics Teaching Hospital from the period of February 2015 ‘ February 2016 with inclusion criteria : singleton pregnancy, who have actual preterm labor that was diagnosed on the basis of presence of both :
Regular painful uterine contraction of at least one per ten minutes.
Cervical changes in form of cervical dilatation of ‘ 3 cm and/or cervical length less than 1 cm .
The exclusion criteria : were patients with moderate or severe vaginal bleeding , placenta praevia , rupture of fetal membranes , signs of chorioammionitis , pre-eclampsia , serious maternal disease (such as cardiac disease , venous thrombo-embolism , server anemia) , fetal death or congenital anomalies of the fetus were excluded from the study .
On admission to the emergency ward , detailed history was taken from all patients. The gestational age was determined by obstetrical criteria depending on accurate dating of the 1^st day of the last menstrual period and early antenatal record confirmed by early ultrasound study . Speculum examination was done to exclde premature rupture of fetal membranes and cervical dilatation , if negative then we did per-vaginal digital examination for assessment of cervical dilatation and effacement .
Patients were investigated for hemoglobin concentration ,random blood sugar which repeated 4 hrs after start of tocolytic agents, blood urea , serum creatinine , midstream urine examination , urine for culture and sensitivity , high vaginal swab , for culture and sensitivity , obstetric ultrasound , ECG , and serum electrolytes .
None of the patients were using any medication except for Iron and folic acid supplements and insulin required for control of diabetic women .
The frequency and intensity of uterine contractions and fetal cardiac rhythm monitored by (CTG).All patients had an informed consent regarding the method of treatment and accepted from Iraqi Local Ethical Committee. Then the patients were randomly divided into 2group:
Fifty five patients were chosen to be a control group receiving salbutamol(2.5mg in 500 ml of 5%dextrose started with 7 drops per minute)& doubled every 15 minutes till subsidence of uterine contraction but the treatment stopped if the patients developed drugs complication and side effects as maternal tachycardia( 140 beat/min).Maintenance of B-Mimi tics for 48 hr. when the patients respond to treatment.
The other 60 patients regarded as a study group received intramuscular(I.M) progesterone in form of primo- lute depot(17 hydroxy progesterone hexanoate in oil ) (250mg) in combination with half dose of salbutamol infusion(1.25mg in 500ml of 5%dextrose) given 7drop per minutes then doubled every 15 min. according to the uterine contraction. Also salbutamol maintenance dose used for 48hr if there was response to treatment and primolut depot dose was repeated for 48hr if uterine contraction returned.
Women of both groups were monitored for uterine contraction, progress of labor, vital signs & maternal side effect of drug were recorded, all patients received dexamethasone 12mg in 2 divided doses & received antibiotic if they have infection, follow up of patients done for 1week,time of delivery was recorded during treatment. Also neonates whose delivered were monitored by pediatrician if need admission in neonatal care unit. If uterine contraction subsided , the patients discharge to home after 48hr and followed up as an out patients.
Result:
Table (1) showed demographic characteristics of the women enrolled in this study. The mean maternal age in control group was( 25.73+7.25) years while in study group was (26.43+7.49)years and the mean gestational age of control group were (31.75+2.48)while for study group were(31.52+1.96)which was not significant, 67.27% of the control group were multiparous while in the study group were 70% .
Table (2) showed (34.55%) of control group delivered within 48 hr. of treatment versus (21.67%) for study group ,(20%) of control group delivered between (48 hr_1 wk.) of treatment versus (28.33%) for study group and(45.45%) of control group delivered after one week of treatment versus (50%) for the study group which were not significant(p =0.265).
Table (3) showed that there were no significant difference in the percentage of neonatal admission after delivery between the control group and the study group 50.91% versus 51.67% ,and 4 patients were delivered outside our hospital and lost from our study (p=0.630).
In table(3-4) show there is highly significant in reducing side effect of salbutamol when using in half dose of it in combination of progesterone regarding tachycardia, which show patient with tachycardia in case group was 49.09% while in control group was8.33%, p value less than 0.005.
Patient with shortness of breath was 63.6% while in control group was 26.67%,which is highly significant reducing shortness of breath .p value less than 0.005.Headach in case group was 18.18% versus in control group was while in control group was 33.33%.Chest pain was in case group was 18.18. versus in control group was 15%.
Table 1: Demographic characteristic of the study group and control group.
Characteristics Control (n =55) Cases (n =60) P
Age (mean ”SD) years 25.73 ”7.52 26.43 ”7.94 0.626 a
GA (mean ”SD) weeks 31.75 ”2.84 31.52 ”1.96 0.613 a
Parity n (%)
Multipara 37 (67.27) 42 (70.00) 0.753 b
Primipara 18 (32.73) 18 (30.00)
Medical problem n (%)
Positive 7 (12.73) 5 (8.33) 0.441 b
Negative 48 (87.27) 55 (91.67)
Previous PTL n (%)
Positive 15 (27.27) 5 (8.33) 0.007 b
Negative 40 (72.73) 55 (91.67)
UTI n (%)
Positive 28 (50.91) 36 (60.00) 0.327 b
Negative 27 (49.09) 24 (40.00)
HVS n (%)
Positive 14 (25.45) 16 (26.67) 0.882 b
Negative
41 (74.55) 44 (73.33)
HVS:
Table 2: Treatment ‘ delivery interval of the control group and the study group.
Control Cases X2 P
48 hrs 19 (34.55%) 13 (21.67%) 2.653 0.265
48-1 week 11 (20.00%) 17 (28.33%)
> 1 week 25 (45.45%) 30 (50.00%)
Table 3: Neonatal admission after delivery of the control group and the study group .
Control (n = 55) Cases (n = 60) ”2 P
Admitted 28 (50.91) 31 (51.67) 0.924 0.630
Not admitted 23 (41.82) 27 (45.00)
Unknown 4 (7.27) 2 (3.33)
Table (4): Comparsion between Control & study groups regarding Side effects of Salbutamol therapy
Side effect Case Control ”2 P
N % N %
Shortness of breath
Positive 35 63.64 16 26.67 15.891 <0.001
Negative 20 36.36 44 73.33
Headache
Positive 10 18.18 5 8.33 2.454 0.117
Negative 45 81.82 55 91.67
Tachycardia
Positive 27 49.09 20 33.33 2.948 0.086
Negative 28 50.91 40 66.67
Chest pain
Positive 10 18.18 9 15.00 0.211 0.646
Negative 45 81.82 51 85.00
Statistical analysis
Data were analyzed using Statistical Package for Social Sciences (SPSS version 20). Numeric variables including age and gestational age were presented as mean ”SD (standard deviation), whereas categorical variables like parity were presented as number and percentage. Chi-square was used to study association between any two categorical variables, while independent samples t-test was used to study difference of mean between any two groups. P-value of ‘ 0.05 is considered significant.
Discussion
Preterm birth is not singularly the consequence of preterm labor, there are three major etiological factors such as preterm rupture of membrane 25%, spontaneous preterm labor with intact fetus membrane 50%, complication of pregnancy that severely jeopardized fetal & maternal health25%.
Approximately two third of preterm labor occur spontaneously, preterm birth is classified in mild preterm (32-36weeks),very preterm (28-31weeks) and very extremely preterm less than 28weeeks.(21)
Preterm labor before 34wk account to 75%cases of neonatal mortality.(22)
Various drugs have been used in inhibiting preterm labor with aim of tocolytic therapy to prolonged gestation long enough till maturation of fetus completed. This is done to delay delivery 48 hrs so that corticosteroid administration is effective for transfer of patient to tertiary care center with neonatal care facility.
Ritodrine and salbutamol are B-agonist associated with significant, potentially life threatening side effects (particularly if given in combination with corticosteroids) .(23)
In our study (9.3%) of patients were 19 years of age and (14.85%) were 35 years of age . This is in contrast to the results of a prospective study done by Andrew B . Onderk et al . (2002) , which show that subjects with PTL ranged in age from less than 20 years old (0.5% of subjects) to more than 40 years old (4.5% of subjects) , with 95% of subjects being between the ages of 20 and 39 also similar to study of Iqbal J et al(24) where no patient below age 19 years old also study of Ghazi et al(25). But our study in contrast to the study of Lookwood CJ et al who found increased risk of preterm birth in women less than 20 years and over 35 years of age(26) In this study most patient were of multiparus which similar to the result of Copper et al (27)
In our study mean gestational age in control group was(31.75+2.48 )and case group was(31.52+-1.96) which is comparable to the study of Weerakul W et al , where mean gestational age 31.7+-1.8(28)
In this study 25(45.45%) with salbutamol was delay delivery after 1week while it is more prolongation of delivery if taken progesteron with salbutamol 30(50%)which is comparable to studies result 85,86% and 81% respectively. (26.27)
In our study (16.8%) of them had at least one previous PTL (less than 37 completed weeks) which is comparable to the results of a prospective study done by Andrew B . Onderdonk et al . (2002) who found that (16%) of their patients had previous PTL .(29)
In our study the microbiological results of culture of midstream urine samples are (78%) of patients with UTI had Escherichia coli , (10%) of them had Proteus mirabilis , and (12%) of them had Klebsiella pneumoniae .
These results are comparable to what have been written in American Academy of Family Physician , Vol . 61/No.3 (February 1 ,2000) that the organisms that cause UTIs during pregnancy are the same as those found in non-pregnant patients . Escherichia coli accounts for 80 to 90 percent of infections . Other gram-negative rode such as Proteus mirabilis and Klebsiella pneumonia are also common .(30)
The administration of high-dosage progesterone has been advocated as a possible tocolytic agent , but its action is slow and its usage has been abandoned for acute tocolysis except in conjunction with ”-agonists . The combination of both has shown synergistic effects by decreasing the need for high concentration of ”-agonists .(20)
In the present study we found that there was no significant difference regarding the treatment-delivery interval between control group and study group who delivered within 48 hrs (17.7% versus 17.6%) , or between 48 hrs. to one week (17.7% versus 19.6%) and after one week (64.4% versus 62.7%) . These findings are comparable with the study of Di Renzo et al . (2003) , who used ritodrine instead of salbutamol . They found that (87%) of control group versus (85%) of study group delivered after 48 hrs. , while (65%) of control group versus (68%) of study group delivered after one week .
In the present study, we found that there is highly significant reduction in maternal side effect of salbutamol in the study group as compared to control group including shortness of breath which p value is 0.001 and is highly significant head ach was (18.18% versus 8.33),tachycardia was (49.09% versus 33.33) and chest pain was(18.18% versus 16%) p value is less than 0.05, these result is comparable with result of study Di Renzo et al (2003) who found difference in maternal side effect of ritodrine between control & study group; maternal tachycardia97% vs52%),tremor (26% vs. 12%) & chest pain (15% vs. 10%)
This study similar to study of Nazhat Rasheed et al found common maternal side effect with salbutamol compared to nifedpin were tachycardia ,palpitation &nausea ,thise also compared to study by Jannet et al(15) conclude maternal pulse rate is significantly increased compared to nifedpin.
Marselles V .et al. study(1985) ,enrolled 57 women all admitted to hospital between 30-36 weeks of gestation for actual PTL . He studied the effect of oral progesterone therapy in a dose of (400 mg) of micronized progesterone (urogestan) in a form of four capsules . These capsules were either each containing (100 mg) progesterone or placebo . He noticed an improvement in uterine contractility in (42.8%) of cases one hour after ingestion of placebo and in (75.8%) of patients one hour after ingestion of progesterone . The frequency of contractions decreased significantly in the group treated with progesterone ( p” 0.001) , while they were not significantly decreased in those treated with placebo (0.05 ” p ” 0.3) .(19)
The usage of prophylactic progesterone at high doses has recently been proposed in women at high of PTL (one or more previous PTL before 32 weeks of gestation) . A randomized controlled trial has shown that weekly administration of 17-alpha-hydroxyprogesterone caproate in a dose of (300 mg/day I.M. ) results in a decrease in almost (50%) in the subsequent incidence of PTL before 32 and 36 week irrespective of etiology .(20)
Conclusion and Recommendation :
Progesterone had a role in the treatment of threatened preterm labor when used in combination with ”-mimetic to minimize the potentially life threatening side effects of ”-mimetic .
Recommended to use of progesterone with salbutamol to decrease the side effects of salbutamol and also more sample size is required.