Discussion

It was often seen that physicians select clinical management strategies not keeping in view the

research support and research guidance and evidences in that matter. The objective of the study

was to establish grounds and rationale for drug administrations in prevention and management of

preterm labour by exploring opinions on prescription of drugs by obstetricians keeping in view

the availability and knowledge about the drug in Pakistan.

This has been the most unique kind of study of its own especially conducted in Pakistan with the

context of barrier faced with respect to the assessment of preterm labour and health systems. The

structured assessment tool was used to discover the kind of strategies used for assessment and

prevention purposes in Pakistani context. A number of varied responses were being catered with

respect to the clinical management & it was observed that there was this uncertainty about the

précised assessment tool for preterm labour in Pakistan. Surprisingly, respondents indicated no

variety of clinical management in terms of assessment and preventions of preterm labour. No

significant differences were seen in prescribing drugs in spontaneous births. The most

outstanding quality of this survey was the noticeable dissimilarity in clinical management

strategies between different maternity units in almost all aspects of the current identification and

management strategies of preterm labour despite of lack of good quality local guidelines.

Talking about the response rate for the present survey, it was low. Surveying obstetric

consultants was considered important in treatment and prevention plan of preterm labour but it

was difficult phase to approach the consultant for their time. Many of the barriers were being

catered in data collection procedure as most of the participant agreed to participate in the

beginning of the study but refused to return the survey form later point in time. Talking about the
response rate, only 28 percent of the medical officers responded to the survey questionnaire. One

of the studies highlighted a number of financial incentives to generate more and more response

rate in order to impact the quality of the study since the area of research has its own importance

with regards to the participation of medical officers, so a greater response can help develop a

greater understanding of the issue and good management plan can be uprooted. It was

highlighted that financial incentive and follow up documentation or sometimes registered emails

can be very helpful increasing the response rate. It was also assumed that the personality trait of

an individual can also impact the response rate (Stathis, 2014). Keeping in view the economic

status of the study, these option were not very much in favor of this study.

4.1. Overall Results;

A repeated pattern of respondents attempting to inhibit the preterm labour for the steroid

administration and for inutero fetal development was seen. The calcium channel blocker

nifedipine was the observed to be commonly used choice tocolytic drug. No apparent differences

were seen in attempting suppression at the early stages of the gestation period. 77% of the total

respondents were in favor before 25th of week of gestation period to attempt suppression.

Without a surprise, one previous study reported that 73% of the respondents were in favor to

discontinue the treatment of tocolytic therapy at 36-37 weeks. One study stressed on the

management techniques being used for prevention of preterm labour (Cook & Peek, 2004). This

was explained by the increased use of corticosteroids and a major advance in neonatal care in the

prevailing years. It suggests the need for both education and the development of guidelines in

this difficult area of managing preterm labour.

It was observed that most of the maternity units use combined therapies to treat women with

preterm labour. Use of multiple treatment modalities may be effective but supported by literature

of interest that these maternity units use therapies in combination to assessment and prevention

of preterm labour. No evident based results were supporting the multiple therapy use to prevent

the preterm labour even when it was apparently effective to suppress the preterm labour. The

units approved the use of this practice.

Hence it can be concluded that many risk factors that may lead to preterm labor are not so

difficult to categorize. The literature proved that preterm infants usually have severe

abnormalities and high death rate (Saigal & Doyle, 2008). These abnormalities can be catered by

intervening the tocolytic therapy at the very early stage or transferring the mother to a care center

where the neonatal care is readily available. Previous studies supported by the factor that

Kangaroo Mother Care (KMC0 can be very helpful in preventing neonatal mortality. The

implications of this community based KMC can actually support and help infants to survive. The

therapy includes teaching and training the new mothers to hold their babies close to skin. The

skin to skin contact can be very helpful in first few weeks of the preterm birth but unfortunately

the low economic states does not even have any idea of this neonatal care and no proper trainings

being provided in this regard (Als & B McAnulty, 2011).

This is an established fact that preterm labour can be a psychological burden on the family and it

can also result in long term hospitalization with financial debts that can cause the mental health

problems. There are some things including the family counseling, couple therapy, educating

good and safe sex and treatment of the sexuality can be way to modify the etiological factors and

may help reduce the pretem births. Studies emphasized the importance of prevention and

intervention plan to address the problem. As Most etiological factors are modifiable and
counseling should emphasize and address these issues (Prakash, Rasquinha, & Rajaratnam,

2016). But unfortunately Pakistan has not potential preventive measures like other progressive

countries to address the problem and reduce its intensity. Even low budget program like KMC

can actually help reduce the death rate of infant in most of the preterm births but there is no

awareness on this topic yet.

The present study highlighted the heterogenic approaches which are being used in clinical

practice with an intention of the management of asymptomatic women at risk of preterm birth. A

nationalize audit coming from the specialist clinics can help addressing these issues or we can

adopt the universal guideline that are being used for the management of these high-risk women.

To our surprise, most of the respondents responded same with regards to the questionnaire and

proposed techniques and management strategies used in clinical practices. It was also seen that

knowledge on the issue was also the same. Many previous studies highlighted a number of

preventive measures with regards to reduce the preterm birth rates. They also suggested

community based and individual based therapies to at least cater the problem if not reduced at

this point in time. Many studies underwent on the processes being observed in research sector to

highlight intervention program in this regard (Gathwala, Singh, & Balhara, 2008). These

strategies can not only impact the mortality rate but also helpful in long term social, physical and

mental health of the child. It was suggested that techniques can be helpful in secured attachment

patterns (Schneider, Charpak, Ruiz‐Peláez, & Tessier, 2012). The current paper suggested that,

the continued expansion of these special clinics can be very helpful to begin the assembling of

real life scenarios where the women at risks were managed with treatment. We believe that this

would help at better prescription of tocolytic drugs for the prevention management.
Preterm birth is the leading cause of neonatal mortality, and is responsible for a large proportion

of all neonatal and infant morbidity. The prevention and management of preterm labour and the

care of women at increased risk of preterm birth are therefore of great importance. Evidence

supporting the use of tocolytics, repeated courses of antenatal corticosteroids, and progesterone

is, however, limited. We surveyed Canadian obstetricians to determine how they prescribe these

medications. The results of the 1997–98 and 2004 surveys indicate that tocolytics are used by

most obstetricians, but their use decreased between 1997–98 and 2004, and many obstetricians

believe it is reasonable not to give tocolytics to women in preterm labour. This trend may

indicate practitioners are aware we lack good evidence that tocolytics reduce neonatal mortality

or serious neonatal morbidity. It is interesting to note that the most frequently prescribed

tocolytic was magnesium sulphate in 1997–98 and indomethacin in 2004, despite there being no

new evidence against the former or in favor of the latter over this six year period. An updated

2006 Cochrane review on magnesium sulphate continues to find no effect favouring magnesium

sulphate over controls (other tocolytics or placebo) in short- or long-term delay in delivery, but a

higher risk of death (fetal and infant) was found when magnesium sulphate was used as a

tocolytic. However, a new evidence has Preterm Labour and Birth: A Survey of Clinical Practice

Regarding Use of Tocolytics, Antenatal Corticosteroids, and Progesterone continued use of

tocolytics (Morency & Bujold, 2007). Initial Survey 1997–98 n = 458 n (%) Follow-up Survey

2004 n = 502 n (%) P Reason for change in prescribing practicei Evidence from published

literature Hospital protocol or national practice guidelines Establishment of a Level III NICU at

the hospital Influence from colleagues Otherk 194 (66.0) 134 (45.6) 14 (4.8) 108 (36.7) 32 (10.9)

292 (75.3) 184 (47.4) 12 (3.1) 134 (34.5) 75 (19.3) Consider it reasonable to not treat women in

preterm labour with tocolyticsl 337 (73.6) 336 (67.9) 0.06 NICU: neonatal intensive care unit;
N/A: not applicable; PPROM: preterm prelabour rupture of membranes. a some respondents did

not use tocolytics (1997–8: 12; 2004: 39) b 31 respondents did not indicate the % of women in

preterm labour for whom they would prescribe a tocolytic in 2004 c 2 missing responses in 2004

d 14 missing responses in 2004 e 12 missing responses in 2004 f 3 missing responses in 2004 g

other tocolytics: atosiban, salbutamol, terbutaline in 1997–8; salbutamol, meperidine, atosiban in

2004 h 2 missing responses in 2004 I some did not change practice (1997–8: 164; 2004: 112) j in

1997–8, 63/294 indicated that they prescribed tocolytics for a different period of time, and 11 of

these 63 reported using tocolytics for a shorter period of time k in 2004, 50/75 “other” comments

referred to the unavailability of some tocolytics or ritodrine specifically l 7 missing responses in

2004 become available with respect to the use of magnesium sulphate for neuroprotection prior

to preterm birth. An Australian multicentre trial of magnesium sulphate (versus placebo) used

immediately prior to preterm birth (at less than 30 weeks’ gestation) indicated no serious harmful

effects and a trend towards improved infant outcomes, thus offering a promising role for

magnesium sulphate for this indication and emphasizing the need for further research into use of

this drug. There has been no new substantive evidence to support the usefulness of indomethacin

as a tocolytic (Hassan et al., 2011).

Some of the changes in prescribing practices found in our survey may have been influenced by

the withdrawal of ritodrine from the Canadian market in 2000. It is of interest that atosiban (an

oxytocin antagonist), which became available in Europe also during that period (in 2000) has not

yet been made available for use in Canada (Joseph et al., 1998).

As well, during this time there has been increasing support for the use of nifedipine for inhibiting

preterm labour. A recent Cochrane Review concluded that when tocolysis is indicated for women

in preterm labour, calcium channel blockers are preferable to other tocolytic agents (Crowther,
Hiller, & Doyle, 2002). Our research also concluded that calcium channel blockers were being

used preferably in practice.

However, the evidence to support nifedipine use is limited, as large placebo-controlled

randomized trials are lacking. We currently awaiting the findings of the Canadian-led

nitroglycerin trial, funded by the Canadian Institute of Health Research. Until we have evidence

that administration of tocolytics not only prolongs pregnancy but also reduces neonatal mortality

or serious neonatal morbidity, they should be used only after careful consideration of the

potential risks and benefits for the individual patient in a given clinical situation. This survey

revealed that most Canadian obstetricians prescribe at least one course of antenatal

corticosteroids for women at increased risk of preterm birth. However, the use of repeat courses

of antenatal corticosteroids has decreased substantially and significantly. Evidence for the use of

a single course of antenatal corticosteroids in the context of preterm labour and birth has been

well established (Kramer et al., 2001).

A Cochrane review in 2006 of 18 randomized controlled trials found a significantly reduced risk

of neonatal mortality, respiratory distress syndrome, and intraventricular hemorrhage after a

single course of antenatal corticosteroids, compared with placebo. As a result, it has been

recommended that women receive a single course of antenatal corticosteroids if they are at 24 to

34 weeks’ gestation and are at an increased risk of preterm birth. The evidence regarding benefits

and risks of repeat courses of antenatal corticosteroids, however, is more controversial. A

randomized placebo-controlled trial in 2001 found no significant reductions in the risk of

stillbirth, neonatal death, or serious neonatal morbidity with repeated weekly courses of antenatal

corticosteroids, compared with a single course, and no evidence of harm (Kramer et al., 2001).
A recently published data reported use of antenatal corticosteroids for women at increased risk of

preterm birth Use of antenatal corticosteroids Initial Survey 1997–98 n = 458 n (%) Follow-up

Survey 2004 n = 502 n (%) P Antenatal corticosteroids prescribed for women at increased risk of

preterm birth* 431 (94.1) 460 (91.8) 0.21 Gestational age for which corticosteroids are believed

to be helpful (weeks) Earliest mean gestational age† Latest mean gestational age‡ 24.9 1.6 33.3

1.0 24.5 1.3 33.3 1.1 < 0.001 0.93 More than one course of antenatal corticosteroids prescribed§

314 (72.9) 84 (18.7) < 0.001 Maximum number of courses prescribed 9 missing responses in

1997–8; 7 missing responses in 2004 randomized placebo-controlled trial found less neonatal

respiratory morbidity with repeat weekly courses, compared with a single course, also without

evidence of harm (Kelly, 2008).

However, a randomized placebo-controlled trial carried out by the National Institute of Child

Health and Human Development, which reported no significant reduction in risk of stillbirth,

neonatal death, or serious neonatal morbidity with repeated weekly courses of antenatal

corticosteroids compared with a single course, found that repeated courses were associated with

an adverse effect on birth weight for the subgroup of infants receiving four courses (da Fonseca,

Bittar, Carvalho, & Zugaib, 2003).

Overall, the evidence suggests potential for benefit as well as harm for repeated courses of

antenatal corticosteroids, but the information is inconclusive. We are awaiting the results of the

Canadian-led placebo-controlled randomized trial (Multiple Courses of Antenatal Corticosteroids

for Preterm Birth Study [MACS]), which is evaluating the effect of repeated courses of antenatal

corticosteroids, given every 14 days, compared with a single course, and is due to complete

recruitment on August 31, 2006.19 regarding the use of progesterone, 7.0% of Canadian

obstetricians reported in 2004 that they offered treatment with progesterone to women at
increased risk of preterm labour and birth. Lack of evidence was cited as the principal reason by

those not using this treatment (70.6%). Several meta-analyses of randomized controlled trials of

progesterone use for the prevention of preterm birth have been published recently. Mackenzie et

al. performed a systematic review and meta-analysis of three trials, and found a significant

reduction in risk of delivery at less than 37 weeks’ gestation with use of progestational agents

(relative risk [RR] 0.57; 95% confidence interval [CI] 0.36–0.90).20 Although there was no

significant effect of progestin therapy on perinatal mortality or serious neonatal morbidity, there

was no evidence of harm. Progestational agents had no effect on the risk of congenital

anomalies, or on the risk of spontaneous abortion (Norman et al., 2009).

Sanchez-Ramos et al. in 2005 performed a meta-analysis of 10 randomized controlled trials that

investigated the effects of progestational agents on the prevention of preterm birth. They found

that the use of progestational agents, specifically 17-alphahydroxyprogesterone caproate,

reduced the incidence of preterm birth and low birth weight.21 A review of prenatal

administration of progesterone for preventing preterm birth was undertaken by the Cochrane

Collaboration.22 For all women administered progesterone, there was a reduction in the risk of

preterm birth at less than 37 weeks’ gestation (RR 0.65; 95% CI 0.54–0.79), and infants were

less likely to have a birth weight of less than 2500 g (RR 0.63; 95% CI 0.49–0.81) or

intraventricular hemorrhage (RR 0.25; 95% CI 0.08–0.82). There was insufficient evidence

regarding potential harms of progesterone.22 Numerous studies have raised the problem of

potential toxic effects of progestins on the fetus.23, 24. Some have reported cases of virilization

of female fetuses, cardiovascular defects, and neural tube defects. A causal relationship between

progestins and these malformations, however, has not been proven (Sanchez-Ramos, Kaunitz, &

Delke, 2005).
The previous experience with in utero exposure to diethylstilbestrol has taught us that fetal

hormone exposure can cause long-term harm.26. We thus need to be convinced that progesterone

treatment is truly beneficial in the short term, and for this we need evidence from an

appropriately sized randomized controlled trial that progesterone reduces neonatal mortality or

serious neonatal morbidity. In addition, long-term follow-up would be important to rule out

evidence of long-term harm. The present research paper provides information concerning

prescribing practices in 2004 and compares these with practices six years before.

Limitations of this study include a moderately low response rate, as well as the fact that the two

surveys included different respondents. Thus, the results of the survey may not be generalizable

to all obstetricians in Canada and should be interpreted with due caution. However, the survey

does indicate uncertainty among physicians and variations in practice, and it supports the need

for continued research into the potential for tocolysis not only to prolong pregnancy but also to

affect neonatal outcome, the use of single versus repeated courses of antenatal corticosteroids,

and the use of progesterone in women at increased risk of preterm birth. The present study can

contribute a lot to the future proposed studies.

ACKNOWLEDGEMENTS:

We gratefully acknowledge Sunny Chan, who helped develop the Teleform electronic version of

the questionnaire, and Freda Assenza who aided in data entry. The University of Toronto

Maternal Infant and Reproductive Health Research Unit at the Centre for Research in Women’s

Health was supported by grants from Sunnybrook and Women’s College Health Sciences Centre

and the Department of Obstetrics and Gynaecology at the University of Toronto.

This review will become increasingly important in the context of revalidation, resource

allocation and standardized outcome reporting. Notwithstanding the need for an individualized

approached in many cases, such variation in management strategies employed by these clinics

remains of concern not managing according to the guidelines.

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