ISAR Consensus Guidelines on Add-Ons Treatment in In vitro Fertilization.

STUDY QUESTION: What are the good practices for the use of ADD-ON Treatments in IVF cycles in INDIA? WHAT IS ALREADY KNOWN: Add on treatments in IVF are procedures and technologies which are offered to patients in hope of improving the success rates. A lot of add on treatments exist; most of them have limited evidence and data for the Indian patient population is miniscule. These interventions may have limited effects, so it is imperative that any new technology that is offered is evaluated properly and has enough evidence to suggest that it is safe and effective. STUDY DESIGN SIZE DURATION: This is the report of a 2-day consensus meeting where two moderators were assigned to a group of experts to collate information on Add on treatments in IVF in INDIA. This meeting utilised surveys, available scientific evidence and personal laboratory experience into various presentations by experts on pre-decided specific topics. PARTICIPANTS/MATERIALS SETTING METHODS: Expert professionals from ISAR representing clinical and embryology fields. MAIN RESULTS AND THE ROLE OF CHANCE: The report is divided in various components including the health of the Offspring, the various ADD ons available to an ART center, consensus points for each technology & qualifications and trainings for embryologists, the report and recommendations of the expert panel reflect the discussion on each of the topics and try to lay down good practice points for labs to follow. LIMITATIONS REASONS FOR CAUTION: The recommendations are solely based on expert opinion. Future availability of data may warrant an update of the same. WIDER IMPLICATIONS OF THE FINDINGS: These guidelines can help labs across the country to standardise their ART services and improve clinical outcomes, it will also motivate clinics to collect data and report the use of Add ons to the national registry. STUDY FUNDING/COMPETING INTERESTS: The consensus meeting and writing of the paper was supported by funds from CooperSurgical India.

Diminished Ovarian Reserve Predisposes to Premature Luteinizing Hormone Surges in Gonadotropin-Releasing Hormone Antagonist Cycles in In vitro Fertilization.

CONTEXT/BACKGROUND: A premature luteinizing hormone (LH) surge, in in vitro fertilization (IVF) cycles with gonadotropin-releasing hormone (GnRH)-antagonist downregulation, leads to cycle cancellation. Currently, risk factors for the development of premature LH surge remain unknown. OBJECTIVE: The aim of the study was to determine the incidence and identify the contributing factors for premature LH surge in IVF cycles with GnRH antagonist suppression. DESIGN: This was a retrospective cohort study. SETTING: IVF-embryo transfer program at a fertility and research center. MATERIALS AND METHODS: The study included all patients undergoing IVF from December 1, 2014, to November 30, 2018, in whom GnRH-antagonist (cetrorelix 0.25 mg/d) flexible protocol was used. The primary outcome measure was the identification of premature LH surges (documented by a 2.5-fold increase in LH from the baseline above a threshold of 17 mIU/mL) with or without a decrease in E2 and appearance of free fluid on ultrasound. RESULTS: Premature LH surges occurred in 15 (2.16%) of 692 patients undergoing IVF with GnRH-antagonist suppression. Patients with premature surges had significantly lower ovarian reserve as compared to the controls (as seen from their higher age group, higher day 2 follicle-stimulating hormone (FSH), lower antral follicle counts, and lower anti-Müllerian hormone). CONCLUSIONS: Premature LH surge in a GnRH-antagonist cycle can lead to cycle cancellation and disappointment. Although this is a rare event, the incidence is higher in patients with diminished ovarian reserve. Further studies are needed to determine if giving the human chorionic gonadotropin trigger a day earlier or giving higher doses of GnRH-antagonist can benefit such cases.

Intracytoplasmic Sperm Injection with Assisted Oocyte Activation Resulting in Successful Pregnancies and Live Birth in Couples with Globozoospermia: A Report of Two Cases.

Globozoospermia, characterized by round-headed acrosomeless sperm, is a rare and severe form of teratozoospermia. We report a successful pregnancy in two cases of total globozoospermia after intracytoplasmic sperm injection (ICSI) with oocyte activation with calcium ionophore. In thefirst case, globozoospermia was diagnosed on the day of oocyte retrieval. Among 11 retrieved oocytes, only one fertilized after ICSI. The pregnancy test 2 weeks after embryo transfer was negative. Two months later, the patient underwent ovarian stimulation again. The 12 retrieved oocytes were exposed to calcium ionophore medium following ICSI. Four oocytes were fertilized and two blastocysts were transferred resulting in a clinical pregnancy. In the second case, among seven retrieved oocytes, three fertilized after ICSI and assisted oocyte activation, and two 8-cell embryos were transferred, resulting in a positive pregnancy. The successful outcome here justifies the use of ICSI with oocyte activation to improve the pregnancy rate significantly when dealing with globozoospermia.

Ventricular tachycardia in a primigravida with Hyperemesis Gravidarum.

Hyperemesis gravidarum is persistent vomiting, seen more often in the first trimester of pregnancy, when the patient is unable to maintain adequate hydration. Intractable vomiting can lead to severe electrolyte imbalance, which may cause electrocardiogram abnormalities. Occasionally, ventricular tachycardia can complicate a pregnancy. Although its occurrence usually indicates an underlying cardiac structural or arrhythmic abnormality, it may rarely occur in a pregnant patient with structurally normal heart. We report a rare case of ventricular tachycardia, secondary to hyperemesis induced hypomagnesemia and hypokalemia, in a pregnant patient with a structurally normal heart.

Zonal rate model for axial and radial flow membrane chromatography, part II: model-based scale-up.

Membrane chromatography (MC) systems are finding increasing use in downstream processing trains for therapeutic proteins due to the unique mass-transfer characteristics they provide. As a result, there is increased need for model-based methods to scale-up MC units using data collected on a scaled-down unit. Here, a strategy is presented for MC unit scale-up using the zonal rate model (ZRM). The ZRM partitions an MC unit into virtual flow zones to account for deviations from ideal plug-flow behavior. To permit scale-up, it is first configured for the specific device geometry and flow profiles within the scaled-down unit so as to achieve decoupling of flow and binding related non-idealities. The ZRM is then configured for the preparative-scale unit, which typically utilizes markedly different flow manifolds and membrane architecture. Breakthrough is first analyzed in both units under non-binding conditions using an inexpensive tracer to independently determine unit geometry related parameters of the ZRM. Binding related parameters are then determined from breakthrough data on the scaled-down MC capsule to minimize sample requirements. Model-based scale-up may then be performed to predict band broadening and breakthrough curves on the preparative-scale unit. Here, the approach is shown to be valid when the Pall XT140 and XT5 capsules serve as the preparative and scaled-down units, respectively. In this case, scale-up is facilitated by our finding that the distribution of linear velocities through the membrane in the XT140 capsule is independent of the feed flow rate and the type of protein transmitted. Introduction of this finding into the ZRM permits quantitative predictions of breakthrough over a range of industrially relevant operating conditions.

Model-based analysis and quantitative prediction of membrane chromatography: extreme scale-up from 0.08 ml to 1200 ml.

A model-based approach is presented for quantitatively decoupling the impacts of non-ideal flow and non-ideal binding in membrane chromatography (MC) capsules at different scales. The internal geometry of Sartobind capsules with 0.08 ml and 1200 ml membrane volume is reconstructed from MRI measurements and manufacturer data. Based on this information, computational fluid dynamics (CFD) simulations are used for computing internal flow patterns of both capsules. Measured breakthrough curves (BTC) under non-binding conditions are used for calibrating PFR and CSTR models of the holdup volumes in the Äkta systems. A suitable binding model is determined and the binding parameters are estimated from binding BTC data of the 0.08 ml capsule. Due to the decoupling of non-idealities, the binding parameters can be directly transferred between the CFD models of both capsules. This advantage is used for quantitatively predicting BTC data of the 1200 ml capsule under binding conditions. The model-based prediction excellently matches with independently measured BTC data, facilitating an extreme scale-up factor of 15,000. The presented approach has previously been shown to be universally applicable to capsules from other vendors with different flow configurations and membrane types.

Computational fluid dynamic simulation of axial and radial flow membrane chromatography: mechanisms of non-ideality and validation of the zonal rate model.

Membrane chromatography (MC) is increasingly being used as a purification platform for large biomolecules due to higher operational flow rates. The zonal rate model (ZRM) has previously been applied to accurately characterize the hydrodynamic behavior in commercial MC capsules at different configurations and scales. Explorations of capsule size, geometry and operating conditions using the model and experiment were used to identify possible causes of inhomogeneous flow and their contributions to band broadening. In the present study, the hydrodynamics within membrane chromatography capsules are more rigorously investigated by computational fluid dynamics (CFD). The CFD models are defined according to precisely measured capsule geometries in order to avoid the estimation of geometry related model parameters. In addition to validating the assumptions and hypotheses regarding non-ideal flow mechanisms encoded in the ZRM, we show that CFD simulations can be used to mechanistically understand and predict non-binding breakthrough curves without need for estimation of any parameters. When applied to a small-scale axial flow MC capsules, CFD simulations identify non-ideal flows in the distribution (hold-up) volumes upstream and downstream of the membrane stack as the major source of band broadening. For the large-scale radial flow capsule, the CFD model quantitatively predicts breakthrough data using binding parameters independently determined using the small-scale axial flow capsule, identifying structural irregularities within the membrane pleats as an important source of band broadening. The modeling and parameter determination scheme described here therefore facilitates a holistic mechanistic-based method for model based scale-up, obviating the need of performing expensive large-scale experiments under binding conditions. As the CFD model described provides a rich mechanistic analysis of membrane chromatography systems and the ability to explore operational space, but requires detailed knowledge of internal capsule geometries and has much greater computational requirements, it is complementary to the previously described strengths and uses of the ZRM for process analysis and design.

Intravenous iron sucrose versus oral iron in treatment of iron deficiency anemia in pregnancy: a randomized clinical trial.

AIM: Iron deficiency is a leading cause of anemia in pregnancy. The present study aimed to compare the efficacy of oral and intravenous iron therapy in improving iron deficiency anemia in pregnancy and restoring iron stores, compare the obstetric outcome in the two groups and evaluate the safety of intravenous iron sucrose. MATERIAL AND METHODS: This was a prospective study, where 100 anemic antenatal women with hemoglobin 7-9 g/dL, mean corpuscular volume <85 fL and serum ferritin <15 ng/mL, were randomized into two groups. In group A (n=50), the women received 200 mg tablets of ferrous sulphate, each containing 60 mg elemental iron, three times a day for 4 weeks. In group B (n=50), iron sucrose was given in divided doses of 200 mg each on alternate days by slow intravenous infusion. Primary outcome measure was treatment efficacy, assessed by measurement of hemoglobin, red blood cell indices and reticulocytes on days 7, 14, 21, and 30 and at delivery, and of ferritin on day 30 and at delivery. Any side-effects of treatment and the neonatal outcome were studied as secondary outcome measures. RESULTS: There was a statistically significant difference in increase of hemoglobin levels (3.1g/dL in group A vs 5.1 g/dL in group B; P=0.002) and ferritin levels between the two groups on day 30 (P=0.005). The adverse effects from iron treatment were mild but more prominent in group A. Neonatal outcome was comparable in the two groups. CONCLUSION: Intravenous administration of iron sucrose is a safe treatment for correction of anemia in pregnancy, without serious side-effects.

Reproductive outcome of couples with recurrent miscarriage and balanced chromosomal abnormalities.

AIM: Despite known association of parental carriers of structural chromosomal rearrangements with a history of recurrent pregnancy loss (RPL), the possibility of having a miscarriage due to an unbalanced chromosomal aberration remains unknown. There has been limited research on the reproductive outcome of such couples. The present study was done to report the distribution of structural chromosome rearrangements in patients experiencing RPL and to describe subsequent pregnancy outcomes in the carriers. MATERIAL AND METHODS: Chromosomal analysis was performed on blood samples from 788 individuals with RPL and distribution of chromosomal anomalies was studied. In couples found to have chromosomal rearrangements, pregnancy outcomes were recorded over 2 years. In the subsequent pregnancy, cytogenetic analysis was done on amniotic fluid (obtained at 16-20 weeks), or on miscarriage specimens (in pregnancies that failed to continue). RESULTS: Chromosomal rearrangements were identified in 6.8% (54/788) cases (including 5.9% reciprocal translocations, 0.7% Robertsonian translocations, and 0.1% inversions). The risk of having a chromosomal aberration was not related to the number of previous miscarriages. Over the next 2 years, two-thirds of the 49 documented pregnancies resulted in a normal live birth, and one-third miscarried. Most miscarriages (56.2%) were euploid, two were trisomic and 12.5% had an unbalanced translocation. CONCLUSION: In couples with no other cause of RPL other than a structural chromosomal rearrangement, nearly two-thirds are likely to have a normal outcome in subsequent pregnancy. Couples with pure abortion histories carry higher risk for cytogenetic abnormality than couples with normal children in addition to abortions.

Zonal rate model for axial and radial flow membrane chromatography. Part I: knowledge transfer across operating conditions and scales.

The zonal rate model (ZRM) has previously been applied for analyzing the performance of axial flow membrane chromatography capsules by independently determining the impacts of flow and binding related non-idealities on measured breakthrough curves. In the present study, the ZRM is extended to radial flow configurations, which are commonly used at larger scales. The axial flow XT5 capsule and the radial flow XT140 capsule from Pall are rigorously analyzed under binding and non-binding conditions with bovine serum albumin (BSA) as test molecule. The binding data of this molecule is much better reproduced by the spreading model, which hypothesizes different binding orientations, than by the well-known Langmuir model. Moreover, a revised cleaning protocol with NaCl instead of NaOH and minimizing the storage time has been identified as most critical for quantitatively reproducing the measured breakthrough curves. The internal geometry of both capsules is visualized by magnetic resonance imaging (MRI). The flow in the external hold-up volumes of the XT140 capsule was found to be more homogeneous as in the previously studied XT5 capsule. An attempt for model-based scale-up was apparently impeded by irregular pleat structures in the used XT140 capsule, which might lead to local variations in the linear velocity through the membrane stack. However, the presented approach is universal and can be applied to different capsules. The ZRM is shown to potentially help save valuable material and time, as the experiments required for model calibration are much cheaper than the predicted large-scale experiment at binding conditions.