RPL: An Update

Added: 2026-05-26

[00:00:04]Hello everyone, I am Ada from IGCP and I warmly welcome to all our respected doctors and participants for today's session. This session is about you by IGCP and today we are discussing an emotionally and clinically significant topic in reproductive medicine. RPL & Update. Recurrent pregnancy loss, commonly known as the RPL, remains one of the most challenging conditions for both patients and clinicians. Beyond the physical aspects, it carries a deep emotion and a psychological impact on couples trying to build a family. With evolving understanding in genetics, immunology, endocrinology, and thrombophilia and reproductive medicine, the approach to RPL diagnosis and management has significantly advanced in recent years.

[00:00:54]Today's discussion will focus on updated clinical perspectives, evaluation strategies and evidence-based management and the importance of compassionate patient-centered care. It is my privilege to introduce our moderator for today, Dr. Deepti Nab Ma'am. She is a Senior Gynecologist at Mother & Help Mother & Child Clinic, Krishna Nagar, Delhi. Dr. Deepti Ma'am is widely respected for her extensive clinical experience and dedicated contribution to women's health and reproductive well- being. We are truly honored to have such an expert with us today. Now I would like to hand over the session to ma'am. Ma'am this is over to you. You can proceed with the next ma'am.

[00:01:39]Ada please invite Dr Sharda Jain ma'am and both the expert commentators also.

[00:01:44]Ok. So we all this we have another another moderator for today's session Dr. Sharda Jain Ma'am She is the Senior Consultant of Obstetrics and Gynecology She is the Director Life Care Centre and Life Care IVF Expert Ethical Committee Member in NMC She is the Secretary General in DGF and She is the Founder and the Chairman in NIGF. Doctor Sharda Jain ma'am is a highly respected leader in women's health care and reproductive medicine known for her immense contribution towards clinical excellence and patient advocacy so with this ma'am this is over to you you can proceed thank you thank you very much for inviting me and today is a very great topic the topic is on recent pregnancy loss and as you all know that when there is a woman has a three pregnancy loss then you know the incidence is around 1% and when she has two recurrent pregnancy losses the incidence is around 5% the people who get it they are distressed and today we have a speaker doctor Deepti who is the current president of Delhi Gynecologist Forum East we have two other experts to discuss on this particular topic after her talk doctor Renu Mishra she has been past senior faculty member of all India Institute of Medical Sciences She is runs a very popular IVF center in Gurugram and we have another person Dr. Sunita Arora She had been just past president of Delhi Hisar and she maintains IVF Bloom center in Delhi and Dr. Renu Mishra has remain the past president of Delhi Gynecologist Forum South So Dr. Renu Mishra any comments before Dr. Deepti Nag makes comments on her presentation thank you ma'am good afternoon everybody so as obstetricians we all know how frustrating this problem is not just to the patients but also to the obstetricians because many times we cannot find a reason for the pregnancy loss and in the desperation we use not only just scientific methods and treatments but a lot of unscientific and unapproved and sometimes potentially harmful treatments are also used to treat this condition. So today we are looking forward to Dr. Deepti Na who is going to enlighten us and tell us what really should be done for us as we are trained gynecologist scientifically and what should be the way Dr. Sunita Arora you have been a very senior IVF expert what is your comment about recent pregnancy she lost before Deepti takes over.

[00:05:01]Thank you ma'am for having me on this forum and recent pregnancy losses as Dr. Sharda Jain ma'am and Dr. Renu has just said. It is inspite of you knowing so much of the work in the field of science. It Is Still a Clinician's Dilemma. So many tests are getting added that you can do this that immunology has really come across in the field of RPL a lot and people are going to the secondary kind of treatments which are more or less empirical at present but sometimes it works also but since there is not so much of clinical evidence added to this add on so that is why it is so difficult and finally I think it is the tender love and care here which is actually benefiting our patients and if you keep on trying and one last you know cycle works even in cases of recurrent pregnancy losses. So not that as a blanket statement we are able to find out the causes in all but yes I am sure Dr. Deepti Nab is going to elaborate on the topic in detail and after that we will again discuss. So over to Dr. Deepti Nab Ma'am please.

[00:06:18]I think things are not that bad you know the days even if you have a couple of abortions you still have a hope of 50 60% to have a life baby so over to you deepi thank you ma'am thank you so much and good afternoon to everyone I will just I is my ppt visible ada yes it is coming yes yes it is coming coming is it full screen so the topic can you put it full screen yes yes ma'am you can see there is a next perfect ok so the topic for today's discussion is current pregnancy loss current guidelines as let's start with the definition according to ashrae 2022 23 guidelines rpl what is recurrent pregnancy loss is defined as spontaneous loss of two or more pregnancies before 24 weeks of testing. And this definition includes both biochemically confirmed pregnancy and clinical pregnancy visualized by ultrasound. But it excludes ectopic and molar pregnancies. It covers losses both after spontaneous conception and ART. It is distinguished between primary where there has been no previous ongoing pregnancy and secondary when one or more previous pregnancies last beyond 24 weeks. According to the RCOG Green Top Guideline No. 17, RPL is defined as loss of three or more consecutive pregnancies before 24 weeks of gestation. However there has been a change now.

[00:08:06]So clinical discretion for after two-term losses is taken into consideration and they need not be executed according to a study conducted by one of the international bodies.

[00:08:18]Spontaneous loss of two or more fetuses in a clinical pregnancy is documented by ultrasound and histopathological examination and they need not be executed. So as time has gone by we are seeing that from three we have come down to two pregnancy losses. Number one, number two they need not be executive.

[00:08:38]Coming to the epidemiology and the situation in India, globally recent pregnancy loss affects one to 2% of couples when it consists of three or more losses but when two losses are considered, the prevalence rises to 5%. However in India the incidence is 7.4 to 7.5% and yet they say that the incidence is underestimated because early losses occur at home where they are unrecognized and these cases are majorly unregistered. What are the factors which contribute to increase incidence? Factors like genital tuberculosis, consanguineous marriages, nutritional deficiencies and limited access to tertiary care contribute to this burden. Number two in India: Secondary recurrent pregnancy losses are more common than primary due to post-infectious endometrial pathology.

[00:09:31]Now let's start with the etiology of recent pregnancy loss. Genetic causes are found in 3 to 5% of cases. The specific cause is parenteral balance structural chromosomal rearrangements like reciprocal translocations and Rapsonian translocations.

[00:09:46]Anatomical defects occur in 10 to 15% of patients. It could be congenital where there is a septate uterus which is the most common than followed by biconvex and uniconvex uterus. Acquired anatomical causes are: R. Assmann syndrome, leiomyomas, polyps and cervical incompetence.

[00:10:05]Immunological (15 to 20% of the cases) Antiphospholipid syndrome (we all have and convert with this) Lupus (anticoagulant antipid antibodies and presence of antibodies to glycoproteins). It could be alloimmune (also where the possible maternal fetal immune system incompatibility is observed). Endocrine (70 to 20% is the incidence) Hypothyroidism (high TSH, anti-Pho antibodies), Uncontrolled diabetes mellitus (PCOS), Should not be PMOS ( Hyperpolytonemia, Neutral Fas deficiency, Two Disorders Less Commonly Accepted) Thrombophilia (Inherited like Factfile) Mutations ( Prothrombin) Mutation Protein CS deficiency is considered in about 10 to 15% of infections. Less than 5% of infections are chronic endocrine gland infections. Chronic endocrine gland infections (TORCH infections), bacterial vaginosis. It is debatable but sometimes it is associated with lifestyle/environmental causes like maternal obesity with a BMI more than 30, single smoking, heavy alcohol consumption, high caffeine intake, more than three cups a day, and environmental toxins. The majority of the change still remains unexplained.

[00:11:16]Brain damage, which takes about 50% of cases were not detected after standard evaluation. No identifiable causes form let's start by these etiologies one by one. Genetic mechanisms contribute to RPL. We know that what are the various causes: parenteral chromosomal rearrangements, sporadic fetal aneuploidies, copy number variation, single gene mutation in women with recurrent pregnancy. Lose the risk of unemployment at each risk is lower as compared to women who have sporadic miscarriages.

[00:11:50]Cytogenetic analysis should be offered on the products of conception of the third and subsequent miscarriages and many times even after second trimester miscarriage. In genetic testing on POC, if it fails and there is no pregnancy tissue available for testing, then parental karyotyping is recommended. It should also be performed in couples on whom the testing of POCs is reported as an unbalanced translocation. So the first step would be to do a micro array of the POCs and the couple karyotyping is indicated in three situations.

[00:12:26]Now, female carriers of a balance translocation have a 10 to 15% risk of an unbalanced conception resulting in repeated miscarriages. The risk is five to 10% higher in male carriers. The options for the couples include either a CVS or a hemosynthesis in the next either a natural conception or IVF with PGTA and then transfer of the unaffected embryos. However, there is insufficient data to suggest that PGTA improves the live birth rate, so routine antibody screening in patients with RPL is not justified due to the anatomical factors. Congenital uterine abnormalities are associated more with second trimester pregnancy losses rather than the first trimester, along with complications of preterm labor and fetal presentation. Increased incidence of C-sections. So the role of uterine malformation in the first trimester is debatable but assessment of the uterine cavity is still recommended.

[00:13:26]Types of uterine anomalies which are relevant to pregnancy loss are separate uterus classes. The strongest correlation is seen and transvaginal 3D ultrasound is the preferred technique to evaluate the uterine cavity. HSG is a sonohysterography that is more accurate than HSG in diagnosing uterine malformations. It can be used when tubal patency has to be investigated. If uterine malformations have been diagnosed, one must look for kidney and ureteric tract abnormalities.

[00:14:01]MRI is not the first line option. The first is 3D transvaginal. If it is not available, then of course you can move on to MRI in India. Post-tubercular intrauterine adduction remains an important and an under- recognized cause of acquired uterine infections and acquired uterine fibroids. Factors in RPL like intrauterine adhesions, subcutaneous fibroids, and polyps account for 16 to 15% of cases. It is strange that the evidence of the necessity of surgical intervention in these findings is still developing, though it is documented that they may impair implantation. So that it becomes an individual choice between the patient and her clinician. All women with RPL should undergo an ultrasound to rule out adenomyosis. This is one of the latest inclusions in the various armamentariums when we investigate a patient with RPL.

[00:14:56]Coming to immunological causes. We all know that successful pregnancy hinges on immune tolerance at the maternal-fetal interface where the fetus hosts a unique mix of cells modulating the response to the paternal antigen. So one half is the maternal, the other half is the paternal and they may be intolerant towards the paternal antigens leading to either failed implantation, placental insufficiency and a fetal rejection. There is an innate immunity. The uterine natural cells are more numerous than the peripheral natural cells, maintaining the balance. Approval immunity is when the regulatory T cells enhance the tolerance. If in RPL it is found that the T cell number falls. Then they are of course other immunological causes include both autoimmune and all immune etiologies. Over general, they overlap with other factors. Also, the autoimmune causes are anti-phospholipid syndrome primary with persistent APLA that is characterized by anti-phospholipid antibodies and cardiolipin antibodies. LPS anti- coagulant antibodies to beta-glycoproteins occur in approximately 15 to 20% of RPL cases. Inclusion of thyroid autoantibody: Look for anti-Pho antibodies and anti-TG antibodies. ANA: Also look for the presence of celiac disease antibodies. These are the autoimmune causes coming to alloimmune causes.

[00:16:20]Polymorphisms in the HLAG genes may affect the gene expression which seems to play a role in RPL cases. Other associations like vitamin D deficiency, obesity, chronic endometritis, all of these causes impair the balance between the natural killer cells and the immune system. Cells the microbiota dysbiosis acars and they effect the immune system which maintains a balance between the TH1 and TH2 ratios what are the diagnostic approaches you have to screen for apla acl lac and for the antibodies for ck disease cellular immunity flowcytometry these are all high and ah tests which are done and endometrial biopsy should be done where you can look up for these ah scular cells and genetic epigenetic tests followed by biomarkers in the vaginal and anal swabs routine testing of women with RPL for inherited thrombophilias is not recommended.

[00:17:17]So screening for cofactor filgradin, prothrombin, gene mutations, protein C and S and antithrombin deficiency may be justified clinically when the patient has a personal history of ETE in the setting of a non-recurrent risk factor like a surgery and a first relative with a known and suspected high thrombophilia. So when these factors are not present, generally we do not recommend testing for inherited thrombophilias. Coming to the hormonal and metabolic causes, thyroid screening for TSH and TPO antibodies is recommended in women with RPS. How do you manage it? Just a brief if the TSH levels are less than 2.5, which is normal.

[00:17:54]Normal thyroid function: No treatment is required. Just routine monitoring. If the TSH levels are between 2.5 and 4, which is mild. Loss of clinical hypothyroidism: Check for the presence of TPO antibodies. If the TPO antibodies are positive and there is a history of recent pregnancy loss, consider use of levothyroxine. If the TPO antibody is negative, then you just need to point to the TSH levels preconception and in early pregnancy. However, if the TSH level is more than 4, it is hypothyroidism.

[00:18:24]Likely start the patient on levothyrine, TSH and preconception and during early pregnancy. Also, if there is overt hypothyroidism, that is, if the TC levels are high and the free TO levels are low, then it is an established thyroid disease.

[00:18:42]Liveropathy can be initiated immediately and monitoring should be carried out every four to six weeks.

[00:18:48]So if the TSH levels are normal but the TPO antibodies are positive, that is thyroid autoimmune without a dysfunction. What you do is routine levothyroxine is not universally recommended. However, you need to monitor the TSH levels every four to six weeks in early pregnancy, where there is an autoimmune effect, but the TSH levels are normal.

[00:19:10]Assessment of PMOS using fasting insulin and fasting glucose is not recommended unless there are clinical features like irregular cycles, masturbation, and obesity which may justify an assessment. Lifestyle modification focusing on weight reduction, diet, exercise, and insulin sensitization may improve the outcome unless the patient has clinical symptoms of oligoamenorrhea. Prolactin testing is not recommended and if prolactin levels are high, bromocriptine therapy is associated with improved low birth rates. Two larger trials are needed for validation. There is no larger test for late-stage inefficiency. Use of histological and biochemical endpoints in diagnostic centers is fundamentally unreliable.

[00:19:56]Administration of progesterone and SCG to women with perinatal miscarriage is ineffective, however, if there is a history of RPL, the RCOG now recommends that Yes, empirical progesterone can be administered further Testing for AMH/ LH elevated levels is not recommended but hypercysteinemia resulting from deficiency of folate B6 and B12 and from genetic mutations such as MTHFR polymorphism is associated with endothelial dysfunction, thrombosis, and placental vasculopathy in any case. We know that elevated hemocysteine levels have been linked with neural tube defects, IUGR, proglycemia, and placental abruption. But measurement of homocysteine ​​levels is not recommended in women with RPL due to inconsistent data. We also don't screen for vitamin D levels, but however, vitamin D supplementation is urgently given and it is widely advised, even up to 4000 units during pregnancy and lactation. Coming to anti-phospholipid antibody syndrome, it is a systemic autoimmune disorder, a notable cause of APL, contributing to 10 to 15% of cases. It is characterized by recent arterial and venous thrombosis, pregnancy morbidity, and persistent presence of APL (LAC) and antibody to glycoprotein given the heterogeneity. So there is lab criteria and then there is presence of miscarriage and then there is the venous and the arterial thrombosis. So there is a heterogeneity of clinical presentation and lab findings. So accurate classification is a must for risk rectification. So earlier we had the Sapporo Criteria 2006 further classified.

[00:21:45]Now this criteria says that there is at least one clinical criterion and one lab criterion for the diagnosis of APS.

[00:21:52]So in this criteria the clinical criteria consist of vascular thrombosis and pregnancy morbidity.

[00:21:58]What is vascular thrombo? It is defined as one or more clinical episodes of arterial, venous, and small vessel thrombosis in any tissue or organ which is confirmed by findings from imaging studies and by topography and by histopathology of note that superficial thrombosis is not included as a clinical criterion.

[00:22:19]Coming to the pregnancy morbidity it could be one more spontaneous abortion at more than 10 weeks one are more premature babies of morphologically healthy newborns at a one before 34 weeks of gestation because of severe preeclampsia and eclampsia and placental insufficiency and they have been three or more unclean executive spontaneous abortions of less than 10 weeks gestation.

[00:22:44]So this is the pregnancy morbidity and those for thrombosis and the factors should be present and all the I have enumerated is the lupus anticoagulant and beta to glycoproteins these antibodies the 2006 revision extended the required interval between the Paul's test from six to 12 weeks they have to be present and ah it was antibody to beta to glycogen was added later on.

[00:23:11]Now that was one criterion that is the support criteria which was revised in 2023. The American College of Rheumatology and the European Alliance of Associations for Rheumatologists introduced a weighted domain-based approach that enhances specificity while refining the definition of obese anti-phospholipid syndrome. There are six clinical domains and two lab domains with weighted scoring to reflect risk and clinical relevance. More faithfully, the clinical domains have been expanded to include microvascular thrombosis and cardiac valve involvement. So this is a detail which you can look up Microvascular Venous, Microvascular Arterial, Microvascular Obstetric, Cardiac Valve and Hematology. These are in the clinical domains and coming to the laboratory domains, positive LAC, positive LAC persistent. So, you can look up this course, ah ah this presentation and makeup.

[00:24:08]Now what is the practical financial approach?

[00:24:11]You need to first exclude other causes of pregnancy loss like genetic, anatomic and endocrine factors. Then you screen the patient for anti-phospholipid antibodies, lupus, anticoagulant, LAC Ig, IgM, anticardiolipin and antibody to glycoprotein. They should be performed on two occasions at least 12 weeks apart. Then this criteria can be applied using weighted clinical and laboratory scores to guide management. The patient received multidisciplinary care with consideration for thromboprophylaxis. Were indicated now for aPL positive but unclassified individual, the potential benefits of treatment must be weighed against the risk with careful follow up.

[00:24:58]Coming to infections and environmental factors, no convincing data is available that infection causes aPL, so there is no clear- cut indication for it. Routine testing for TORCH mycoplasma Humanus euplasma and others found in the vaginal and cervical culture and serum from patients with RPL in India Genital tuberculosis remains a notifiable cause leading to chronic endometriosis addition so high suspicion is warranted in which case of biopsy and hysteroscopy may be advised We must keep in mind the exposure to hazardous chemicals, pollutants, radiation and toxins which definitely interfere with reproductive process. Coming to lifestyle factors, the older maternal age correlates with chromosomal abnormalities. So maternal age and number of previous miscarriages independently predict future miscarriages, increasing from 11 to 90% with increasing age. Smoking is also linked to impaired toxoblastic function. Exposure to secondhand smoke also increases a risk.

[00:25:57]Limit alcohol and caffeine consumption to less than 200 mg a day. An elevated BMI of more than 25 is also a significant modifiable risk factor. It is associated with chronic inflammation, hormonal disturbance, and insulin resistance, and it can impair implantation. Not only the elevated BMI, but also the underweight BMI of less than 18 is associated with increased odds of RP. Nutrition also affects the dietary environment and chronic stress.

[00:26:25]Ongoing stress can disrupt the immune regulation and hormonal balance and may indirectly be responsible for miscarriage.

[00:26:35]Male factors also play a significant role in miscarriage. It is recommended to assess the lifestyle of the male partner. The age, smoking, alcohol consumption, exercise pattern and the body weight.

[00:26:46]Abnormal DNA fragmentation is seen in the setting of advanced maternal age and because of exogenous heat, toxic exposure, increased ROS in the semen.

[00:26:58]An assessment of sperm DNA fragmentation in couples with RPL could be considered for diagnostic purposes.

[00:27:05]Psychological factors were important.

[00:27:08]A possible psychological etiology for RPL was suggested by a published trial. A cohort of 158 couples with more than three executive impairments and no identifiable etiology were divided into two groups: one received routine alternative care during the next pregnancy and the other condition. One received TLC. TLC is defined as psychological support with weekly medical ultrasonographic examinations.

[00:27:33]Instructions to avoid heavy work, travel, and sexual activity. TLC stands for tender loving care. What was the result?

[00:27:42]The difference was in the love life birth rates: 36% in the control and 85% in the group which received, in addition to the apathetic care, tender loving care. But we need to interpret them with caution. Randomized and non- randomized studies have shown significant improvement of subsequent pregnancy outcomes with close monitoring and support at a dedicated RPL clinic. So the patient should be seen in an RPL clinic where extensive counselling is a must.

[00:28:12]Unexplained RPL I have already talked about that no apparent cause positive factor is seen in 50 to 75% of cases with RPL.

[00:28:20]It is important to assess the patient with an unclear RPL that the chances for a future successful pregnancy can exceed 50 to 60%, however depending upon the maternal age and the parity. So having talked about the etiology, let's start with the diagnostic evaluation. It is a stepwise structure.

[00:28:40]Perform a clinical assessment. How do you go about it? A very detailed medical and reproductive history is a must. You need to note down the number sequence and just the age of losses. History of any preterm delivery and stillbirth. What was the mode of conception. Any personal and family history of thrombosis. Irregularities in any peak cause features should be POMS. Any thyroid symptoms. History of surgical infections.

[00:29:07]Any urethra. Biometry and tuberculosis. There is a physical examination which should assess the BMI, blood pressure, thyroid, and canthosis. Nape of neck should be looked into christotism and science of any chronic disease a preconception opt optimization is a must her BAMI should be less than 30 and you tell her FS size that even a 5 to 10% reduction will improve the outcome a glycemic control maintain HPAC less than 6% thyroid normalization adjust levothyrox and doses for euthyroid state folic acid 400 to 800 micrograms per day and vitamin D more than 30 nanograms per ml supplementation should be advised lifestyle stop smoking limit caffeine intake alcohol manage stress through mindfulness and through therapy what are the baseline laboratory investigations TSH and pT4 the target TSH should be less than 2.5 hBNC target less than six prolactin LHFSH ratio fasting insulin when endocrine causes are suspected anti Phospholipid antibodies (entire panel), lupus anticoagulant (anti- anticariolipin) and antibody to GABA protein (should be advised). Parental karyotyping (I have already indicated if there is no fetal tissue and there was a problem indicating a translocation). And of course, a CBC and vitamin D levels are a must. Coming to the imaging part, the preferred sequence is: You start with 3D TVS for causative malformation. Further confirmation is a hysteroscopy (if you rule out any addition or addition syndromes). MRI (if there are complex malformations).

[00:30:52]Histospingography (if other motility is available and you want to check for tubal patency). Also, a genetic testing (if the products of conception are available).

[00:31:01]Chromosomal microarrays can distinguish embryonic aneuploidy from maternal causes. Parental karyotyping is Indicated when recent miscarriage and transduction are suspected. Routine genetic testing of every miscarriage is unnecessary. Until and unless recurrent and structural abnormalities occur, tests for thrombophilia and immunology tests for APS according to the revised SPODO criteria. Inherited thrombophilia testing, NKSLSA, cytokine profiling, sperm DNA fragmentation are not recommended for routine evaluation. However, in high-risk patients, you have to take your own choice. Infection and environmental workup: Screen for genital tuberculosis, chronic endometritis, STDs when clinically indicated. Address the modifiable environmental factors such as smoking and occupational exposure to toxins. Then we go in for targeted therapies.

[00:31:55]Genetic Counselling and Assisted Reproduction: Couples with transfusion should receive genetic counselling. Options include natural conception, the prenatal diagnosis and IVF with PGT, SR, surgical correction, septum rejection, Adrenaline/ Polybectomy under hysteroscopic examination. Significantly improves the low birth rate. Endocrine/metabolic management (Mefomin/PMOS), weight reduction, thyroid correction, etc., form the cornerstone of APS therapy. Combination of lodosulfame K, aspirin, and LM-WA from conception till 36 weeks of pregnancy is strongly recommended.

[00:32:34]Vaginal and oral support is also now available. RCOG also now says it can be given. Vaginal and oral therapy will reduce the risk in women with prior early losses. Evidence remains for moderate treatment of chronic endometritis and tuberculosis, for which appropriate antibiotic and anti-tubercular therapy, wherever indicated, should be started. Now just a brief about some of the new emerging treatments Corticosteroids Low molecule weight heparin I have already talked about it Vitamin D we are giving but it can be given up to 40 units a day Intravenous immunoglobulins 400 mg every one to three weeks If they have been more than four losses it is continued every four weeks during pregnancy till 32 weeks of devastation with a dosage of 400 mg per kg body weight Hydroxychloroquine 200 to 400 mg It can be continued It is continued till 32 weeks beta hCG is positive. The therapy is has some followers and some non- followers where the we inject the lymphocytes from the male partner to induce maternal immune tolerance around 80 to 100 ml of male partner blood sample collected WBC prepared injected subcutaneously into the female partner. This corrects the TH one TA to imbalance. IV lipids in a dose of 100 ml of 20% infusion during the treatment cycle than trachomatis 2 to 4 mg daily starting from 2 to 3 days before the embryo transfer until serum beta hCG levels are positive GSSF to improve the endometrial thickness and alpha thecin alternate day dosing starting from the treatment and it is continued till the embryo transfer now once she becomes pregnant how do you monitor her early ultrasound at 6 to 8 weeks serial beta hCG if viability is uncertain screening for diabetes at gestation at first week and repeat at 24 to 28 weeks and growth and doctor scan at 20 weeks besides all this a very important part is the supportive and empirical care the psychosocial and patient centered care so based diagnostics and therapy light of modern RPL management patient centered care couples ofon Experience Grief Guilt Fear of future loss Repeated investigations without any clear answers can deepen the distress Here, clinicians must validate emotional experiences Avoid dispassionate reassurances Communicate results and uncertainty Transparently engage both partners in decision-making Coordinate multidisciplinary inputs (Reproductive Endology, Psychology, Genetics) They must all be involved Provide culturally appropriate counseling in society Where motherhood is defined Social identity Empathetic communication Phrases: It was not your fault You still have a strong chance of success Carry as much therapeutic value as a medical prescription What is the future direction? The landscape of RPL is shifting towards prevention and prevention Emerging fronts include genomic and transcriptomic profiling of the endometrium to Identify implantation failure pathways Endometrial microbiome analysis to detect dysbiosis link to chronic inflammation AI models predicting recurrence risk and guiding personalized management Stem cell and regenerative therapy for post-infection of fibrotic endometrium Global and Registries to Strengthen the Epidemiological Data and Generate Region- Specific Protocols Which is So What Are the Key Changes Based on Recent Updates ASRE 23 RCG Green Top Guideline 17 and ASRM More Refined Evidence Base Recommendations Have Come Up Strong Stands Against Over Testing They Have Reaffirmed That No Natural Killer Cells Cytokine HLA Routine Through Testing Is to Be Done There Is a Shift in the Definition That You Start Investigation After Two Losses Evaluation for Adenomyosis Is the New Addition Male Factors Have Been Norm Highlighted Lifestyle In Med Partner Smoking Obesity Alcohol Should Be Too Progestation Is Getting a Sting Support Genetics Becoming Central Look for Employee ID and POC Testing Progressive Base Counseling Move Towards Reassurance Medicine Focus on Supportive Care Supportive Care Conics Strongly Reject IVIG Steroids Intralipids Emergency Anticoagulation So Conclude What You Should Change in Practice Now Start Evaluation After Two Loss Avoid Unnecessary Tests Counsel Strongly It Leads to Good Prognosis Focus on APS Uterus Genetics and Thyroid Use Prostone Selectively Emphasize on Supportive Care Again and Again Supportive Care Dedicated RPL Clinics Lifestyle and It Should Be a Couple Based Approach Both Should Be Counsel Simultaneously Recent Pregnancy Loss Is No Longer a Journey of Uncertainty Alone It Is a Space Where Science Meets Sensitivity Our Role Is Not Just Two Investigate and treat but to restore hope and that perhaps is the most powerful therapy we can offer to our patients thank you so much RPL may be recent but fortunately so successful when we get it right wonderful I think it had been an absolutely exhaustive presentation of years I would like now to my two experts to be giving absolutely practical tips from their own experience first coming to doctor Renu Mishra what is in your practice you will see to it based on history that what investigation needs to be done and you know what is your you know way of treating such patients based on TLC doctor Renu Mishra thank you ma'am first of all thank you doctor Deepti for such an exhaustive presentation if I were to summarize it for clean then I would say the most common cause is genetic how what percentage you can assign a genetic cause depends on how extensively Use genetics so we moved from karyotype to micro array but micro array also shows only aneuploidy similarity and imbalance transport so there was a study done on aneuploid embryos when they applied whole genome sequencing they found that so many of the embryos had monogenic variants which could explain pregnancy loss. So genetics is probably 70% I am underlying rough figures 10% eucrine cause 10% humanological cause and 10% is you know little significator and there can be affected. In fact, I read an editorial a few years ago. Maybe it was a little exaggerated, but it's the personal view of the editor that if you did proper genetic testing, then only 5% of recurrent pregnancy losses are actually unclean, 95% can be explained, so maybe it's slightest, but I would still say at least 70% can be explained, so coming to treatment, of course, like genetic causes, of course, you know, we need to go for genetic counseling, and now days, we can do a lot on genetics, also to make noise that the next pregnancy goes further and ends up in a live boot [nasal sound] because we all no longer apply, but ma'am was asking about my experience, so I just wanted to say, all I have not published is this, but in my experience when abortion happens in the second trimester, and you Might find like suddenly on ultrasound you find a missed abortion at 12 weeks or 18 weeks and I have had this in the last whatever 30-40 years, maybe six patients and all the patients actually had some due to thrombophilia, I know that it is no guideline recommends that you should do it but from my own experience now if a pregnancy loss is more than 10 weeks I always do thrombophilia pain and I have found that the most commonly affected protein is low levels of CNS and when I give them low molecular weight happens of course people give anyway then I could take them to full term life base so that is my experience the other thing what we should sort of evaluate should not be done the kind of test like torch lot of people still keep doing torch fancy immunological test which doesn't guide us What is to be done? We just do all these expensive tests. Still, you know, we're doing the same thing, still giving them, just progestin, and it may be, of course, it depends on how courageous the evidence is. Because people give intravenously, people give IBIG. There are few indications IBIG which have come in decent richer and may be helpful, but it is used pretty sort of without good evidence.

[00:41:57]So, like I said, what should not be done is very clear thyroid antibodies on their own. They do not increase pregnancy loss. If it's a young thyroid patient, vitamin D may help.

[00:42:10]Again, can't be. It's so difficult to actually pinpoint and make such a single factor, like this, so okay, vitamin D deficiency is causing absorption. So, because you know, like millions of people tested for vitamin D, still have babies without a problem? Because vitamin D is low, we would like to be.

[00:42:28]Vitamin D and many other things like lifestyle and all this I am saying they contribute even the EDC in the environment they contribute but our problem is that they are so difficult to quantify and how do we know that this is the cause so we need to focus on causes that we can identify we can reproduce and we can treat effectively scientifically that is all I can think of thank you doctor Renu Mishra your experience is rich and I think I am glad that you share about thrombophilia in your own practice I will ask now doctor Doctor Arora you have a large practice of infertility in IVF share your own personal experience what investigations you love and what treatment you strategize and do you know madam mentioned about the new trends emerging as but the treatment part is concern your own experience thank you mam so doctor Deepti it was a wonderful talk first Of all and I I think it was everything was considered and discussed. So very exhaustive talk which covered every aspect of RPL. So as you mention in your concluding slides also after two abortions it is high time now that you know like every pregnancy actually is we start investigating.

[00:43:59]So I will you know do some subheadings like for the benefit of my audience whenever a case of RPL comes then we have to look at whether it looks like gamemate is the cause just to make it simple if gamemate is a cause is is it going towards the female side or is it going towards the male side? If the cervix sample looks compromised, it always does have DFI and sometimes DFI really turns out to be very high. It may be in the range of 50 to 60%. Not only in smokers, but in obese males as well as in diabetic males, sometimes we find very high DFI, which may be a pointer towards male factor. If we feel it is the higher female age which is leading on to recurrent abortions, then yes, if the patient is adamant on using her own eggs, in IVF practice, we can always do PGTA. As Dr. Deepti said, there is no strong clinical evidence, but if you look at all the reasons of doing PGTA, then recurrent abortions is one of the reasons that we can go for this than gametes. You know when we talk of gametes, it is a cause of recurrent pregnancy loss than karyotype also. Comes in picture. So what doctor Renu talked about whole genome sequencing rather than karyotype that is in concern to the PGTA she is saying but for partners male and female partners karyotype we can not miss in such cases because there had been so many cases of structural rearrangement trans locus which we have solved and I am sure all people who are practicing this PGTSR is the word we do structural rearrangement testing PGTSR and and if it is balance translocation you can still use it. If it is an abnormal translocation then that embryo is not to be used and that clearly may be a reason for recent pregnancy loss in that patient.

[00:46:04]As far as gametes is concerned we move on to donor eggs in case the egg is on the higher side and the gamete female gamete is looking like the cause. Then coming to the uterus. So, gametes as a cause then uterus as a cause. So a very good 3D ultrasound done in good hands does a very nice job as far as looking at the uterus is concern and based on there doctor deepthi said genital tuberculosis i have seen cases of genital tuberculosis i am sure all of us have seen having recurrent abortion because pregnancy is not supported well and there is an infection. So people keep on the lady will keep on aborting.

[00:46:46]So that is always to be looked into and then comes the immunology and what our body has certain factors. So there is the role of Hb A1c thyroid antiTPO antibodies.

[00:46:59]I always do as far as natural killer cells ah TNF alpha all this is concern I'm not doing that but there are few cases of recurrent pregnancy loss. I would like to share this experience here on this platform. I have a patient who was aborting a euploid embryo at seven weeks each time and then when she was told that you know surrogacy can be an answer for you because it is a euploid embryo which you are aborting, she refused. And then she got help by lid therapy. So already there is no strong evidence but you can always individualize your cases and why I remember this case because yesterday only at 37 weeks she happened to deliver in LaFame Hospital so there are no therapies we can't endorse on this platform I agree with this but once in a while they are helping as far as IVIG is concerned I am not using it even alpha thymosin which is coming up with the big bang which they say that it is mainly for recurrent implantation failure but also can help in recurrent pregnancy losses.

[00:48:13]I haven't yet used it as well. But yes in recent pregnancy losses I do give ah some empirical therapy which I don't know whether it is helping or it is again tender love and care. So I do give them Intralipid therapy. Again no strong evidence. I agree but I am giving Intralipid in a very small dose in IVF cases on the day of embryo transfer and I am adding on a very small dose of steroids as well and these patients sometimes they are helped. Now look at the endocrine problems like PMOS PCOS earlier. So you know my experience is if the patient was having this metabolic issue with may be HPNC on higher side and sugar fasting on higher side insulin intolerance is suggested in those cases get help even by metformin also so these are few things which we can say that yes no strong evidence but in individualized cases they help especially in insulin tolerance this is going to help so this is how we should categorize is the different reasons and should try to reach at you know may be we are able to treat many cases out of some cases we are able to find the cause. Sometimes in ah recurrent pregnancy losses. Especially with the history of previous DNCs, it is a good idea to put it in a hysteroscope. And look at the cavity. And so many times the 3D scan comes out to be normal. Even in experienced hands, there can be some reason which you can find while hysteroscopy is done. So this is my line of you know management and a karyotype and balance translocation unbalance translocation cases I have done plenty of such cases and we have given pregnancy after PGTSR to such couples.

[00:50:05]Over to you ma'am. For your feedback you know what we find is that recent abortion had been a problem 15 years back but I think you know some how all of us have devised ways and methods that we can give a life pregnancy to most of the patients because of tender love and care and the scientific innovation which has come I will take three to four things one thing in reason I find good number of patients have to do this so as a routine we even if there is a blighted ovum repeatedly also we get works testing done and we find you know some how the results if they are positive you treat them it is good as well as the emerging treatments are a concern let me just share with you lid therapy had I was very fond of doing lid therapy but when people like me reached National Medical Council my husband said this is a high time you should stop it. If someone tells you to do this unscientific thing. But I will never say that it was unscientific. In my experience, majority of the patients who had Lit therapy definitely had a successful pregnancy. And I am definitely fond of taking lomalik weight heparin wherever I definitely smell that there is a problem of thrombosis especially in till 12 weeks of pregnancy. I am found of giving IBIG every three weeks and lately on the request of Brigadier Sharma I have started giving Hydrochloroquine I think that is also effective. So I think you know all four of us have opened a Pandora's box to everyone and the people who are listening must have made up their minds because they are already experts. So thank you very much Doctor Deepti and Doctor Doctor Mishra as well as Doctor Aruna you have made a great contribution I think you know we are very thankful for the same for solving this complicated problem people should go with the message whatever it may be you have if you go to the competent doctor you have a good chance of 50 to 60% to have a life baby whatever it may be so thank you everybody thank you very much last minute and last minute Doctor Mishra you want to add one thing and Doctor Aruna add one thing one sentence I think like Sunita was saying we have to look at the case individually and see but I still feel like recent pregnancy loss and recent implantation failure are basically spectrum of the same problem so still like for RF like we say the embryo is the mostant and then the uterus similarly I feel for accent Pregnancy loss is the most important so what I was talking about was genetic testing was not on the PBT but on the POC that if we find out we can at least explain to the patient and it gives a lot of reassurance that it was not a problem with her and her uterus and that the embryo was abnormal and that is what led to the pregnancy loss. So it is a lot of consultation when you can find a cause even if you can't Fee Wonderful Doctor Deepti Last sentence from you Closing Ma'am I think that you need to give them lot of time. So a dedicated clinic calls them at a separate time. Sit with them go to the entire history and many times just a history and an examination will give you a reason or a hint that it is where you need to focus upon. So a lot of time needs to be given and yes you not only not only you should give I think your staff should also be very curious and smiling as well Sachish so thank you very much thank you very much ok thank you so much ma'am today's discussion highlighted the importance of updated clinical understanding ma'am so on before of IGCP ma'am I extend my sincere thanks to everyone ah for joining us and being a part of this meaningful academic discussion ma'am. Let us continue working towards more compassionate, evidence-based, and patient-centered reproductive health care.

[00:54:28]Thank you everyone and wishing you a healthy and hopeful evening ahead. Thank you. Thank you.