Role of progesterone in prevention of PTL

Why progesterone in prevention of PTL??  Is progesterone is an ideal drug to control inflammation & release of cytokines?? Does progesterone favorably control the immunology of preterm labor?

What goes wrong in most cases of preterm labour ?  Spontaneous preterm labor and birth is the leading cause of neonatal morbidity and mortality. It is obvious that preterm labor is much more than labor occurring early. There are a number of possible reasons that the quiescent myometrium gets activated to contract before term, A)  immune mechanisms may be looked upon as contributors from the point of view that the maternal tolerance of the fetal/placental allograft is exhausted, leading to its expulsion. B) Chronic chorioamnionitis, the most common placental lesion in late spontaneous preterm birth, which is characterized by maternal T-cell infiltration of the chorion laeve with trophoblast apoptosis, resembles allograft rejection.

Maternal sensitization to fetal human leukocyte antigens (HLAs) is frequently found in patients with chronic chorioamnionitis and is accompanied by complement deposition in umbilical vein endothelium. A novel form of fetal systemic inflammation characterized by over-expression of T-cell chemokines (e.g., CXCL-10) has been observed in chronic chorioamnionitis.

Breakdown of maternal-fetal tolerance may be particularly relevant to preterm labor occurring after fetal surgery or stem cell transplantation—interventions in which there is an increase in the number of maternal T cells in the fetal circulation. The mechanisms linking disorders in tolerance and spontaneous preterm labor remain to be defined.

The immune response is also of importance in the pathway leading to myometrial activation from other causes such as infection. The current understanding of this process is that the switch of the myometrium from a quiescent to a contractile state is accompanied by a shift in signaling between anti-inflammatory and proinflammatory pathways, including chemokines (interleukin-8), cytokines (interleukin-1 and -6) and contraction-associated proteins (oxytocin receptor, connexin 43, prostaglandin receptors). Increased expression of inflammatory cytokines (TNF-a and IL-1) and chemokines, increased activity of proteases [matrix metalloproteinase (MMP)-8 and MMP-9, dissolution of cellular cements such as fibronectin and apoptosis have been implicated in the process of membrane rupture.

These mechanisms are relevant because we need to look for new interventions to reduce preterm births. The mainstay of current clinical practice is tocolysis. This has been of limited value in preventing preterm birth. New approaches addressing the root cause rather than the symptom of uterine contractions need to be evaluated to tackle this problem.

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A primigravida woman at 32 weeks gestation presents to the birth suite with painful regular contractions. She has presented twice previously with the same complaint and each time been determined to have a closed, non-effacing cervix, a normal CTG and has been discharged home after 24

hours of observation. At her first presentation at 28 weeks she was given two doses of betamethasone. How should her pregnancy be managed?

a

Threatened preterm For women experiencing ongoing uterine irritability without any labour (TPL) is a serious and should be treated according to best practice guidelines.

 1 While some women who experience preterm contractions will settle spontaneously, some will continue to experience painful contractions, without cervical changes, for the remainder of their pregnancy. The management of the ‘irritable uterus’ represents a dilemma in management for clinicians.Any woman presenting with painful regular contractions should be offered adequate analgesia and assessed for imminent delivery. Physical assessment of the mother, including abdominal palpation /.and cervical assessment via a speculum examination, vaginal examination or a transvaginal ultrasound scan for cervical length

(TVCL) 2 should be undertaken, as well as tests such as fetal fibronectin (fFN) detection to establish the likelihood of delivery.

Depending on gestation and local facility guidelines, it may be

appropriate to consider tocolysis and steroid cover. A number of

women will not demonstrate any of the features of labour and a

diagnosis of irritable uterus may be entertained.

Irritable uterine activity may commence at any stage during a

pregnancy and persist for its entirety or be only a transient experience Inflammatory conditions, such as subclinical horioamnionitis, upper genital tract infection and urinary tract infections or pyelonephritis,

may be associated with irritable contractions. 5,6 Likewise,

gastrointestinal problems, such as gastroenteritis with vomiting and

diarrhoea or even significant constipation, may also trigger uterine

irritability. Assessment should include investigations for inflammatory

causes, genital and cervical culture swabs. Other causes for uterine

irritability include subchorionic placental bleeding. ultrasound scan

for fetal growth and well-being and examination of the placenta for

evidence of concealed bleeding may be performed in conjunction

with TVCL assessment.

Identification and, where possible, treatment of underlying causes

of uterine irritability may allow for complete resolution. Admission to

the antenatal ward for ongoing observation and assessment is often

warranted. Occasionally, contractions thought to be associated

with TPL or uterine irritability may be the result of pseudo-labour, a

poorly understood variant of conversion disorder, often associated

with anxiety and emotional disturbance. 7

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obvious cause, antenatal care can usually proceed in the normal

manner. Maintenance tocolysis is not recommended for uterine

irritability. 8,9,10,11,12 Not only have studies demonstrated that they are

of questionable value in terms of prolonging the pregnancy, but it is

also suggested that women with uterine irritability may demonstrate

resistance to commonly used tocolytics. 13 Vaginal progesterone may

play a role in prolonging pregnancy to 34 weeks. 14,15,16,17 Further

analysis is still required to determine if improvement in neonatal

outcomes warrants this intervention for women with irritable uterus.

uterine irritability is associated with a higher rate of preterm delivery

than the general population (although lower than for women with

other preterm labour risk factors). 13 It is possible that a woman with

ongoing irritable uterine contractions may develop preterm labour,

but fail to recognise it until ‘too late’. Thus the question facing

clinicians revolves around how to mitigate these risks.

Administering corticosteroids for fetal lung maturity is a routine

part of managing preterm labour. It has been demonstrated that a

single course of corticosteroids administered after 27 weeks is as

efficacious as multiple ‘rescue’ doses. 18 It could be proposed that

all women presenting with contractions after 27 weeks gestation

be given corticosteroids at their initial presentation, regardless of

cervical assessment or likelihood of imminent delivery, in order to

ensure optimal fetal lung maturity.

Infants delivered prior to 37 weeks gestation are at increased

risk from group B streptococcal infection and women in preterm

labour should receive antibiotic prophylaxis. 1,19 Antibiotic cover

needs to be initiated at least hours hours prior to delivery in order

to have the full protective effect. The key to management remains

careful surveillance.

Many women will self-refer for assessment due to concerns

regarding the changing nature of their ‘regular’ uterine irritability,

suspected ruptured membranes, bleeding or altered fetal movement

patterns. For women with other risk factors for preterm labour,

regular TVCL measurement may be necessary and repeat fFN

assessment may be warranted.

Our primigravida is almost certainly experiencing an irritable uterus.

She was given corticosteroids at her first admission at 28 weeks,

and evidence suggests her baby will not benefit from any further

Women’s health

doses. Management at this presentation should consist of analgesia

and routine assessment, including CTG monitoring. She should

have cervical assessment incorporating swabs for fFN, vaginal and

endocervical cultures. Cervical dilatation should be checked and

urine analysis performed.

If it is determined she is in labour, she will require antibiotics and

possibly transfer to an appropriate facility. If the assessment does

not suggest imminent delivery, she should have an ultrasound scan

arranged, including TVCL. Admission to the antenatal ward may be

appropriate and any possible underlying causes of uterine irritability

should be identified and treated.

Her ongoing antenatal care should involve careful assessment

of uterine activity and causes of uterine irritation should

continue to be explored. There is no indication for prophylactic

tocolysis; however, vaginal progesterone may be of benefit. Her

management should include assessment of any contributing

psycho-social factors, in addition to providing reassurance that her

concerns are being taken seriously.

Encouragingly, many women with this presentation will continue

their pregnancy to term and deliver without complications.