Judith M. Orvos, ELS

Judith M. Orvos, ELS, is a a BELS-certified medical writer and editor and an editorial consultant for Contemporary OB/GYN.

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The first-of-its-kind analysis, done in a small sample of pregnant patients, shows that placenta-specific DNA increases prior to clinical development of gestational diabetes and that cell-free RNA (cfRNA) has a high positive predictive ability in detection of APOs.

 the results are from a study funded by the National Institute of Child Health and Human Development’s Human Placenta Project, a collaborative effort aimed at understanding the role of the placenta in health and disease. The study of cell-free DNA (cfDNA) methylation and transcriptomic signature prediction was led by researchers from UCLA.

For the analysis, the authors applied a method developed to deconvolute trace amounts of tumor DNA from the plasma background and extended it to extremely low-coverage sequencing data. 

They used the method, along with RNA sequencing, to test the hypothesis that cfDNA and cfRNA in maternal circulation may correlate with placental health and could be employed to differentiate between gestational disorders and normal, complication-free gestation.

DNA sequencing technique may help prenatally detect NIHF

The participants were women in their first trimester from February 2017 to 2019 who were enrolled in the PARENTS prospective cohort study, which is looking at mechanisms for and prediction of APOs. Of the 160 subjects in that study who have delivered, 61 had APOs.

The present placenta-specific DNA research included nine women with normal pregnancies, five with preeclampsia, three with gestational hypertension, and seven with gestational diabetes mellitus (GDM). 

GDM was defined as any degree of glucose intolerance initially recognized in pregnancy. Preeclampsia was defined as blood pressure ≥140/90 on two occasions at least 4 hours apart after 20 weeks’ gestation with a previously normal blood pressure and proteinuria of 300 mg for ≥24 hours.

Five different samples were taken from each subject at time points from 12 to 17 weeks, 18 to 22 weeks, 35 to 37 weeks, at delivery, and from cord blood. Plasma was also collected from seven women who served as controls.

The authors found that the placental fraction in GDM significantly increased compared with normal pregnancies in the first trimester and the trend persisted through the second and third trimesters, although it was not statistically significant. 

Early detection of a difference between pregnancies with GDM (mean 7.2%) and that were normal (mean 4%) based on the placental fraction, the researchers said, is of interest for future development of predictive biomarkers.

Non-placental tissue-of-origin, namely pancreatic cfDNA fraction, also was significantly increased only in the first trimester in subjects who went on to develop GDM. Pancreatic cfDNA also increased in the GDM cord blood, perhaps signaling future pancreatic dysregulation in the offspring.

The authors used cfRNA sequencing information from the first trimester to identify candidate biomarkers for detection of likelihood of developing APOs. 

A logistic regression model showed that upregulation of the genes 

 was associated with APOs as were upregulation of 

. The classifier had a positive predictive value of 0.91 for APOs, 0.86 for preeclampsia alone, and 0.64 for GDM.

Taking these results together, the researchers “presented cfDNA methylation signatures and transcriptomic signatures early in gestation that collectively could potentially assist in the prediction of subsequent development of APOs, prior to emergence of characteristic clinical features.” 

Their findings, the authors said, point to a need for a larger multicenter clinical trial and suggest that “these non-invasive approaches may be used effectively early in gestation.”

Del Vecchio G, Li Q, Li W, et al. Cell-free DNA methylation and transcriptomic signature prediction of pregnancies with adverse outcomes. 

. Published online: 13 Oct 2020 doi: 10.1080/15592294.2020.1816774

Articles

New research suggests that placental DNA may have potential as a biomarker for adverse pregnancy outcomes (APOs). 

Placental DNA may predict pregnancy complications

The findings suggest a new avenue of research on the interrelationship between endometriosis and infertility.

 the conclusions are from a cross-sectional analysis of women aged 18 to 42 who underwent surgery for benign gynecological conditions at a single center between May 2005 and May 2018. 

Indications for surgery included conditions associated with 

The study population was 496 patients, who were broken into three groups: no infertility (n=361), primary infertility (n=84), and secondary infertility (n=51). Half were diagnosed with adenomyosis on magnetic resonance imaging (MRI) and half had no adenomyosis. 

Focal adenomyosis (FAOM) was defined on T2-weighted images as a localized, ill-defined, low-signal-intensity mass, inhomogeneous circumscribed area located in the outer shell of the uterus, with indistinct margins separating it from the maximal junctional zone (JZmax). 

Diffuse adenomyosis was defined as a JZmax ≥ 12 mm and a ratio maximum > 40%. 

Radiologists performing the MRIs were blinded to results of clinical findings and to the results of the patients’ previous imaging studies.

Significantly more women in the primary infertility group had ≥ 1 FAOM lesion compared with those in the no infertility or secondary infertility groups (42/84 [50%] vs 111/361 [30.7%] and 17/51 [33.3%], respectively; 

Presence of diffuse adenomyosis was not significantly associated with primary or secondary infertility (101/361 [28.0%] in the primary infertility group, 21/84 [25.0%] in the primary infertility group, and 17/51 [33.3%] in the secondary infertility group; 

Of the women with adenomyosis, 30.2% overall had infertility. In 19.8% the infertility was primary and in 10.5% it was secondary; some women had both types.

Presence of FAOM remained independently associated with primary infertility (adjusted odds ratio 1.98; 95% confidence interval 1.1 to 3.3) after multivariable analysis and adjustment for age and presence of FAOM or diffuse adenomyosis, endometriosis, and leiomyomas.

“Almost one-third of the adenomyosis population had reported infertility, and most of these patients exhibited FAOM,” concluded the authors. “Using specific imaging tools, therefore, appears to be crucial to properly characterize the adenomyosis phenotype and to offer optimal management to infertile women.”

Bourdon M, Santulli P, Oliveira J, Marcellin L, Maignien C, Melka L, et al. Focal adenomyosis is associated with primary infertility. 

. 2020 Aug 28;S0015-0282(20)30590-2. doi: 10.1016/j.fertnstert.2020.06.018

A new study by French investigators shows that adenomyosis confined to the outer myometrium is associated with primary infertility—but not more diffuse disease. 

Study links focal adenomyosis and primary infertility

The novel procedure involves creating a temporary latticework to provide support during healing, by intertwining sutures from a midline anterior colporrhaphy with the obturator sutures.

A description of the surgery and experience with it in a pilot study of 109 patients were published in 

.1 All of the women had Stage 2 or greater anterior compartment prolapse, based on examination with Valsalva in the dorsal lithotomy position. Their average age was 62 and average body mass index was 28.

Of the women, 34% had a bothersome recurrence after a previous anterior repair. All of them completed the three questionnaires in the Pelvic Floors Disorders Inventory-2 (PDFI2.0) in anticipation of a primary outcome of recurrence of anterior prolapse. 

Secondary outcomes consisted of time to anterior recurrence; recurrence of any compartment; recurrence of bothersome bulge symptoms; incidence of intraoperative, perioperative, and postoperative complications; and patient characteristics associated with recurrence.

The key steps in creation of the latticework, as depicted in the report, are (1) dissection of the vaginal epithelium off the perivesical fascia laterally to the obturator fascia; (2) placement of 2.0 PDS sutures distally and proximally on each side at the level of the obturator fascia/arcus tendinous followed by midline anterior colporrhaphy with four 2.0 PDS sutures; and (3) intertwining of the four lateral and four midline sutures, which are then tied together.

The mean surgical time was 132 minutes, and 60 minutes for patients who only had an anterior repair. No intraoperative complications were reported. At 30 days post-surgery, six patients (5.5%) had new-onset stress urinary incontinence (SUI). 

Seventeen patients (15.3%) had urinary tract infection (>20,000 bacterial colonies with irritative voiding symptoms). Forty-eight patients (43.9%) had new-onset overactive bladder, 11 of whom required medical treatment. Thirty-seven patients (34%) required catheterization for transient urinary retention, all of whom eventually voided to completion.

Mean follow-up in the study was 12 months, during which 12 patients (11%) had anatomic recurrence of POP. Mean time to recurrence was 13.9 months. There was a 31% improvement in PDF12.0 (

 = .02), mostly associated with a 55% improvement in patient responses to the Pelvic Organ Prolapse Distress Inventory.

The authors said their technique of interlocking central defect sutures unilaterally to the arcus tendinous fascial pelvis, “encourages scarring throughout the defect, maintaining the repair after the sutures dissolve. 

This results in a reduction of the midline defect with a concomitant elevation of the whole bladder laterally in the paravaginal space.” While acknowledging the increased risk of retention associated with the procedure, the authors characterized it as “self-limiting” and said it “may decrease the likelihood of developing SUI.” 

They also noted that “longer follow up is needed in order to evaluate the durability of these initial encouraging results.”

Rude T, Sanford M, Cai J, Sevilla C, Ginsberg D, Rodriguez LV. Transvaginal paravaginal native tissue anterior repair technique: initial outcomes. 

. https://doi.org/10.1016/j.urology.2020.06.070



A new technique for repair of pelvic organ prolapse (POP) appears to be associated with good short-term outcomes, based on results of a new pilot study. 

Pilot study of novel technique for POP repair

Every year, more than 1 million cases of abnormal uterine bleeding (AUB)—a condition that has a significant impact on women’s quality of life—are reported in the United States. A new literature review suggests that several major barriers exist to care for the condition.

 by New Zealand researchers, the report assesses qualitative studies of the lived experiences of women with abnormal menstrual symptoms

The authors performed a systematic literature review through August 8, 2019, and identified 12 studies involving interviews or focus groups related to women aged 18 years or older. The Clinical Appraisal Skills Program Checklist was used to assess the quality of the reports, which spanned 1999 to 2018.

Of the studies, 6 were from the UK, 3 from New Zealand, 2 from the United States, and 1 from Australia. The methodology used ranged from open, unstructured, and semi-structured interviews with 16 to 60 participants. 

In half the studies, women were recruited from the community and the other half from attendance at clinics.

 identified by the authors of the systematic review were: (1) lack of health literacy; (2) taboo around and normalization of menstrual issues; and (3) poor communication with health care providers.

Of note, in one of the US studies, women found identification of “normal” menstrual bleeding challenging and, they began to normalize heavy or excessive bleeding if it occurred for a long enough period of time. As a result, they may not have sought medical attention for AUB.

Over half the women surveyed who had fibroids minimized their symptoms and overall, the participants prioritized other health issues over those involving uterine or vaginal health.

Regarding communication with health providers, most of the studies assessed found that it was a key barrier to the investigation of AUB. Eight of the 12 studies identified normalization and dismissal of concerns of women’s concerns by general practitioners as an important impediment to accessing appropriate care. 

Notably, in one US study of more than 400 general practitioners, 87% said they ask patients a quality-of-life question in relation to AUB but only 18% thought that was essential when evaluating a woman with AUB.

The findings from the literature review, the authors said, “indicate that improving access to care [for AUB] will require multi-level approaches that include consideration of local socio-cultural needs along with improved training for primary healthcare providers such as GPs.”

Henry C, Ekeroma A, Filoche S. Barriers to seeking consultation for abnormal uterine bleeding: systematic review of qualitative research. 

. 2020 Jun 12;20(1);123 doi: 10.1186/s12905-020-00986-8

A new literature review suggests that several major barriers exist to care for the condition.

Author | Judith M. Orvos, ELS

Articles

Placental DNA may predict pregnancy complications

Study links focal adenomyosis and primary infertility

Pilot study of novel technique for POP repair

Barriers to care for abnormal uterine bleeding