Intra-amniotic debris linked to Preterm Birth independent of Cervical Funnel

Amniotic fluid ‘‘sludge’’ (A) with normal cervix (B) with short cervix
courtesy:https://www.researchgate.net/figure

Presence of Intra-amniotic debris or sludge identified by sonography is linked to increased risk of Preterm Birth(PTB) before 34 weeks of pregnancy in nulliparous women with a cervical length less than 30 mm, reports the results of a secondary cohort study accepted for publication in Journal Ultrasound in Obstetrics and Gynecology.

This secondary analysis of multicentric trial was funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network.

The exact composition of amniotic fluid debris is not known. They may be formed of hemorrhage, meconium or a mixture of bacteria and inflammatory cells, that is encased in a biofilm that is resistant to antibiotics. They are probably a sign of placental senescence, and preterm delivery seems to be a protective phenomenon to shuttle the fetus out of the already compromised environment.

The initial trial was conducted to study the effect of progesterone injections to prevent preterm birth in nulliparous women with a short cervix.

A total of 657 women between 16 and 22 weeks of gestation were randomized to progesterone or placebo. All of them had a transvaginal ultrasound by a certified sonologist, 78 were found to have intra-amniotic debris, 112 women had cervical funnel on ultrasound.

A significant number of women with debris had a preterm labor (35% vs. 23%), as also women who cervical funnel (37% vs.21%).

After multivariate analysis, only amniotic fluid debris was found to be significantly associated with preterm birth prior to 34 or 32 weeks (aOR 1.85, 95% CI 1.00-3.44; aOR 2.78, 95% CI 1.42-5.45) respectively.

Earlier study have also shown that Amniotic fluid debris or ‘‘sludge’’ (AFS) is an independent risk factor for preterm delivery in women with CL< 25 mm. During Ultrasound it is recognized as a hyperechogenic matter in the amniotic fluid close to the uterine cervix and its prevalence is 22.3% in patients with preterm labor.

Abstract

OPPTIMUM Trial: vaginal progesterone does not help in preterm birth prevention !

Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location.

Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth).

However, the OPPTIMUM study results presented recently at the Society for Maternal and Fetal Medicine (SMFM) 36^th Annual pregnancy meeting at Atlanta Georgia in February, 2016 have shown that vaginal progesterone confers no obstetrical or neonatal benefit, and no long-term benefit with respect to cognitive and neurosensory outcomes in children when used to prevent preterm birth.


The findings from OPPTIMUM – the largest trial to date looking at progesterone for the prevention of preterm birth – have important implications for current practice. Vaginal progesterone is not currently approved for the prevention of preterm birth in the United States, but is commonly used off label for this purpose.

The OPPTIMUM study is a randomized double blind placebo controlled trial recruited over 1,228 women around  UK to test whether giving natural progesterone daily from 22 to 34 weeks of gestation is a cost-effective way to reduce the likelihood of preterm birth.  It also aims to look whether compared to placebo, vaginal progesterone:

• improve obstetric outcome by lengthening pregnancy and thus reducing the incidence of preterm delivery (before 34 weeks gestation)?
• improve neonatal outcome by reducing a composite of death and major morbidity?
• lead to improved childhood cognitive and neurosensory outcomes at two years?
• represent cost effective management for women at high risk of preterm delivery?

Dr. Jane Norman, MD, from the University of Edinburgh in the United Kingdom said “We saw no significant effect of vaginal progesterone on obstetrical, neonatal, or childhood outcomes, this was true even for women with a cervix of 25 mm or less, and "we found no evidence of benefit in any identifiable subgroups."

A Cochrane meta-analysis  in 2013 assessed the role of both the vaginal and intramuscular form of progesterone in preventing PTB (Cochrane Database Syst Rev. 2013;7:CD004947). Progesterone was shown to prevent preterm births, reduce perinatal mortality, reduce the incidence of birthweight below 2500 g, and reduce neonatal deaths. In women with a short cervix, progesterone was shown to reduce preterm births, but did not affect the other parameters. 

But there has been little information about the long-term risk this may have on children Dr Norman explained. "We felt we needed to look at the long-term effects. We cannot assume that things with short-term benefit will not have long-term harm," she added.

The study recruited 1228 women with singleton pregnancies at risk for preterm birth because of a positive fetal fibronectin test, a history of spontaneous preterm birth at 34 weeks of gestation or earlier, or a cervical length 25 mm or less.

About 618 women were randomized to receive 200 mg of natural vaginal progesterone starting at 22-24 weeks and continuing to 34 weeks, compared with 600 women who received placebo.

The primary obstetric outcome was delivery <34 weeks of gestation, the primary neonatal outcome is a composite of death or two markers of neonatal morbidity (brain injury or bronchopulmonary dysplasia); and the primary childhood outcome is developmental status at two years. A formal economic evaluation was also a key part of the study.

It was seen that progesterone had no significant effect on either the obstetric or childhood outcomes. It also had no significant effect on any components of the primary outcome, including fetal death or live-born delivery before 34 weeks.

“A secondary analysis looking at the individual components of the composite neonatal outcomes showed that progesterone reduced the risk of brain injury and neonatal death, but not bronchopulmonary dysplasia.” Dr. Norman said.

“We were really surprised that we didn’t show that progesterone prevented preterm birth, and we became concerned that perhaps our cutoff of 34 weeks was just the wrong time to choose a cutoff,” Dr. Norman said, noting that a post hoc survival curve analysis was performed to look at the trajectory to delivery, and a “very marginal benefit” was seen with progesterone, but the difference was not statistically significant.

On subgroup analysis it was seen that in women with a short cervix, no evidence was seen that progesterone was more or less effective than in women with a longer cervix. Other subgroups studied included fibronectin-positive and fibronectin-negative women and women with a history of preterm birth. Progesterone was no more or less effective in any of these subgroups. 

“OPPTIMUM is the largest trial of progesterone to prevent preterm birth, and after adjusting for multiple comparisons as we planned, we did not disprove the null hypothesis that progesterone doesn’t prevent preterm birth, it doesn’t reduce adverse neonatal outcomes, and it doesn’t have a beneficial effect on childhood outcomes,” Dr. Norman said, concluding that “there is a remaining unmet need for a safe and effective agent to prevent preterm birth.”

Further it was commented at the  Society for Maternal and Fetal Medicine (SMFM) conference by Mary D'Alton, MD, the William C. Rappleye Professor of Obstetrics and Gynecology at the Columbia University Medical Center in New York Citythat that the results should not be extrapolated to 17-hydroxyprogesterone, which was not part of this analysis.

This certainly gives pause around vaginal progesterone," said Mary D'Alton, MD, the William C. Rappleye Professor of Obstetrics and Gynecology at the Columbia University Medical Center in New York City. But she said she would not advise a change in practice before seeing the final published results.

The US Food and Drug Administration has not approved vaginal progesterone for the prevention of preterm birth in women with a short cervix.

Few decisive articles in obstetrics from 2015

Role of progesterone in preventing recurrent preterm births (PTB)

It is widely accepted that progesterone supplementation in pregnancy reduces the risk of recurrent preterm birth. But, according to a secondary analysis of data  from Maternal-Fetal Medicine Units Network Trial of hydroxyprogesterone caproate for prevention of recurrent preterm birth before 37wks concluded that the drug may not be effective in women with a BMI>30 kg/m^2. The cut off weight is 168 pounds or 75 kg. This finding may be due to subtherapeutic serum levels in women with increased BMI or weight. Further larger and planned studies in women with BMI >30 kg/m² are warranted and also the universal use of progesterone in women independent of BMI also deserves reassessment.

Heyborne KD et al - Does 17-alpha hydroxyprogesterone caproate prevent recurrent preterm birth in obese women?

Am J Obstet Gynecol. 2015 Aug;

Maternal Hypertension in Pregnancy predisposes the offspring for higher risks of Congenital Heart Disease

According to a systemic review and metaanalysis published in the journal of pediatric cardiology robust associations were observed between maternal hypertension and overall CHDs, irrespective of being treated or untreated. The authors identified 16 studies that met the study criteria. The effect was also uniform across all the subtypes of CHDs. The results were also similar for various type of antihypertensive medications used.

The authors propose to understand the mechanisms to design strategies to reduce the risks..

Ramakrishnan A et al- Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.

Pediatr Cardiol. 2015 Oct;36(7):1442-51. Epub 2015 May 8.

The downside of improved control of malaria.

We are recently seeing improved malaria control in many endemic areas worldwide, leading to a decrease in immunity in the population. A large observational study carried out in Mozambique assessed the prevalence of Plasmodium falciparum infection among 1819 Mozambican women who delivered infants between 2003 and 2012.

A major decline in maternal level of antimalarial IgG antibodies were seen in pregnant women both for pregnancy specific parasitic lines as well as general parasitic lines.

It was also seen that those women who developed malaria antenatally had a larger reduction in hemoglobin levels as well as the neonatal birthweight as the immunity declined.

Mayor A et al- Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy. N Engl J Med. 2015 Oct 22;373(17):1607-17.

Uterine exteriorization at cesarean delivery

Uterine exteriorization vs in situ repair has always been a topic of debate among obstetricians.  In A large meta-analysis of 16 studies amounting to a total of 19,439 subjects 9,736 underwent exteriorization, 9,703 had in situ uterine repair. It was seen that the estimated blood loss was not statistically significant between the two groups as well as other perioperative outcomes. Individual preferences and individual intraoperative circumstances should guide the decision.

Zaphiratos V et al- Uterine exteriorization compared with in situ repair for Cesarean delivery: a systematic review and meta-analysis.

Can J Anaesth. 2015 Nov;62(11):1209-1220.

The best time to perform External Cephalic Version (ECV)

The optimum age to perform ECV has always been a debatable issue.

External cephalic version (ECV) of the breech fetus at term (after 37 weeks) has been shown to be effective in reducing the number of breech presentations and caesarean sections, but the rates of success are relatively low. This systemic review of Cochrane Data base examines studies initiating ECV prior to term (before 37 weeks' gestation).

Pooled results suggested that early ECV reduced the risk of non-cephalic presentation at birth, failure to achieve vaginal cephalic birth, and vaginal breech delivery. However there was no statistical significant difference in Caesarean Section rate between the two groups. There was evidence that risk of preterm labour was increased with early ECV compared with ECV after 37 weeks. Future research reporting infant morbidity outcomes in these late preterm births is warranted.

Hutton E.K et al- External cephalic version for breech presentation before term.

Cochrane Database Syst Rev. 2015 Jul 29;7:CD000084.

Limited value of fetal ST-segment analysis

STAN S31 is a one-of-a-kind fetal monitor which exclusively combines standard CTG technology with ST-Analysis of the fetal ECG (FECG) during labour. The combined analysis of the CTG and fetal ECG helps to detect a fetus that is exposed to hypoxia and which needs remedial action, and also provides reassurance when no intervention is required.

However, It is not clear whether use of STAN 31 as an adjunct to other conventional fetal heart rate monitor improves the intrapartum and neonatal outcome.

This Multicenter RCT of about 11,108 subjects included women with a single fetus undergoing vaginal delivery at more than 36 weeks of gestation with cervical dilation of 2 to 7 cm. They were randomly assigned to "open" or "masked" monitoring with fetal ST-segment analysis. The masked system functioned as a normal fetal heart-rate monitor (FHR). The open system functioned as both FHR as well as fetal ECG monitor.

The primary outcome was a composite of intrapartum fetal death, neonatal death, an Apgar score of 3 or less at 5 minutes, neonatal seizure, an umbilical-artery blood pH of 7.05 or less with a base deficit of 12 mmol per liter or more, intubation for ventilation at delivery, or neonatal encephalopathy.

It was observed that fetal ECG monitoring along with FHR  did not improve perinatal outcome or decreased the rate of caesarean delivery. The primary outcome occurred in 52 fetuses or neonates of women in the Fetal ECG group  and 40 fetuses or neonates of women in the FHR  group.

Belfort M.A- A Randomized Trial of Intrapartum Fetal ECG ST-Segment Analysis.

N Engl J Med. 2015 Aug 13;373(7):632-41.

Expectant management of mild preeclampsia near term is feasible.

There is little guidelines for the management of women with mild preeclampsia with stable maternal and fetal conditions at 34 to 36 weeks of gestation. The study by Broekhuijsen K et al in Lancet 2015, investigated the effect of immediate delivery versus expectant monitoring on maternal and neonatal outcomes in such women. This open-label, randomised controlled trial, in seven academic hospitals and 44 non-academic hospitals in the Netherlands confirmed that most patients will reach term without progressing into severe disease and the expectant management buys us valuable time for optimum neonatal maturity without any harm to the mother.

References:

• Relation of body mass index to frequency of recurrent preterm birth in women treated with 17-alpha hydroxyprogesterone caproate.Co AL, Walker HC, Hade EM, Iams JD. Am J Obstet Gynecol. 2015 Aug; 213(2):233.e1-5
• Ramakrihnan A et al- Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.Pediatr Cardiol. 2015 Oct;36(7):1442-51
• Mayor A et al- Changing Trends in P. falciparum Burden, Immunity, and Disease in Pregnancy. N Engl J Med. 2015 Oct 22;373(17):1607-17.
• Zaphiratos V et al- Uterine exteriorization compared with in situ repair for Cesarean delivery: a systematic review and meta-analysis.Can J Anaesth. 2015 Nov;62(11):1209-1220.
• http://www.news-medical.net/Stan-S31-Fetal-Monitor-from-Neovent