Vaginal fluid Interleukin-6 seems to be a promising non-invasive marker for the prediction of inflammation in amniotic cavity in PPROM.

Preterm PROM complicates 3% of all pregnancies and is responsible for one third of preterm labors which leads to significant fetal morbidity and mortality. [1]Once the membrane ruptures the protective and sterile environment of the amniotic cavity is breeched linking it to bacterial cervicovaginal flora. This increases the risk of amniochorial infection which in turn is responsible for fetal inflammatory response syndrome.

Obstetricians have to weigh the benefits of prolonging the pregnancy at the risk of intrauterine infection. vs active induction of  labor. Numerous biomarkers have been studied in predicting the occurrence of infection and decide the clinical course of the pregnancy.

Maternal serum markers are not much useful in prediction of the fetal inflammatory response; hence researchers have studied various biomarkers from vaginal fluid like tumor necrosis factor-α, metalloproteinase-8 (MMP-8), soluble HLA-G (sHLA-G) and interleukin-6.

A recent paper published ahead of print in July issue of American Journal of Perinatology concluded that MMP-8, IL-6, glucose, and lactate concentrations in vaginal fluid did predict poor neonatal outcome but it was not reach statistical significance. Only increased levels of metalloproteinase-8 (MMP-8) were associated with poor neurological outcome. [2]

A recent study published in the forthcoming issue of American Journal of Obstetrics and Gynecology aimed to determine the diagnostic indices and predictive value of vaginal fluid interleukin-6 concentration as a point of care tool(POCT) in predicting microbial invasion of the amniotic cavity(MIAC), intra-amniotic inflammation, and microbial-associated intra-amniotic inflammation in patients with preterm PROM.[3]

The researchers also intended to know the relationship between vaginal and amniotic fluid interleukin-6 concentrations in fresh unprocessed samples obtained simultaneously.

This prospective cohort study recruited 153 women with singleton pregnancy who had PROM at between 24+0 and 36+6 weeks. Preterm PROM was confirmed by examination with a sterile speculum to verify the pooling of amniotic fluid in the vagina.

Samples of vaginal and amniotic fluids were collected from posterior fornix and transabdominal. IL6 assessment was done in both fluids by lateral immunoassay.

The cut-off level to define Intra-amniotic inflammation for IL6 was ≥745 pg/mL.

Out of 153 women in the study, samples of vaginal fluid were obtained in 141 women. It was possible to predict the microbial invasion of the amniotic cavity, intra-amniotic inflammation or microbial-associated intra-amniotic inflammation by higher vaginal fluid interleukin-6 concentrations.

The levels of vaginal fluid IL-6 were higher than amniotic fluid IL-6 concentrations.

A IL6 level of ≥2500 pg/mL identified patients with MIAC, intra-amniotic inflammation, and microbial associated intra-amniotic inflammation. Levels of IL6 < 2500 pg/mL could 100 % exclude patients with microbial-associated intra-amniotic inflammation. These findings need future corroboration by larger studies and meta-analysis before a clinical recommendation is made.

This finding has very important clinical implications, because in future it can be used as triage, to decide the expectant vs active management of women with preterm PROM.

By using this easy, cheap, noninvasive and rapid method, women will be spared of the invasive procedure of amniocentesis to evaluate the intrauterine environment.

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[1] http://www.aafp.org/afp/2006/0215/p659.html

[2] http://www.ncbi.nlm.nih.gov/pubmed/27120475

[3] http://www.ajog.org/article/S0002-9378(16)30439-2/abstract

Predicting spontaneous preterm birth in twin pregnancies utilizing cervical length and gestational age: Individual patient data meta-analysis.

Multiple births are steadily climbing all around the world. Developed countries making a significantly higher contribution to this rising rate because of women delaying childbirth, elderly mothers and increased use of ARTs.

US twinning rate rose by 101% from 1980 – 2006. About 68,339 twins were born in 1980 that doubled to 137,085 in 2006. The US current twin birth rate is 33.9 per 1,000 live births.

 According to WHO the rate of singleton preterm birth ranges between 5% to 18% for singleton pregnancy worldwide, the average being 11%, while almost 60% of twins are delivered preterm. About 13% of twins are born before 34 weeks and 7% before 32 weeks.

A multitude of prophylactic therapies have been in use like to gain valuable gestational weeks by supplementing progesterone, vaginal pessaries and strict bed rest without substantially significant results.

The next step was to develop essential biomarkers that can predict the chances of preterm births. Cervical length(CL) has long   been used as a predictive indicator of preterm birth. An earlier review has shown that a CL < or=20 mm at 20-24 weeks' gestation was the most accurate in predicting preterm birth at <32 and <34 weeks respectively. Many other studies have combined fetal fibronectin with CL. 

Studies in singleton pregnancies have also shown that the relationship between CL and spontaneous preterm birth (sPTB) is dependent on the Gestational age (GA) at which the USG is done, a shorter CL early in pregnancy has greater significance than the same measurement at a later GA.

Such studies in twins are few with small sample size and are not comparable. Previous meta-analysis has shown a relationship between CL and sPTB in twins, but did not correlate the GA at screening with prediction of sPTB.

This recent study published in the May, 2016 issue of BJOG is a meta-analysis of independent patient data(IPD), and provides a new estimate in which CL and GA are treated as continuous variables to predict weeks at delivery.

Specific data collected for each patient from the original authors of the study included the exact GA at CL screening, the CL measurement in millimeters and the exact GA at birth in weeks and days.

23 studies met the inclusion criteria, resulting in a total of 6188 transvaginal scans, performed on 4409 twin pregnancies. 

In the first analysis, univariate regression was performed to see what other confounders like maternal age, ethnicity, smoking, BMI, chorionicity, parity and study location affects the GA at birth. 

As second analysis multinomial logistic regression model was derived predicting the probabilities of very early preterm, early preterm, late preterm, and term birth using GA at USG and CL as continuous variables.

Important study results were:

• BMI was the only other variable that correlated significantly with GA at birth in the univariate analysis, but when it was incorporated into multinomial logistic regression model with CL and GA at ultrasound, prediction of GA at birth did not improve.
• A short CL measured at ≤20⁺⁰ weeks by USG indicates a probability of birth significantly earlier than if the same CL was taken at a later GA.
• When screening before 18⁺⁰ weeks, any cervical length <30 mm has a higher risk of sPTB at ≤28⁺⁰ weeks in twins than in singletons.Whereas the best prediction of birth between 28⁺¹ and 36⁺⁰ weeks was provided by screening at ≥24⁺⁰ weeks.
• A 100% probability of preterm birth not occurring before 28 weeks is achieved by CL of 65 mm and 43 mm at ultrasound GA at ≤18⁺⁰ weeks and at 22⁺¹ to 24⁺⁰ weeks, respectively.

In the third analysis, the accuracy of the model to correctly predict term delivery as compared to preterm was assessed. The model has a 68.2% true negative rate, classifying correctly those who were predicted to deliver at ≥36⁺¹ weeks, compared with 26.2, 13.3 and 36.2% correctly predicted to deliver at ≤28⁺⁰, 28⁺¹ to 32⁺⁰ and 32⁺¹ to 36⁺⁰ weeks, respectively (true positive rate).

Although effective intervention for sPTB in twins are limited, the study provides risks of very early, early and late preterm birth, so a personalized cost effective delivery plan, optimal timing of corticosteroids and referring to neonatal unit can be managed. It also justifies serial CL measurements, so that early and late sPTB could be predicted.

To conclude the authors, recommend to start the screening at ≤18⁺⁰ weeks with repeat screening at >22⁺⁰ weeks; this best identifies the patients that may deliver very early at ≤28⁺⁰ weeks as well as the more common later group of sPTB between 28⁺⁰ to 36⁺⁰ weeks. 

References:

http://www.cdc.gov/nchs/fastats/multiple.htm

http://www.who.int/mediacentre/factsheets/fs363/en/

http://www.ncbi.nlm.nih.gov/pubmed/24360590

http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.13575/full

http://onlinelibrary.wiley.com/doi/10.1111/1471-0528.13710/full

Serum Biomarkers to predict outcome in women with threatened abortion: A systemic review and diagnostic accuracy meta-analysis.

Threatened abortion approximately affect 20% of pregnancies and 50% of those will end up in miscarriage.  It has also been associated with poor obstetric outcome such as preterm labor, low lying placenta, low birth weight and PROM.

The uncertainty of prognosis makes it a challenging task for healthcare professionals.Various biomarkers have been used, with variable results to predict the prognosis of bleeding in early pregnancy.

This systemic review and meta-analysis was published in the forthcoming issue of Human Reproduction update, it aims to determine the diagnostic accuracy of various biomarkers.

A total of 19 studies were found after electronic searching of databases to determine outcomes for women with threatened abortion at 5–23 weeks gestational age.

15 studies (including 1263 women) were found eligible using QUADAS-2 (Quality Assessment for Diagnostic Accuracy Studies-2: A Revised Tool) to include in the qualitative data assessment.

The biomarkers that were looked into included serum progesterone, hCG, pregnancy associated plasma protein A, estradiol and cancer antigen 125 (CA 125).

Interestingly, serum CA 125 appeared to be the most promising marker (n = 648 women, 7 studies), whereas serum progesterone and hCG are less useful once fetal viability is established.

CA-125 is a glycoprotein and its origin is uncertain during pregnancy. It arises during the first trimester and return to a non-pregnancy range in late pregnancy.

CA 125 showed a sensitivity of 90% (95% confidence interval (CI) 83–94%), specificity of 88% (95% CI 79–93%), positive likelihood ratio of 7.86 (95% CI 4.23–14.60) and negative likelihood ratio of 0.10 (95% CI 0.06–0.20). The inverse of negative likelihood ratio was 9.31 (95% CI 5–17.1) indicating that a negative test is likely to identify those who are likely to continue with the pregnancy.

Nevertheless, when vaginal bleeding had been present for 3 days or more and there was high maternal serum CA125 activity, the abortion risk was found to be 100%.

Since this was a qualitative analysis, no cut-off value for CA125 was determined but in most studies patients who eventually aborted had values of CA-125 more than 125 IU/ml while the control had a value not more than 93 IU/ml.

A rising value of CA 125 combined with gestational sac diameter that does not correspond to the pregnancy dating is highly significant in predicting the prognosis.

Serum estradiol was the next best marker with a sensitivity of 45% (95% CI 6–90%), a specificity of 87% (95% CI 81–92%), a positive likelihood ratio of 3.72 (95% CI 1.01–13.71) and a negative likelihood ratio of 0.62 (95% CI 0.20–1.84).

References:

https://humupd.oxfordjournals.org/content/22/2/228.abstract 

https://www.researchgate.net/publication/21703609_The_prognostic_significance_of_maternal_serum_CA125_measurement_in_threatened_abortion.

https://www.researchgate.net/publication /237514290_Threatened_abortion_A_risk_factor_for_poor_pregnancy_outcome

https://www.glowm.com/pdf/FromPreconceptionToPostpartum-InTech-CC%20BY-Ch05.pdf

http://europepmc.org/abstract/MED/12235698

http://www.reproductivemedicine.com/toc/auto_abstract.php?id=17836

http://www.ncbi.nlm.nih.gov/pubmed/12235698