Michela Quaranta

Caesarean Section: Could Different Transverse Abdominal Incision Techniques Influence Postpartum Pain and Subsequent Quality of Life? A Systematic Review

The choice of the type of abdominal incision performed in caesarean delivery is made chiefly on the basis of the individual surgeon’s experience and preference. A general consensus on the most appropriate surgical technique has not yet been reached. The aim of this systematic review of the literature is to compare the two most commonly used transverse abdominal incisions for caesarean delivery, the Pfannenstiel incision and the modified Joel-Cohen incision, in terms of acute and chronic post-surgical pain and their subsequent influence in terms of quality of life. Electronic database searches formed the basis of the literature search and the following databases were searched in the time frame between January 1997 and December 2013: MEDLINE, EMBASE Sciencedirect and the Cochrane Library. Key search terms included: “acute pain”, “chronic pain”, “Pfannenstiel incision”, “Misgav-Ladach”, “Joel Cohen incision”, in combination with “Caesarean Section”, “abdominal incision”, “numbness”, “neuropathic pain” and “nerve entrapment”. Data on 4771 patients who underwent caesarean section (CS) was collected with regards to the relation between surgical techniques and postoperative outcomes defined as acute or chronic pain and future pregnancy desire. The Misgav-Ladach incision was associated with a significant advantage in terms of reduction of post-surgical acute and chronic pain. It was indicated as the optimal technique in view of its characteristic of reducing lower pelvic discomfort and pain, thus improving quality of life and future fertility desire. Further studies which are not subject to important bias like pre-existing chronic pain, non-standardized analgesia administration, variable length of skin incision and previous abdominal surgery are required.

“Empiric” inositol supplementation in normal-weight non insulin resistant women with polycystic ovarian disease: from the absence of benefit to the potential adverse effects

We read with great interest the manuscript titled ‘‘Evaluation of ovarian function and metabolic factors in women affected by polycystic ovary syndrome after treatment with D-Chiro-Inositol’’ by Lagana et al. [1] recently published in your prestigious Journal. The authors conducted an interesting prospective cohort study evaluating the effects of D-chiro inositol (DCI) supplementation in non-overweight women affected by polycystic ovarian syndrome (PCOS). Authors demonstrated that normal weight PCOS (BMI \ 25) benefited from a 6 months dietary DCI supplementation with 1 gram daily. They observed menstrual cycle regularization and restoration of ovulation in 62.5 % of cases (30 of 48 patients) most likely due to significant improvements in the metabolic (evaluated by glucose profile and serum glucose to insulin ratio) and hormonal profile (evaluated by LH to FSH ratio and androgen levels) [1]. In our opinion, the manuscript by Lagana et al. is both interesting and innovative as only one other study investigating hormonal and metabolic changes following inositol supplementation in lean women with PCOS phenotype is reported in the literature [2]. Iuorno et al. [2] following 600 mg daily DCI supplementation for a period of 6–8 weeks described metabolic and hormonal improvements strictly comparable with the ones reported by Lagana. Interestingly, both study noted the rate of ovulation restoration after DCI supplementation. Intriguingly, despite both studies being conducted on a very small number of patients (48 women by Lagana et al. and 20 by Iuorno et al.), the rate of ovulation restoration was very similar, at around 60 %. Unfortunately, even if Lagana et al. achieved statistical significance evaluating the endpoint ovulation restoration, Iuorno et al. did not. Certainly our speculation does not take into account the statistical result, probably strongly influenced by methodology and sample size (study protocol by Lagana did not include a control group while Iuorno et al. performed a case–control study on 20 patients) but rather focuses on the possible mechanisms involved and on the different effects that DCI supplementation may have on non-overweight PCOS patients as opposed to the well documented improvements in ovulation restoration in obese PCOS women [3, 4]. Despite further studies with larger sample size are required to confirm evidences of DCI supplementation in lean PCOS patients, we aim to stress the importance this data, which may indirectly explain the differences in the pathophysiological mechanisms (respect to the obese women) responsible for chronic anovulation and open the door for future improvements in terms of treatment. The most accredited theory for anovulation in PCOS women was insulin-resistance directly related with obesity This comment refers to the article available at doi:10.1007/s00404014-3552-6 and an author’s reply to this comment is available at doi:10.1007/s00404-015-3663-8.

Statins as Targeted “Magical Pills” for the Conservative Treatment of Endometriosis May Potential Adverse Effects on Female Fertility Represent the “Dark Side of the Same Coin”? A Systematic Review of Literature

The aim of the study was to analyze all the available evidence from both in vitro and in vivo studies regarding the efficacy of statin therapy in the treatment of endometriosis, evaluating the potential efficacy, side effects, and contraindications of their administration in humans. We focused on defining the potential benefits that the administration of statins may have on patients affected by endometriosis and the possible adverse effects of such a therapy on ovarian function and fertility profile. According to our article selection criteria, we included in the review in vitro and in vivo studies performed on human or animal models. The systematic review of literature identified 24 eligible articles, 12 of which reported evidence regarding the effects of statins on endometrial/endometriotic cells and 12 regarding their effects on ovarian function and fertility. All articles seem to emphasize the utility of statin administration in the treatment of endometriosis due to their anti-proliferative/proapoptotic effects, their ability to reduce cell viability and migration, and the inhibition of angiogenesis and anti-inflammatory activities. Regarding the potential adverse effects on gonadal activities, steroidogenesis and fertility function, no conclusive data were collected in human models (excluding women affected by polycystic ovary syndrome in which significant decline of androgen levels was reported after statin treatment), while contrasting results were reported by studies conducted in in vitro and in vivo in animal models. Despite evidence supporting statins as the potential therapeutic agent for a targeted conservative treatment of endometriosis, the uncertainties regarding their impact on gonadal function may not define them as an appropriate therapy for all young fertile women.

Intrauterine morcellator devices: The icon of hysteroscopic future or merely a marketing image? A systematic review regarding safety, efficacy, advantages, and contraindications

The aim of this study was to analyze all available evidence regarding the use of intrauterine morcellator (IUM), for treatment of the most prevalent intrauterine benign lesions, compared to both traditional resectoscopy and conventional outpatient operative hysteroscopy in terms of safety, efficacy, contraindications, perioperative complications, operating time, and estimated learning curve. We reported data regarding a total of 1185 patients. Concerning polypectomy and myomectomy procedures, IUM systems demonstrated a better outcome in terms of operative time and fluid deficit compared to standard surgical procedures. Complication rates in the inpatient setting were as follows: 0.02% for IUM using Truclear 8.0 (Smith & Nephew Endoscopy, Andover, Massachusetts) and 0.4% for resectoscopic hysteroscopy. No complications were described using Versapoint devices. Office polipectomy reported a total complication rate of 10.1% using Versapoint device (Ethicon Women’s Health and Urology, Somerville, New Jersey) and 1.6% using Truclear 5.0 (Smith & Nephew Endoscopy). The reported recurrence rate after polypectomy was 9.8% using Versapoint device and 2.6% using Truclear 8.0. Finally, the reported intraoperative and postoperative complication rate of IUM related to removal of placental remnants using Truclear 8.0 and MyoSure (Hologic, Marlborough, Massachusetts) was 12.3%. The available evidence allows us to consider IUM devices as a safe, effective, and cost-effective tool for the removal of intrauterine lesions such as polyps, myomas (type 0 and type 1), and placental remnants. Evidence regarding Truclear 5.0 suggests that it may represent the best choice for office hysteroscopy. Further studies are needed to confirm the available evidence and to validate the long-term safety of IUM in procedures for which current data are not exhaustive (placental remnants removal).

The Potential Role of GnRH Agonists and Antagonists in Inducing Thyroid Physiopathological Changes During IVF.

We conducted an observational cohort study to evaluate whether drugs used for hypothalamic inhibition may impact thyroid function of infertile women scheduled for fresh nondonor in vitro fertilization/intracytoplasmic sperm injection treatment. We considered eligible for inclusion in the study only women with normal thyroid function (serum thyroid-stimulating hormone [TSH] range: 0.2-4.0 mIU/L, serum thyroxin values: 9-22 pmol/L) and negative personal history for previous thyroid disorders. According to which protocols were implemented to gain hypothalamic inhibition, patients were assigned to group A (70 women treated by long gonadotropin-releasing hormone [GnRH] agonist protocol) or to group B (86 women treated by flexible GnRH antagonist protocol). Before initiating controlled ovarian stimulation (COS), both groups were further stratified into 4 subgroups: A1 (46 of the 70 women) and B1 (61 of the 86 women) in women with a baseline TSH value <2.5 mIU/L, whereas those with a baseline value ≥2.5 mIU/L were assigned to groups A2 (24 of the 70 women) and B2 (25 of the 86 women). Prior to initiating stimulation (T-0), 17-β-estradiol (E2) and TSH serum values were dosed in all women and repeated on T-5 (day 5 of COS) and subsequently every 2 days until T-ov-ind (ovulation induction day) and T-pick-up (oocytes retrieval day). In case of detection of TSH levels above the cutoff, patients were screened for thyroxin and thyroid autoantibody serum values. In group A, E2 at T-ov-ind was significantly increased compared to group B (P < .01), whereas TSH values showed an opposite trend (not significantly modified in group A, whereas significantly increased in group B; P < .001). A total of 64 women were found to have TSH values above the cutoff during COS: 7 in group A (11%) and 57 in group B (89%). Among them, 5 (71.4%) of the 7 in group A displayed hypothyroidism (and 4 of the 5 autoantibody positivity), whereas in group B, 6 (10.5%) of the 57 displayed hypothyroidism (and 2 of the 6 autoantibody positivity; P < .001). No pregnancies were observed in women with hypothyroidism, whereas in the 53 women with “isolated” increased TSH (normal T4, negative antibodies), we reported a 20.7% clinical pregnancy rate and a 54.5% ongoing pregnancy rate. Our preliminary data, despite requiring further confirmation, seem to suggest that the various drugs used for gaining hypothalamic control during COS could interfere through different mechanisms with physiological function of thyroid axis, potentially affecting its regulation.

Preventive and Therapeutic Role of Dietary Inositol Supplementation in Periconceptional Period and During Pregnancy: A Summary of Evidences and Future Applications

Although inositol dietary deficiency in the general population has not been demonstrated at the serum level, several findings are emerging regarding the impact of inositol supplementation in periconceptional period and in early phases of pregnancy. We are aimed to summarize all experimental (murine in vivo and in vitro murine embryo studies) and clinical (human) evidences regarding the role of inositol in the prevention and treatment of folate-resistant embryo neural tube defects (FR-NTDs) and gestational diabetes mellitus (GDM). We also collected all information regarding the effect that inositol supplementation may have in the metabolic reassessment of early and late pregnancy in order to draw evidence-based conclusions and suggest further studies defining the potential therapeutic role of this molecule in human reproduction. The systematic review of literature clearly showed that inositol supplementation in preconceptional period and in early phase of pregnancy reduces the risk of developing GDM in patients at increased risk. Furthermore, continued intake during pregnancy improves the metabolic status of affected patients, but further studies are needed to confirm this end point. All women at risk of FR-NTDs assuming inositol from the periconceptional period until late pregnancy are reported to have healthy newborns without any significant complications linked to inositol supplementation.

Surgery, endometriosis-related infertility and negative impact on ovarian reserve: “which came first, the hen or the egg?” An unresolved dilemma

We greatly appreciate the opportunity to reply to the interesting comments by Coccia et al. [1] regarding our manuscript titled ‘‘Could surgeon’s expertise resolve the debate about surgery effectiveness in treatment of endometriosis-related infertility?’’ recently published in your prestigious journal [2]. In the recent past, great strides have been made in the clinical management of patients affected by endometriosis. The proposal of innovative diagnostic techniques in association with the discovery of new targeted conservative treatments allows clinicians a narrow selection of patients who may benefit from surgery [3–7]. Unfortunately, when considering patients affected by endometriosis-related infertility, the dilemma regarding the real advantages of surgery with the intent to improve fertility by removing endometriosis and restoring normal anatomy remains a debate yet unresolved [2]. Despite that the end goal of surgical intervention in patients suffering from endometriosis-related infertility is re-establishment of correct anatomical relationship among pelvic organs and preservation of function, evidences reporting severe reductions in ovarian reserve after surgery in addition to an absence of spontaneous fertility restoration have fuelled doubts and debates regarding the real sense of surgery [8]. Similar to the unresolved paradox of ‘‘Whether the hen or the egg came first’’, it is still unclear whether the ovarian reserve of patients affected by ovarian endometriosis is more impaired by the persistence of endometriomas or by the surgical excision of those lesions. Contrasting evidences on fertility outcome following surgery augment the ongoing debate. On one hand, we can find data reporting a significant increase in spontaneous conception after surgery when compared with expectant management (considering all AFS/ASRM stages) while on the other hand, a great deal of literature underlines the absence of benefits even in terms of an increased success rate in assisted reproduction [9, 10]. We are in full agreement with what was stated by Coccia et al. regarding the fundamental role that ‘‘wellexperienced’’ surgeons have in the surgical treatment of endometriosis-related infertility. However, our manuscript introduced the idea of ‘‘dedicated’’ well-experienced surgeons and reported significant improvements in both spontaneous fertility and assisted reproduction outcomes (despite time limited) following surgical treatment. In fact, what Coccia et al. defined as ‘‘ideal’’ (ideally, surgeon dedicated to endometriosis-related infertility should also have a know-how in reproductive medicine to adopt a very conservative and anatomical–functional approach to preserve function of reproductive organs) was routine clinical practice in our setting. Our pioneeristic results suggest that this approach should be ‘‘the way everyone should do it’’. Only data collected from dedicated and highly-skilled specialist settings may contribute to divulgate bias-free This reply refers tothe comment available at doi:10.1007/s00404-015-3791-1.

An Update on Maternal Hydration Strategies for Amniotic Fluid Improvement in Isolated Oligohydramnios and Normohydramnios: Evidence from a Systematic Review of Literature and Meta-Analysis.

Objective Several trials aimed at evaluating the efficacy of maternal hydration (MH) in increasing amniotic-fluid-volume (AFV) in pregnancies with isolated oligohydramnios or normohydramnos have been conducted. Unfortunately, no evidences support this intervention in routine-clinical-practice. The aim of this systematic-literature-review and meta-analysis was to collect all data regarding proposed strategies and their efficacy in relation to each clinical condition for which MH-therapy was performed with the aim of increasing amniotic-fluid (AF) and improving perinatal outcomes. Materials and Methods A systematic literature search was conducted in electronic-database MEDLINE, EMBASE, ScienceDirect and the Cochrane-Library in the time interval between 1991 and 2014. Following the identification of eligible trials, we estimated the methodological quality of each study (using QADAS-2) and clustered patients according to the following outcome measures: route of administration (oral versus intravenous versus combined), total daily dose of fluids administered (<2000 versus >2000), duration of hydration therapy: (1 day, >1 day but <1 week, >1 week), type of fluid administered (isotonic versus hypotonic versus combination). Results In isolated-oligohydramnios (IO), maternal oral hydration is more effective than intravenous hydration and hypotonic solutions superior to isotonic solutions. The improvement in AFV appears to be time-dependent rather than daily-dose dependent. Regarding normohydramnios pregnancies, all strategies seem equivalent though the administration of hypotonic-fluid appears to have a slightly greater effect than isotonic-fluid. Regarding perinatal outcomes, data is fragmentary and heterogeneous and does not allow us to define the real clinical utility of MH. Conclusions Available data suggests that MH may be a safe, well-tolerated and useful strategy to improve AFV especially in cases of IO. In view of the numerous obstetric situations in which a reduced AFV may pose a threat, particularly to the fetus, the possibility of increasing AFV with a simple and inexpensive practice like MH-therapy may have potential clinical applications. Considering the various strategies of maternal hydration implemented in the treatment of IO, better results were observed when treatment was based on a combination of intravenous (for a period of 1 day) and oral (for a period of at least 14 days) hypotonic fluids (≥2000ml).

Innovative ultrasound techniques for diagnosis of deep pelvic endometriosis: more confusion or a possible solution to the dilemma?

It was with great interest that we read the manuscript by Reid et al.1, published recently in the Journal, which proposed a new modified transvaginal ultrasound (TVS) technique (office gel sonovaginography, SVG) with the intention of improving the preoperative diagnostic accuracy of standard TVS in the assessment of deep infiltrating endometriosis (DIE) of the posterior compartment (rectosigmoid (RS), rectovaginal septum (RVS), posterior vaginal wall (PVW) and uterosacral ligaments (USL)). The authors highlighted the high accuracy of this innovative approach in predicting bowel DIE (sensitivity, 88.4%; specificity, 93.2%; positive predictive value, 79.2%; negative predictive value, 96.5%). Unfortunately, however, the accuracy of this technique in the preoperative assessment of disease involving USL, PVW and RVS sites, while maintaining high specificity (97.8%, 99.4%, 100% respectively), demonstrated a greatly reduced sensitivity (40.0%, 18.2%, 18.2%, respectively). In 2012, our study group published data regarding a ‘new technique’ known as saline contrast sonovaginography (SCSV)2, which differs from SVG solely in the contrast medium used to create an ‘acoustic window’ (using saline solution rather than ultrasound gel). Considering all pelvic DIE sites, we found SCSV to have a diagnostic accuracy, particularly specificity, comparable to that reported by Reid et al. for SVG (RS, 93.8%; USL, 95.6%; vaginal wall, 97.1%; and RVS, 100%) and in fact considerably better sensitivity (RS, 66.7%; USL, 88.9%; vaginal wall, 94.7%; RVS, 80.6%)2. Despite the fact that both these studies may appear interesting and innovative for the specialist, in our opinion neither manages to resolve the dilemma regarding which diagnostic approach would be the best method of choice for ascertaining the presence and severity of disease at each anatomical site. In the past two decades more than 50 articles have been published with the intention of defining the most accurate and reproducible sonographic technique that would be applicable on a large scale; however, we await a definitive answer and strong evidence is lacking. In a large proportion of studies, standard TVS was used as the ‘gold standard’ against which experimental techniques, such as rectal endoscopic sonography (RES) and so-called ‘modified-TVS’ techniques (including SCSV, SVG, tenderness-guided TVS, rectal-water contrast TVS, TVS with bowel preparation and TVS sliding sign), were compared. The search to identify the most effective diagnostic approach prompted Hudelist et al.3 to perform a meta-analysis of data on standard TVS, at present considered to be the first-line technique. Unfortunately, this ambitious project failed in intent in so much as it was affected by considerable bias in the data analysis and consequently in the results, since there was no discrimination between different sites of DIE in the pelvis.

May Underdiagnosed Nutrition Imbalances Be Responsible for a Portion of So-Called Unexplained Infertility? From Diagnosis to Potential Treatment Options

The aim of the study was to investigate whether women affected by unexplained infertility may have undiagnosed dietary imbalances which negatively affect fertility. Secondarily, we investigated whether varying degrees of nutritional abnormalities may benefit from different periconceptional dietary supplementations, evaluating the most effective intervention in improving pregnancy rate after in vitro fertilization (IVF). We conducted a survey on 2 cohorts of patients (group A: unexplained infertility and group B: healthy first trimester spontaneous pregnancies) with the scope of investigating and comparing their dietary status discriminating women without dietary abnormalities (cohort 1) from those with abnormalities exclusively in micronutrient intake (cohort 2) or combined abnormalities in both micronutrient and macronutrient intake and associated obesity (cohort 3). All women included in group A were offered the opportunity to receive a prescription for one of the 3 designated daily dietary supplementation schemes (subgroups A1, A2, and A3) which were to be implemented in the 3 months immediately prior to beginning IVF treatment. When compared with fertile women, patients having unexplained infertility showed significant abnormalities in dietary habits. These differences ranged from a minimal imbalance in micronutrient intake (potentially avoidable with dietary supplementation) to severe combined macronutrient and micronutrient imbalance frequently associated with obesity (partially amendable by inositol supplementation and frequently requiring long-term dietary reeducation before establishment of fertility). Nutritional investigation and treatment may explain and resolve a portion of cases of unexplained infertility, improving the outcome of IVF treatment and, with minimal imbalances, likely restore spontaneous fertility.