A Brief Overview on Female Infertility, It's Causes and Diagnostic Approaches

Female infertility is the major disorder which has altered the man kind foe lack of conception and reproducibility, stressful world, excess radiation, lack of biological food, genetically disorder ,changing life style, increased electronic discharge have resulted the female infertility. Infertility/ childlessness cause great personal suffering & distress. Most of this agony & misery is hidden from the public gaze. That is the reason this topic is not discussed about openly. The dismal ignorance & neglect about the causes of childlessness and its treatment are main reason for the lack of public support for childless couple. Female fertility can be limited or diminished or destroyed in a number of ways. Women have a finite number of germs cells and follicles that are available for a limited period, from menarche to menopause, during their lifetimes. The process of ovulation is mediated by the interactions of hypothalamic, pituitary and ovarian hormones. Interference with ovulation can occur at any one or combinations of these sites. The oviducts can be distorted or blocked by the consequences of endometriosis or infection. The quality of the ova and spontaneous pregnancy decreases steadily with age. Drugs are available that stimulate ovulation and donor eggs can be used. The cryopreservation of ova or ovarian tissue is technique now receiving research attention. Diagnosis is straightforward when causes are severe and laparoscopy is still the preferred method for assessing for tubal factor infertility and endometriosis. IVF remains the dominant treatment, although traditional measures still have a major role. Internationally, IVF opportunities are limited in view of cost. About 10 -15% of couples experience some difficulty with fertility. Remedies range from a visit to a primary physician, education and adjustments in timing attempts to conceive, to placing the entire reproductive process in the hands of specialist.The purpose of the study is to evaluate existing literature for possible associations between female infertility, infertility-associated diagnoses, and the following areas of disease: infertility and mental health significance of the study common factors ,diagnosis methods artificial fertility treatment

ethical issues about Keywords- Infertility, IVF, ART, Endoscopy, Miscarriage

Infertility is a medical condition that can cause psychological, physical, mental, spiritual, and medical detriments to the patient. The unique quality of this medical condition involves affecting both the patient and the patient's partner as a couple. Although male infertility is an important part of any infertility International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 2 discussion, this paper will review the evaluation, management, and treatment of female infertility. One must understand normal fecundability, the probability of achieving pregnancy in one menstrual cycle, to understand infertility. This basic understanding will help the healthcare team properly counsel the patient on referrals and provide basic education and understanding of this medical condition. The research community has established a fecundability rate multiple times, which has helped establish normal pregnancy rates to assist in diagnosing infertility. The largest study identified that 85% of women would conceive within 12 months. Based on this study's findings, fecund a bility is 25% in the first three months of unprotected intercourse and then decreased to 15% for the remaining nine months.[1]This research has helped the American Society of Reproductive Medicine (ASRM) establish when a couple should undergo an infertility evaluation. The ASRM recommends initiating an evaluation for infertility after failing to achieve pregnancy within 12 months of unprotected intercourse or therapeutic donor insemination in women younger than 35 years or within 6 months in women older than 35.[2] INFERTILITY AND MENTAL HEALTH Six studies included in this review evaluated the impact of infertility on mental health. Universally, authors concluded that women with a history of infertility or an infertility- related diagnosis, specifically PCOS, were at increased risk to develop mental health disorders [3]. Four out of the six studies that found correlations with mental health issues used women with PCOS as their primary population [4] Depression risk was found to be elevated in four out of the six studies based on scores from validated scales such as the Edinburgh Depression Scale [5]. Five of the six studies noted significant increases in diagnoses of anxiety or psychosocial distress in the specific study populations [6] The sole study which did not find an increase in anxiety was by Baldur -Felskov et al. This study was a retrospective cohort study published in 2013 that included 98,320 Danish women who were evaluated for infertility between 1973 and 2008, with a median follow up of 11.3 years. Women who sought infertility treatment were tracked through medical registries to determine rates of subsequent psychiatric hospitalizations. While there was no statistically significant increase in hospitalizations related to anxiety in the PCOS/infertile population, it is difficult to assess whether actual levels of anxiety were elevated but simply did not lead to subsequent hospitalizations. A main drawback of the Baldur -Felskov study was the fact that only inpatient hospitalizations were tracked, likely underestimating the true correlation between infertility and psychiatric disease. Importantly, the Baldur -Felskov study did note a significant increase in hospitalizations related to alcohol and drug abuse in the PCOS/infertile population [7] EPIDIMIOLOGY Infertility is a complex disorder with significant medical, psychosocial, and economic problems [8]. Data from population - based studies suggest that 10 -15 % of couples in the world experience infertility [9]. In Africa, its prevalence i s particularly high in sub -Sahara ranging from 20% to 60% of couples International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 3 [10]. It is estimated that female factors and unexplained infertility accounts for 50 -80% while the male factor accounts for 20 -50% of the cause of infertility in different parts of Nigeria [11]. Available evidence suggests that the social consequences of infertility are particularly profound for African women as compared to men[12]. Community based data suggest that up to 30 per cent of couples in some parts of Nigeria may have proven difficulties in achieving a desired conception after two years of marriage without the use of contraceptives [13] SIGNIFICANCE OF THE STUDY Infertile women should seek counseling and consider natural at home options for feelings of sadness, and depression. Not doing anything about it and keeping it to her isn't going to help. Cruel feelings of loss, depression and trauma are so stressful emotionally and psychologically that they can lead to physical manifestations in the body; actually affect physical functions of the body. Once psychological health affects the physical body, the situation gets worse than physical symptoms feed the depression.[14] Infertility is a very real part of millions of people's lives, and all of those going through these deserve to be heard and guided to psychological health support on this cruel journey. In fact, the psychological health aspect of infertility needs to be part of every couple's health plan. Whether a couple decides to continue to pursue parenthood or not, a psych ological health plan must be part of the overall picture.[15] Akker (2005) mentioned that, investigations on infertility are voluminous and have shown that involuntary childlessness can be devastating, and it is associated with psychological distress.[16] Infertility seem to have comprehensive effects in woman's life, it is not only restricted to sexual or reproductive areas of life but also impact burden on several psychosocial areas of human existence.[16,17,18,19] Impairments have been reported regarding distinct aspects, such as relationship abilities, psychopathology, family life, marital life, and economic terms. [20 21 22] Beauty of life for children and we do not have a happy life without them. Deprivation from the grace of reproduction is meaningless life and the couple's relationship getting in the deterioration and lacks stability. If infertility period is prolonged, it put a childless woman in severe pressure on herself, may become depressed and concern for her married life, and sometimes because they have lost the most important role of her creation, moreover her marriage became threatens. These increase Psychological disorders and depression symptoms, especially if the husband isn't a concerted. OPERATIONAL DEFINATIONS Infertility: Infertility, as defined by the World Health Organization, is a disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse, without the use of contraception.[23] Primary infertility: Couples who have been no prior conception after at least one year, having sex without usage birth control methods.[24] Secondary infertility: Couples who have been able to get pregnant at least once, but now are unable to conceive.[24] International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 4 Psychological distress: A state of emotional suffering that may impact on social functioning and day to day living of individuals characterized by symptoms of depression, anxiety, stress and tension.[25, 26] THE MOST COMMON IDENTIFIABLE FACTORS OF FEMALE INFERTILITY  Ovulatory disorders - 25%  Hyperprolactinemia-7%  Pelvic adhesions-12%  Tubal blockage-11%  Other tubal/congenital uterian anomalies-11%  Endometriosis-15% Fig no.1:- Tests for ovulation function. Each of these causes will be further investigated in later portions of this paper. Male and unknown factors are outside the scope of this paper and will be discussed elsewhere. Even though these factors are not discussed here, it is important to realize that male factor infertility represents a substantial portion of the identifiable factors causing infertility. ANOVULATION Disorders of anovulation account for about 30% of infertility and often present with irregular periods (oligomenorrhoea) or an absence of periods (amenorrhoea). Many of the treatments are simple and effective, so couples may need only limited contact with doctors. This makes it easier for a couple to maintain a private loving relationship than in the stressful, more technological environment of assisted conception. However, not all causes of anovulation are amenable to treatment by ovulation induction. Anovulation can sometimes be treated with medical or surgical induction, but it is the cause of the anovulation that will determine whether ovulation induction is possible[27] International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 5 HYPOTHALAMIC-PITUITARY CAUSES:- Hypogonadotropic hypogonadism is characterized by a selective failure of the pituitary gland to produce FSH and LH. The commonest cause is excessive exercise, being underweight, or both. Women who have a low body mass index (BMI), f or example <18Kg/m2 or who exercise excessively, for example gymnasts, marathon runners, ballerinas, may develop amenorrhoea because of a physiological reduction in the hypothalamic production of gonadotropin releasing hormone. Women who are underweight for their height when they get pregnant are more likely to have .small for dates. babies; and children of women who have eating disorders are more likely to be admitted to hospital with failure to thrive. Sheehan.s syndrome (panhypopituitarism), caused by infarction of the anterior pituitary venous complex (usually after massive postpartum haemorrhage or trauma), and Kallman.s syndrome (amenorrhoea with anosmia caused by congenital lack of hypothalamic production of gonadotropin releasing hormone) are rare. Children treated for a craniopharyngioma or some forms of leukaemia may have hypogonadotropic hypogonadism secondary to cerebral irradiation, which may affect the hypothalamus or the pituitary[27] OVARIAN CAUSES:- Polycystic ovary syndrome is the commonest cause (70%) of anovulatory infertility [28-32] The primary abnormality seems to be an excess of androgen production within the ovary[33,34] that leads to the recruitment of large numbers of small preovulatory follicles, which fail to respond to normal concentrations of follicle stimulating hormone[35]. Thus, a dominant follicle is rarely produced. Women with polycystic ovary syndrome commonly present their late teens or early 20s with hirsutism, acne, or irregular periods (cycle length > 35days). Even if they ovulate, the chance of conception for these women is reduced because fewer ovulatory events occur in a given time frame. Obesity is present in varying degrees (30% to 70%) in women with the syndrome and is usually of the central type [36-38]. Central obesity, being a prominent feature of the so-called metabolic syndrome, is directly linked to increased peripheral insulin resistance (IR) [39]. Furthermore, PCOS itself has been shown to confer a risk for insulin resistance, beyond that caused by obesity alone[40] fig no.2:-normal ovary and polycystic ovary International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 6 CAUSES UNSUITABLE FOR OVULATION INDUCTION Premature ovarian failure:-Premature ovarian failure (POF) is the cessation of ovarian function before 40 years of age. The term refers to the condition when the ovaries have lost their germinative and hormonal functions because of the exhaustion of the number of ovarian follicles prior to the typical age for physiological menopause, which in Poland averages 51 years [41]. The physician may encounter this condition when examining a young female patient who is struggling to get pregnant or is experiencing secondary amenorrhoea. In order to make a diagnosis in the case of a young female, it might be helpful to determine if there a re any menopausal symptoms. The medical history of patients with POF usually reveals a normal age of menarche [42 43] and regular menstrual cycles, followed by oligomenorrhoea or sudden amenorrhoea. In some cases, secondary loss of menses is diagnosed after stopping contraceptive pills [44-46]. Most frequently, women suffer from hot flushes, excessive sweating, hair loss, as well as skin and mucous membrane dryness Genetic abnormality -The commonest genetic abnormality is Turner.s syndromeTurner syndrome was first reported as a clinical syndrome (prior to the availability of karyotyping) in seven women with short stature, sexual immaturity, neck webbing, and cubitus valgus in a paper published in 1938 by Henri Turner, an Oklahoma physician [47]. However, Otto Ulrich had already described an eight-year-old girl with a similar phenotype several years earlier [48]. Turner syndrome is the most common sex chromosome abnormality in females and occurs in approximately 1 in 2000 to 1 in 2500 live female births, based on epidemiological and newborn genetic screening data from Europe, Japan, and the United States [49 -51]. The true prevalence of Turner syndrome remains difficult to ascertain because patients with a milder phenotype may remain undiagnosed. Some indiv iduals are not diagnosed until late adulthood if their phenotype is mild [52]. Turner syndrome occurs with more or less the same prevalence in all ethnic groups and in different countries. However, the prevalence at birth may be declining in some countries. This is related to the increased use of ultrasonographic screening prenatally and the fact that some mothers carrying fetuses with Turner syndrome choose to terminate the pregnancy [53 54] . On the other hand, most gestations (likely more than 99 percent) affected by X chromosome monosomy (45,X) do not survive to birth. The 45,X genotype is found in at least 10 percent of all spontaneous abortions [55-59]The diagnosis of TS could be obtained prior to birth using prenatal diagnostic testing such as chorionic villus sampling or amniocentesis. Using those tests, an analysisof the fetal chromosomal structure would defiantly confirm the diagnosis. TS should be clinically suspected in thepresence of prodromal symptoms. For example, thepresence of fetal hydrops, cystic hygroma, or cardiac defects on a prenatal ultrasound would raise the suspicionof TS [60 61]. Post-delivery karyotype testing is often required to confirmthe diagnosis. In cases where the TS is a result ofmosaicism, karyotype can come back normal. If a high suspicion of TS remains despite a normal karyotype,fluorescence in situ hybridization analysis can offer an additional modality to the karyotype [60].Later in life, patients with TS who went undiscovered might present with developmental abnormalities such asthe delayed onset of puberty or amenorrhea. A high concentration of the follicle - stimulating hormone is highlyindicative of TS. Anti-Mullerian hormone offers a highlysensitive marker for ovarian failure prediction [62 63]. International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 7 OVULATION INDUCTION Treating specific causes Waight change -Weight reduction through dietary modification and exercise is recommended for overweight PCOS patient [64]. Some studies show that over 10% of women with PCOS will regain spontaneous ovulation when placed on low calorie, low -fat diet, and exercise or with surgery. The aim of dietary restriction and exercise is toward losing about 5 –10% of their body weight. This form of treatment alone or in combination with pharmacologic agents would reduce insulin resistance and is advocated for overweight to obese women of BMI > 24 [64]. The drawbacks of this method of treatment are that such women lack the motivation to remain on diet and exercise, and may not be able to achieve the desired weight loss to trigger spontaneous ovulation, and most times pharmacologic agents are added to assist ovulation. The duration it takes to achieve the desired body weight to bring about ovulation is not defined, but differs among patients. Other drawbacks are that it may not trea t anovulation in normal-weight women even though they also have insulin resistance as well. The advantage is that it is cost -effective and will not produce any form of drug reactions. It will also reduce the high level of luteinizing hormone and reduce early pregnancy loss. A combination of lifestyle modification with weight loss before pharmacologic ovulation-inducing agents improved ovulation and live birth in women with PCOS in a USA study [65] and in addition, required lower doses of pharmacologic agent for ovulation induction. HYPERPROLACTINEMIA The prevalence of hyperprolactinemia ranges from 0.4% in unselected normal adult females to as high as 9%–17% in 1,2 females with reproductive health disorders. Its prevalence was found to be 5% in a family planning clinic, 9% in women with adult -onset amenorrhea, and 17% among women with 1 polycystic ovary syndrome.[66] Diagnostic evaluation -For the correct identification of the etiology of hyperprolactinemia, some parameters must be taken into accoun t: medical history, physical examination, clinical features, laboratory findings (especially PRL serum levels), as well as imaging studies of the pituitary and sella turcica. Furthermore, the screening for macroprolactinemia should often be considered. In addition to PRL determination, TSH, free T 4 , and creatinine levels should be obtained to rule out secondary causes of hyperprolactinemia[67 68 69]. Moreover, acromegaly must be investigated by means of IGF -1 measurement in all patients with a macroade nomas, even though there are no manifestations of this disease[70]. Finally, b-hCG measurement is mandatory in any childbearing woman with amenorrhea[67 68] Hypothyroidism-WHO estimates the overall prevalence of primary infertility in India to be 3.5 - 16.8%.2 Both hyperthyroidism and hypothyroidism have profound effects on estrogen and androgen metabolism, menstrual function and fertility [71] They may cause delayed onset of puberty, menstrual abnormalities, anovulatory cycles, miscarriages and infertility.[72]Hypothyroidism can be easily International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 8 detected by assessing serum thyroid stimulating hormone (TSH) levels. A slight increase in TSH levels with normal T3 and T4 indicates subclinical hypothyroidism whereas high TSH levels accompanied by low T3 and T4 levels in dicate clinical hypothyroidism. Elevated thyrotropin- releasing hormone levels due to hypothyroidism are often associated with increased prolactin (PRL) levels and a delayed LH response to GnRH. [73] Thyroid dysfunction is implicated in abroad spectrum of r eproductive disorders, ranging from abnormal sexual development to menstrual irregularities and infertility.[74] It has been proved that for normal sexual function, thyroid secretion of T3, T4 need to be approximately normal. We had conducted this study to collect some specific information regarding hypothyroidism in infertile women and to assess their responses in treatment procedures. Diagnostic evaluation -Thyroid d ysfunction is a common cause of infertility which can be easily managed by correcting the appropriate levels of thyroid hormones.[75 76] It has been recommended that in the presence of raised TSH along with raised PRL levels, the treatment should be first to correct the hypothyroidism before evaluating further causes of hyperprolactinemia. Hormone therapy with thyroxine is the choice of treatment in established hypothyroidism. It normalizes the menstrual cycle, PRL levels and improves the fertility rate. Therefore, with simple oral treatment for hypothyroidism, 76.6% infertile women with hypothyroidism conceived after 6 weeks to 1 year of therapy. We tried to maintain normal TSH levels; compliance and adequacy of hypothyroid drug dose were checked by TSH measurement after 6 to 8 weeks interval. Therefore, the normal TSH levels are the pre -requisite requirements for fertilization. The decision to initiate thyroid replacement therapy in subclinical hypothyroidism at early stage is justified in infertile women. Our data also indicate that variations in TSH levels in the narrower range or borde rline cases, i.e. 4 –5, 5 –6, and >6.0 μIU/ml, should not be ignored in infertile women which are otherwise asymptomatic for clinical hypothyroidism. This group of infertile women, if only carefully diagnosed and treated for hypothyroidism, can benefit a lot rather than going for unnecessary battery of hormone assays and costly invasive procedures. For better management of infertility cause, we should plan further studies with the large sample size and long -term follow-up which are necessary to validate the variation in TSH and PRL levels. PELVIC ADHESION In the case of pelvic inflammatory disease, or any other infection of the reproductive tract, the fallopian tubes can become inflamed. The inflamed surfaces can develop scar tissue or adhesions within the tubes. These adhesions prevent egg and sperm from coming together.[77]Adhesions caused by endometriosis usually occur in the pelvic cavity. They may be present near the fallopian tubes or ovaries. Endometrial adhesions may interfere with ovulation.[78]Sometimes, endometrial adhesions prevent the fallopian tube from moving naturally. The ovary is not attached directly to the fallopian tubes. During ovulation, when an egg is released from the ovary, it must find its way into the fallopian tube If adhesions interfere with the fallopian tubes natural movement, an egg may not make it into the fallopian tube.[79] This decreases fertility. International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 9 Diagnosis-If the adhesions are within the fallopian tubes, surgical repair may be possible.[80]However,IVF treatment may be more successful and cost-effective.If Asherman‟s syndrome is the cause of infertility, the adhesions may be removed during an operative hysteroscopy. You may be able to conceive naturally afterward, or you may require fertility treatment in addition to surgery.[81]In the case of pelvic adhesions or endometriosis, removal of the adhesions may reduce pain and may improve the odds of pregnancy success. However, depending on the situation, you may still need IVF or fertility treatment after surgery.[82] TUBAL BLOCKAGE-Blocked fallopian tubes are a common cause of infertility. Sperm and an egg meet in the fallopian tube for fertilization. A blocked tube can prevent them from joining.If both tubes are fully blocked, pregnancy without treatment will be impossib le. If the fallopian tubes are partially blocked, you can potentially get pregnant. However, the risk of an ectopic pregnancy increases.This is because it‟s harder for a fertilized egg to move through a blockage to the uterus. In these cases, your doctor might recommend in vitro fertilization (IVF), depending on whether treatment is possible.If only one fallopian tube is blocked, the blockage most likely won‟t affect fertility because an egg can still travel through the unaffected fallopian tube. Fertility drugs can help increase your chance of ovulating on the open side HYSTEROSALPINGOGRAPHY (HSG): The diagnosis of tubal patency based on radiologica lfindings is not considered a complete or an absolute diagnosis. X-ray gives an idea about the size and shapeof the uterine cavity, the isthmus and the cervical canalwhen viewing anteroposterior or profile films. [83] HSG iswidely used and has some advantages, including thelack of need for anesthesia, relative speed with which the procedure is completed, and a potential therapeutic effect with oil soluble contrast media.[84] The therapeutic impact of HSG is, in part, due to the flushing of tubal debris. In addition, in-vitro studies have shown that oil- based flushing media prevents peritoneal mast cell phagocytosis of spermatozoa and increases fecundity in subfertile mice. A pathognomonic finding on HSG is seen with SIN, in which the contrast filled diverticular projections result in a radiographically honeycombed appearance.[85]Hydrosalpinx also has a characteristic appearance; however, transvaginal ultrasound better evaluates the volume of the dilated tubes.[86] HSG findings can be used to stage tubal disease and the appearance of the intraluminal mucosal architecture as a rugal pattern is a good prognostic factor forsubsequent pregnancy.[87 88] A potential limitation of HSG is tubal spasm, especially with elevated contrast injection pressure. Based on hysteroscopic tubalcannulation, it has been estimated that HSG may give a false positive diagnosis of proximal tubal obstruction 50 % of the time. [ 8 9 ] Lower pressure, the use of spasmolytic agents, such as glucagon, diazepam and terbutaline and follow -up imaging to assess contrast spillage following resolution of spasm have been proposed. [ 9 0 , 9 1 , 9 2 ] . However, intermittent tubalobstruction during HSG may suggest underlying tubal pathology, especially in the setting of low injection pressures, and thus the value of spasmolytic agents may be limited.[90] Furthermore, the efficacy of these agents with respect to reversal of tubal spasm remainsto be established.[93 94] A recent study suggested thatunilateral cornual obstruction may be resolved in International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 10 morethan 50% of patients by rotating the patient so that theobstructed tube is in a more inferior position.[95] Fig no.3:-hysterosalpingogram ENDOSCOPIC EVALUATION When managing a woman with infertility, it is important to avoid missing the correct diagnosis and treating a woman empirically for having an unexplained infertility, while existent tubal pathology might benefit of surgery. HSG has been considered as a screening test for tubal pathology, making only abnormal results an indication for laparoscopy to confirm the diagnosis, exclude artifacts resulting from transient tubal contractions and undergo a fertility -enhancing surgical intervention. However, many authors have stressed on the relative low sensitivity and the false negative rates when using HSG alone. Compared to laparoscopy, HSG has a sensitivity of 40 to 70% in the detection of bilateral tubal occlusion[96]Contrast intravasation into uterine and ovarian veins can be mistaken for tubal filling, with a false negative rate reaching 50% in proximal tubal occlusion, and 60% in distal tubal occlusion[97]Laparoscopy with direct visual examination of the pelvic anatomy is the ideal method available to diagnose tubal and peritoneal abnormalities that may impair fertility, in contrast with HSG which can miss pelvic adhesions and endometriotic implants [98] When it was first implemented, laparoscopy was suggested as a mandatory step to rule out the existence of eendometriosis and peritubal adhesions as a cause of infertility, even when tubal patency with free spillage of injected dye has been demonstrated by HSG [99]great difference in the rate of abnormal findings was noted at that time between laparoscopy and the other noninvasive tests. In 1975, the first published paper concluded that laparoscopy frequently identifies a possible cause of infertility in women whose failu re to conceive has remained unexplained by other methods of investigation[100]The majority of these lesions are endometriotic ones, with accompanying tubal adhesions found in 20% of cases. Unilateral or bilateral tubal occlusion could still be found as well in a minority of cases[96]Fallopian tubes can be patent under high pressures but dysfunctional physiologically [101]such abnormalities can be corrected during laparoscopy using neosalpingostomy, increasing therefore the pregnancy rates both spontaneously and with IVF [102] International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 11 Fig no 4:-laproscopy CONGENITAL UTERINE ANOMALIES Congenital uterine anomalies result from the abnormal differentiation, migration, fusion, and subsequent canalization of Mullerian ducts during embryogenesis [103]. They have been reported to be implicated as a potential cause of reduced fertility and miscarriages [104 -106]. Basing on anomalies in the embryological development process, the uterine malformations can be divided in unification defects of the Mullerian du cts (unicornuate, bicornuate or didelphys uterus), canalization defects for incomplete resorption of the midline septum (sub - septate or septate uterus), Mullerian agenesis and arcuate uterus [107]. Data from literature, demonstrated that the aforementioned anomalies are present in 1-10% of unselected population, 2 -8% of infertile women and 5 -30% of women with a history of miscarriage [108]; however, the prevalence rate is uncertain due to the application of several diagnostic methods such as hysterosalpingography, hysteroscopy, laparoscopy, magnetic resonance imaging and three- dimensional sonography. In the same view, the use of three different classification systems developed by the American Society of Reproductive Medicine (ASRM, 2006) [109], the European Society of Human Reproduction and Embryology (ESHRE, 2013) and the European Society for Gynecological Endoscopy (ESGE, 2013) does not permit to establish a unique consensus about the prevalence of these malformations [104]. Moreover, uterine anomalies are often asymptomatic and accidentally diagnosed during ultrasounds for other gynecological pathologies, assessment of tubal patency or pregnancy [110 111]. Moreover, they may also be recognized at delivery during spontaneous or cesarean section [112]. The presence of congenital uterine alterations represents a potential cause of infertility, recurrent pregnancy loss, preterm delivery, fetal malpresentation as well as small -for-gestational age infants, with greater effects being evident in women with more profound defects [113] International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 12 Fig no 5:-uterian anomalies Diagnosis-As most CUAs are asymptomatic, the majority of them are detected incidentally. A significant proportion of anomalies are diagnosed during fertility investigations. Accurate diagnosis and correct classification help in the appropriate counselling of women about their potential reproductive prognosis and risks and for planning any intervention with a view to improve the reproductive outcome. Evaluation of the internal and external fundal contours of the uterus is the key in making a diagnosis and correctly classifying a uterine anomaly. Considering this, the gold standard test has been the combined laparoscopy and hysteroscopy, albeit invasive, in the past. Imaging modalities such as ultrasonography, hysterosalpingogram (HSG), sonohysterogram and magnetic resonance imaging (MRI) are less invasive modes of screening and classifying various uterine anomalies[113]. While conventional 2D tran svaginal ultrasound (TVS) and HSG are considered as good screening modalities, 3D TVS and MRI can accurately diagnose and classify the types of CUAs[114 115], as they can define both external and internal uterine contours. ENDOMETRIOSIS:- Endometriosis is defined as the presence of endometrial glands and stroma like lesions outside of the uterus[116]. The lesions can be peritoneal lesions, superficial implants or cysts on the ovary, or deep infiltrating disease[117]. While there is no definitive etiology of endometriosis, there are several hypotheses regarding how endometriotic lesions develop. One possible mechanism is retrograde menstruation, a feature of the menstrual cycle in women and non-human primates, which is an outflow of the endometrial lining thr ough the patent fallopian tubes into the pelvic space. This retrograde flow, along with potential hematogenous or lymphatic circulation, may result in the seeding of endometrial tissue in ectopic sites. However, retrograde menstruation is common (perhaps universal among menstruating women) while endometriosis is much less common. Therefore, other factors, such as hormonal, inflammatory, or immunologic milieu may determine whether lesions deposited in the pelvic International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 13 cavity implant and persist [118–121]. Alternati vely, endometriosis lesions may arise from Müllerian remnants that did not properly differentiate or migrate during fetal development or from circulating blood cells that transdifferentiate into endometriosis [122–124]. Similarly, the characteristics of the local environment would influence the maintenance of these endometriotic lesions. When considering these etiologic hypotheses, it is important to recognize that endometriotic lesions are antigenically similar to eutopic endometrium but not necessarily endometrium. Endometriosis affects 10–15% of all women of reproductive age [116] and 70% of women with chronic pelvic pain [125]. Unfortunately, for many of these women there is often a delay in diagnosis of endometriosis resulting in unnecessary suffering a nd reduced quality of life. In patients aged 18–45 years, the average delay is 6.7 years[126]. As most women with endometriosis report the onset of symptoms during adolescence, early referral, diagnosis, identification of disease and treatment may mitigate pain, prevent disease progression and thus preserve fertility[127–129]. Barriers to early diagnosis include the high cost of diagnosis and treatment in adolescent patients and presentation of confounding symptoms such as cyclic and acyclic pain. Thus, a non-invasive tool to diagnose endometriosis could facilitate earlier diagnosis and intervention that could ultimately improve quality of life and preserve fertility Fig no.6-Endometriosis MEDICAL INDUCTION Pulsatile gonadotropin releasing hormone :-The pulsatile release of GnRH and LH plays an important role in the development of sex function and in the normal regulation of the menstrual cycle. In 1970, Dierschke et al. first observed LH pulses in the ovariectomized monkey[130]. Later studies also showed this phenomenon in the human and rat. This LH pulse is produced by a corresponding GnRH pulse from the hypothalamus [131]. Both the frequency and amplitude of the GnRH pulse are critical for normal gonadotropin release [132]. One reason for the GnRH secreti on in a pulsatile manner is to avoid the down-regulation of the GnRH receptor in the pituitary. In rhesus monkeys with hypothalamic lesions that abolish pituitary gonadotropin release, the constant infusion of exogenous GnRH fails to restore International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 14 sustained gonadotropin secration but intermittent administration of GnRH once per hour reestablishes gonadotropin secretion[133]. Westel et al. showed that intrinsic pulsatile secretory activity was seen in immortalized GnRH neurons indicating that the pulse generator is cell autonomous[134]. Furthermore, it is known that the activity of each GnRH neuron is synchronized in vivo and immortalized GnRH neurons will spontaneously synchronize in perfusion culture[135] Even though pulsatility of GnRH is recognized as a major d eterminant for differential gonadotropin subunit gene expression and gonadotropin secretion, very little is yet known about the signaling circuits governing GnRH action at the pituitary level. In this article, we review the current knowledge of the role of pulsatile GnRH on pituitary function and reproduction Antiestrogen treatment: clomiphene citrate -Two or 3 days after starting clomiphene administration in the follicular phase of the ovarian cycle, the pulse frequency of LH increases, suggesting that the main action of the drug is to increase pulsatile secretion of gonadotrophin-releasing hormone (GnRH) by the hypothalamus (Sir et al., 1989).Clomiphene could also have a direct oestrogenic effect on the gonadotrophs, enhancing sensitivity to GnRH. As a consequence of the effects mentioned above, there is an increase in plasma concentration of gonadotrophins and in the number of follicles recruited. There is a resulting increase in plasma concentrations of oestradiol before ovulation and of progesterone durin g the luteal phase. Between 30 and 35% of patients who ovulate with clomiphene do so with a follicular rupture diameter that is larger than expected, as compared with spontaneous cycles. Moreover, clomiphene has a direct oestrogenic effect on the ovary, re sembling that described for the pituitary gland. It sensitizes granulosa cells in the follicle to the action of gonadotrophins and up-regulates aromatase activity. Its effects on the cervix and endometrium are mainly anti-oestrogenic The different modulating effects (agonistic or antagonistic) shown by clomiphene on the effectors of the genital tract might be due to the different populations of α - or β -oestrogen receptors in those tissues [136] Clomiphene citrate induces ovulation in the majority of women. The ovulation rate ranges between 70% and 92%; however, the pregnancy rate is much lower. The discrepancy between the high ovulation rates and relatively low pregnancy rates may be due to the following factors: 1. Antiestrogen effects on the endometrium 2. Antiestrogen effects on the cervical mucus 3. Decrease of uterine blood flow 4. Impaired placental protein 14 synthesis 5. Subclinical pregnancy loss 6.Effect on tubal transport 6. Detrimental effects on the oocytes[199] International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 15 Fig.no:7(A) Clomiphene citrate is available as a racemic mixture of two stereochemical isomers referred to as (cis) Zu -clomiphene or the (trans) En -clomiphene confi guration, the former being signifi cantly more potent. In the preparations commercially available, the isomers are in the ratio of 38% Zu- and 62% En-clomiphene. 7(B) The isomeric models in a different confi guration. Gonadotropins:- Patients remaining anovulatory [CC -resistant anovulation (CRA)] and patients failing to conceive during CC treatment [CC failure to conceive (C CF)] are generally treated with exogenous gonadotropins[137]. Recently, it has become more accepted to treat CRA patients with a combination of CC and an insulin sensitizer before treatment with exogenous gonadotropins is started. Individual differences in the daily amount of FSH required to induce ongoing follicle growth and ovulation (the FSH response dose) have been suggested to be the main factor of hyper -responsiveness and severe complications during FSH ovulation induction[138]. This individual variat ion resulted in two different approaches in ovulation induction with gonadotropins. The 'step -up' protocol aims at slowly and prudently surpassing the FSH -threshold to reduce the chances of these complications. However, this approach might result in a prolonged treatment period and late follicular phase FSH accumulation, increasing the risk of multifollicular growth. In an attempt to overcome these problems, the 'step-down' protocol has been developed, which mimics the physiological FSH profile more closely[139]. The FSH starting dose is presumed to be the response dose; hence, dominant follicle growth is established more quickly. Thereafter, the FSH doses can be reduced slowly, resulting in the development of a single dominant follicle[139]. Frequent monitoring of the ovarian response is especially important during the step-down protocol, because the duration of FSH threshold being suppressed determines whether there will be mono-or multifollicular growth[140] . Stimulation is cancelled when multifollicular growth is apparent and more than three follicles >12mm in diameter are present. Metformin:-This drug is used when insulin resistance is a known or suspected cause of infertility, usually in women with a diagnosis of PCOS. Metformin (Fortamet) helps improve insulin resistance, which can improve the likelihood of ovulation.Metformin is administered orally and has an absolute bioavailability of 50–60%, and gastrointestinal absorption is International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 16 apparently complete within six hours of ingestion. Metformin is rapidly distributed following absorption and does not bind to plasma proteins. No metabolites or conjugates of metformin have been identifi ed. Metformin undergoes renal excretion and has a mean plasma elimination half -life after oral administration of between four and 8.7 hours. Food decreases the extent of and slightly delays the absorption of metformin Letrozole:-Letrozole (Femara) belongs to a class of drugs known as aromatase inhibitors and works in a similar fashion to clomiphene. Letrozole is usually used for woman younger than 39 who have PCOS. Bromocriptine:-Bromocriptine (Cycloset, Parlodel), a dopamine agonist, might be used when ovulation problems are caused by excess production of prolactin (hyperprolactinemia) by the pituitary gland[141]

OF REPRODUCTIVE ASSISTANCE Intrauterine insemination (IUI) and ovarian stimulation are part of the initial management of couples with infertility, known as low-complexity assisted reproductive technologies (ART). IUI requires basic supplies and simple training, constituting a low -cost technique, accessible for the majority of couples. However, its effectiveness has not been fully researched. Both, patients and the public in our country, believe IUI is very effective. Some researchers consider IUI as a trivial procedure for certain indications and recommend patients to go directly to high complexity ART[142]Others, point to it as a procedure with potential complications, specifically associated with multiple pregnancies[143] Fig no.8:-intrauterine insemination Intrauterine insemination involves careful coordination before the actual procedure Preparing the semen sample:-Your partner provides a semen sample at the doctor's office, or a vial of frozen donor sperm can be thawed and prepared. Because nonsperm elements in semen can cause reactions in the woman's body that interfere with fertilization, the sample will be washed in a way that separates the highly active, normal sperm from lower quality sperm and other elements. The likelihood International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 17 of achieving pregnancy increases by using a small, highly concentrated sample of healthy sperm. Monitoring for ovulation: -Because the timing of IUI is crucial, monitoring for signs of impending ovulation is critical. To do this, you might use an at-home urine ovulation predictor kit that detects when your body produces a surge or release of luteinizing hormone (LH). Or, an imaging method that lets your doctor visualize your ovaries and egg growth (transvaginal ultrasound) can be done. You also may be given an injection of human chorionic gonadotropin (HCG) or medications to make you ovulate one or more eggs at the right time. Determining optimal timing:-Most IUIs are done a day or two after detecting ovulation. Your doctor or other care provider will have a plan spelled out for the timing of your procedure and what to expect. Fig no.9:-transvaginal ultrasound INTRA UTERIAN INSEMINATION PROCEDURE:- Once collected, the semen sample is then “washed” in the laboratory to concentrate the sperm and remove the seminal fluid (seminal fluid can cause severe cramping in the woman). This process can take up to 2 hours to complete.IUI is performed near the time that the woman is ovulating. The IUI procedure is relatively simple and only takes a few minutes once the semen sample is ready. The woman lies on an examining table and the clinician inserts a speculum into her vagina to see her cervix. A catheter (narrow tube) is inserted through the cervix into the uterus and the washed semen sample is slowly injected. Usually this procedure is painless, but some women have mild cramps. Some women may experience spotting for a day or two after the IUI. IN VITRO FERTILIZATION Techniques that involve manipulation of oocytes outside the body are termed assisted reproductive technology (ART) with in vitro fertilization (IVF) as the most common form. The term „in vitro‟ means outside a living organism as oocytes mature in vivo in the ovary and embryos develop into pregnancy in the uterus, but the oocytes are fertilized in a petri dish. Robert Edwards, Ph.D., and Patrick Steptoe, MD, reported the first live birth from IVF in July 1978 in England. This achievement would later earn Dr. Edwards the Nobel Prize in Medicine in 2010.[144] International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 18 Fig.10:-IUI procedure Since this major breakthrough in the treatment of infertility, the field of reproductive endocrinology/infertility (REI) has progressed rapidly, and IVF now accounts for 1.6% and 4.5% of all live births in the United States and Europe, respectively. [145] Initially developed as a way to bypass irreparable tubal disease, IVF is now widely applied for the treatment of infertility due to a variety of causes, including endometriosis, male factor, and unexplained infertility. Women who cannot use their own oocytes due to primary ovarian insufficiency (POI) or age-related decline in oocyte number can now become successfully pregnant utilizing donor oocyte IVF. TECHNIQUE Controlled Ovarian Stimulation: -Complex endocrine changes happen while a woman undergoes ovarian stimulation as part of IVF treatment. The two main aims of COS are: (a) to create a cohort of developing follicles; and (b) to prevent premature spontaneous ovulation. GnRH agonists are administered intramuscu larly, subcutaneously or intranasally. In the 'long protocol', the initial flare effect of the GnRH agonists is followed by desensitisation and down‐ regulation of the pituitary gland with an internalisation of the GnRH receptors. This protocol is associate d with a higher oocyte number and clinical pregnancy rates, but there is evidence of an increase in the requirement of gonadotrophins compared to a 'short protocol[146]GnRH antagonists act by binding to the GnRH receptors and prevent endogenous release of GnRH from the pituitary gland. GnRH antagonist protocols are associated with immediate LH suppression and decreased gonadotrophin use. As a result, antagonist protocols are associated with a significant reduction in ovarian hyperstimulation syndrome (OHSS) without reducing significantly the live birth rate[147] Oocyte Retrieval:-A needle is passed through the top of the vagina under ultrasound guidance to get to the ovary and follicles. The fluid in the follicles is aspirated through the needle and the eggs detach from the follicle wall and are sucked out of the ovary (see video above). International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 19 The oocyte -cumulus complex is pulled from the follicle wall when we aspirate the fluid through the needle. The procedure usually takes about 10 minutes at our clinic The fluid with the eggs is passed to the IVF lab where the eggs are identified, rinsed in culture media, and placed in small drops in plastic culture dishes. The dishes with the eggs are then kept in specialized IVF incubators under carefully controlled environmental conditions. Embryo Fertilization:-When the fertilized egg divides, it becomes an embryo. Laboratory staff will regularly check the embryo to make sure it is growing properly. Within about 5 days, a normal embryo has several cells that are actively dividing. Couples who have a high risk of passing a genetic (hereditary) disorder to a child may consider pre- implantation genetic diagnosis (PGD). The procedure is most often done 3 to 5 days after fertilization. Laboratory scientists remove a single cell or cells from each embryo and screen the material for specific genetic disorders. According to the American Society for Reproductive Medicine, PGD can help parents decide which embryos to implant. This decreases the chance of passing a disorder onto a child. The technique is controversial and not offered at all centers. Embryo transfer -Embryos are placed into the woman's womb 3 to 5 days after egg retrieval and fertilization.The procedure is done in the doctor's office while the woman is awake. The doctor inserts a thin tube (catheter) containing the embryos into the woman's vagina, through the cervix, and up into the womb. If an embryo sticks to (implants) in the lining of the womb and grows, pregnancy results.More than one embryo may be placed into the womb at the same time, which can lead to twins, triplets, or more. The exact number of embryos transferred is a complex issue that depends on many factors, especially the woman's age.Unused embryos may be frozen and implanted or donated at a later date. Fig no.11:-ivf process International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 20 INTRACYTOPLASMIC SPERM INJECTION(ICSI) intracytoplasmic sperm injection(ICSI) was introduced in 1992 to improve fertilization in couples with male factor infertility undergoing in vitro fertilization (IVF) or in couples with fertilization failure in a prior IVF cycle without detectable abnormalities of semen parameters [148-150]. Although the diagnostic criteria used to identify male factor infertility fail to predict with perfect accuracy poor or absent fertiliza tion in assisted reproductive technology (ART) [151–154], studies to date support the safety and efficacy of ICSI to treat various male factor conditions. The use of ICSI for patients with borderline or even normal semen parameters has become more common[155 156] Fig no.12:-intracytoplasmic sperm injection ASSISTED REPRODUCTIVE TECHNOLOGY (ART) When couples do not achieve pregnancy from infertility treatments or traditional ART, they may choose to use a third party–assisted ART method to get pregnant.[157] ASSISTANCE CAN CONSIST OF:  Sperm Donation  Egg Donation  Surrogates and Gestational Carriers  Embryo Donation SPERM DONATION:-Assisted reproductive technology (ART) has become increasingly popular over the past several decades. The advances in human sperm cryopreservation in the past 50 years and the creation of sperm banks have facilitated the increase in artificial insemination with donor sperm (AID) [158 159]. In cases of severe male infertility, the use of donor sperm is the only approach to infertility treatment[160]Sperm donation is used for the artificial insemination with a third party donor (AID). The donor becomes the biological father of the child, but he will not be considered the legal or social father. As a consequence, the child will have three parents, two fathers and a mother International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 21 Fig no 13:-biological and legal relation of mother and father to child EGG DONATION:-The procedure typically involves a doctor removing an egg or eggs from the donor, fertilizing them in a laboratory, and then transferring the resulting embryos into the recipient‟s uterus. Doctors do this using an implantation procedure, such as in vitro fertilization (IVF).Sometimes, specialists at the facility may freeze some or all of the embryos for later use or implantation in different women.Egg donation frequently benefits women who cannot use their own eggs for various reasons, including ovarian failure, avoiding congenital anomalies in the fetus egg donation follows the steps of IVF treatment (till egg retrieval). The main difference between IVF and egg donation is the role of donor and the recipient. In the entire procedure of egg donation India, egg donor plays a vital role to achieve success.Without nourished and healthy eggs, the step of fertilization can‟t take place, and this is the main reason, why donor is tested in a comprehensive route. The entire procedure of egg donation India majorly depends upon egg donor.Fertility veterans of Egg Donation Clinic in India start giving fertility medication and hormonal injections to the donor. The duration of this medication goes usually 12-14 days. Fertility medication is given to the donor so that she will come up with multiple eggs at the time of egg retrieval or egg collection phase. Once the e ggs become fully matured, then with the help of hollow thin needle the eggs are picked up by the fertility veterans of Egg Donation Clinic in India.Once the eggs are taken out from the donor, the semen sample is collected from the recipient‟s male duo. Now eggs and sperms are kept on the culture dish for fertilization, where motile sperm self penetrates with the egg‟s wall and goes into the cytoplasm of the egg, resulting from cell division or fusion. Once the cells begin to divide successfully, fertilization happens.After 3-4 days of fertilization, the healthiest embryo is chosen by the experts and then transferred into the uterus of the infertile female for implantation. Now from here, recipient, that means infertile woman‟s role starts. Embryo transfer ha rdly takes 35 -45 minutes for the completion and once the embryo is placed, a recipient can go back her home on the same day[161] Fig no.14:-Egg donation process International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 22 SURROGATES AND GESTATIONAL CARRIERS:- The word “surrogate” is rooted in Latin “Subrogare” (to substitute), which means “appointed to act in the place of.” It means a substitute, especially a person deputizing for another in a specific role, so the surrogate mother implies a woman who becomes pregnant and gives birth to a child with the intention of giving away this child to another person or couple, commonly referred to as the “intended” or “commissioning” parents[162] The surrogate embryo transfer could be fresh or frozen transfer and subject to availability of the gestational carrier. With advent of excellent vitrification techniques, surrogacy cycles have become less difficult for assisted reproductive technology (ART) clinic with good embryology laboratory and freezing facility.For a fresh surrogate transfer, the surrogate and the intended mother cycle may be synchronized with oral contraceptive pills or progesterone pills or surrogate may be put on agonist injection for flexibility of transfer dates.The surrogate is started on estrogen tablets from the 3rd day of her cycle for around 10 days. On reaching of minimum 8 mm, she is then put on progesterone supplementation for 3 days/5 days before a planned cleavage stage/blastocyst transfer, respectively CARE OF SURROGATE Once a pregnancy is confirmed in the gestational carrier depending on the facility of the ART clinic, she either stays in the surrogate house or at her home. The concept of surrogate house has recently caught a lot of attention for various reasons. Surrogate house is a place where surrogate stays for her entire antenatal period till the date of delivery and all her medical and pers onal requirements are taken care of. The obstetrics care of surrogate is extensive due to the preciousness of the pregnancy. She stays under the supervision of 24 -h nursing staff alon g with dietician, physiotherapist, counselors, and gynecologist for her medical care. It is due to this care and available facilities that intended couples have taken up more liking towards the concept of surrogate house. Although staying at surrogate house is preferred practice these days, considering the other side of coin, it could be emotionally taxing for surrogate and her entire family as she has to live away from her own child/children and family; however, during their stay at surrogate house, surrogate can go home for few weeks during pregnancy and her family members can also visit her at surrogate house. Staying at surrogate house should be optional and not compulsion for surrogate mother and she should be given a choice. Surrogates undergo obstetrics assessment every 20 days till the date of delivery, obstetrics scans at 6–8 weeks, anomaly scan at 11 –13 weeks, anomaly scan and 3D -4D at 20–22 weeks, and growth scan at 28 weeks and 34–36 weeks. Any additional scan is subject to the obstetric need. The intended couple is sent regular update regarding the surrogate's pregnancy in the form of her weight gain, vitals, fetal growth, and antenatal investigation reports and scans. Postdelivery, the surrogate is kept under observation for a minimum of 15 days before discharge International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 23 RISKS ASSOCIATED WITH SURROGACY The major risk associated with surrogacy is that of obstetrics complication and multiple order pregnancy being the most common. Recently, lot of recommendations are being made by American Society for Reproductive Medicine (ASRM) and European Society of Human Reproduction and Embryology committees for single embryo transfer, but yet only 15% –20% of clinics follow single embryo transfer norms.[163] Pregnancy, birth, and the postpartum period includes complications such as preeclampsia and eclampsia, urinary tract infections, stress incontinence, and gestational diabetes and rare complications such as amniotic fluid embolism and possibility of postpartum hemorrhage, but these risks are associated with pregnancy in general and not specific to surrogacy. Apart from physical risk, surrogacy may be reason for emotional trauma as the study by Foster (1987) states that many surrogate mothers face emotional problems after having to relinquish t he child. However, a study by Jadva et al.[164] indicates that although some women experience emotional problems in handing over the baby, these feelings appeared to lessen during the weeks following the birth.[164] Fig no.15:-Timeline of surrogacy process EMBRYO DONATION In the current practice of in vitro fertilization (IVF), some patients may create more embryos (fertilized eggs) than they need. The extra embryos may be cryopreserved (frozen) so that they can be transferred later. However, sometimes these embryos may not be used. These patients have the option to have their embryos discarded, donated to research or donated to another woman to achieve pregnancy.[165] International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 24 MISCARRIAGE AFTER FERTILITY TREATMENT Miscarriage is common, with a rate of between 10% and 30% of all spontaneous pregnancies[174]Infertility is also common, affecting about 15% of couples.[175] The causes of infertility are multiple and diverse yet some, for example endometriosis and the polycystic ovary syndrome (PCOS) may also affect successful implantation and pregnancy outcome. With the development of assisted conception it is now possible to overcome or circumvent many of the problems presented by the subfertile couple. The main questions arising from the various therapies available are: do they increase the rate of miscarriage or fetal malformations? by examining both the influence on miscarriage of the drugs used in ovulation induction and the effect of the different techniques employed in assisted conception. First it is important to consider special factors that pertain to miscarriage in the infertile couple. THE INFLUENCE ON MISCARRIAGE OF THE DRUGS USED IN FERTILITY THERAPY Ovulatory failure accounts for about a fifth of cases of infertility. Over the last 30 years drug regimens of increasing complexity have evolved to induce ovulation. The drugs prescribed to anovulatory women are also used to induce multifollicular growth in women who ovulate normally. These women benefit from superovulation as the production of several oocytes increases the success of assisted conception therapies. The most commonly used preparations are the anti -estrogens (e.g. clomifene citrate), the gonadotropins and gonadotropin-releasing hormone analogs . Information about the sequelae of the use of fertility drugs therefore chiefly refers to these three groups ANTI-ESTROGENS The most widely prescribed anti -estrogen is clomifene citrate. Its use in ovulation induction was first reported by Greenblatt et al[176] at a time when human pituitary and menopausal urinary gonadotropins were also beginning to be extracted and standardized. In an early report of pregnancy outcome in a small number of women, Greenblatt et al found the incidence of spontaneous abortion to be 22%.[177] Karow and Payne[178] reported on a heterogeneous group of 410 infertile women, in whom a pregnancy rate of 39.8% was achieved. The spontaneous abortion rate was 19%, similar to that seen in infertility patients prior to the advent of the drug. The inciden ce of twins was 8.6%, contributing to a premature delivery rate of 12%. There was no confirmation of an earlier theory that conception in the first treatment cycle resulted in an increased chance of miscarriage or multiple pregnancy. Also in 1968, a series of 2196 clomifene -induced pregnancies was reported, [179] in which the miscarriage rate was 17.6%, the multiple pregnancy rate 10.2%, and the incidence of congenital anomalies 2.5%. Although clomifene was found to induce ovulation in about 90% of infertile women and pregnancy in 50%, the multiple pregnancy rate was sometimes as high as 50%. In general the miscarriage rate after clomifene treatment has been reported to be between 20% and 27%, the rate of multiple pregnancy 10–15%, and the incidence of congenital abnormalities about 2–3%.[180-182] One series reported an overall miscarriage rate of 9.3%, 28.1% if conception occurred during the first cycle of treatment, and as high as 70% if conception resulted after seven cycles. It was thought that prolonged usage of clomifene might have a deleterious effect on the endometrium, causing atrophy and implantation failure. The relatively International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 25 high miscarriage rate during the first cycle of treatment that was seen in this study was postulated as being secondary to the release of “overripe” oocytes after a prolonged period of anovulation. Interpreting data from the early use of clomifene is complicated by the lack of uniformityin presenting details of maternal age and the cause of infertility. Monitoring was li mited to measurement of urinary estrogens or vaginal cytology and often omitted. Pregnancy diagnosis was not as advanced as at present and so it is inappropriate to compare miscarriage data between the different series. Most women who require clomifene to induce ovulation have PCOS and are likely to have a tendency to hypersecrete LH. Clomifene achieves its action through stimulation of both follicle stimulating hormone (FSH) and LH secretion by the pituitary and women with PCOS can respond with an exaggera ted release of LH and a resultant reduction in the chance of conception and increase in the risk of miscarriage.[183] CONGENITAL ABNORMALITIES WITH CLOMIFENE CITRATE The risk of congenital abnormalities and the physical development of infants born to mothers who have received clomifene has not been found to be different to that of the general population, yet concern was expressed about the finding of an increased frequency of chromosomal abnormalities after induced ovulation,[184] an effect that appeared to persist during the subsequent, non-stimulated cycle. Following the report of two cases of neural tube defects after clomifene therapy, [185] other isolated cases of congenital abnormalities appeared in the literature. Most have felt that factors relat ed to infertility itself may be to blame, rather than ovulation induction, and that babies born after ovulation induction are no more at risk of being malformed than if they were conceived spontaneously. [186]Whereas there continue to be reports that suggest a more than coincidental association between ovulation induction, specifically using clomifene, and neural tube defects, [187] other reports are reassuring and suggest no evidence for this.[188] Shoham et al reviewed 3751 births after clomifene ther apy and found an overall incidence of major and minor malformations of 32.5 per 1000 births,1 this figure being within the range found among the normal population.[186] OVULATION INDUCTION WITH GONADOTROPINS Women who do not respond to oral therapy may succeed in having ovulation induced with gonadotropin therapy. The preparations available either contain both LH and FSH or contain FSH alone . It was thought that the use of FSH alone would benefit women with the PCOS by minimizing circulating LH levels. However, these women are usually very sensitive to both forms of treatment and the use of FSH alone confers no advantage as serum concentrations of LH are still within the normal range when human menopausal gonadotropin (hMG) is used. The amount of LH in hM G preparations is small compared with the amount secreted by the pituitary and so is rapidly diluted after administration; furthermore, with unifollicular ovulation induction the developing follicle secretes hormones that feed back to the hypothalamus and pituitary and suppress endogenous LH secretion. Studies to date indicate that miscarriage rates are similar irrespective of the gonadotropin used. As for the actual reported miscarriage rate after gonadotropin -induced ovulation, this varies between 11.3% and 27.5%. Lunenfeld et al also reported an analysis of the abortion rates in both the first and subsequent treatment cycles and the first and subsequent pregnancies.[189]Miscarriage after fertility treatment In this study it was found that whereas the abortion rate was 28.8% in a first pregnancy, it was International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 26 only 12.8% in a second pregnancy. This figure is similar to the 13% of women who aborted after a spontaneous conception that followed a successful gonadotropininduced pregnancy. There was no difference in the abortion rates of patients who became pregnant after the first or subsequent treatment cycles. This goes against a commonly proposed theory that anovulatory women release eggs of “poor quality” in their first ovulation induction cycle.[190]Other grou ps have also found a higher miscarriage rate in the first gonadotropin-induced pregnancy. One series reported a reduction in miscarriage rate from 28.5% in first hMGpregnancies to 11.9% in those conceiving for a second time;[190]another series found these figures to be 33% and 9.8%, respectively.[191] In contrast to these studies, a more recent paper reported an overall spontaneous abortion rate in 350 pregnancies after first treatment cycles of 24.2%, yet a 48% abortion rate in a subsequent pregnancy in women whose first hMG pregnancy ended in a spontaneous abortion; this compared to an incidence of abortion of 6.7% if the first hMG -induced pregnancy was normal.[192]These data are in keeping with the notion that the risk of miscarriage following a natural c onception is directly related to a woman‟s past obstetric history. We reported a retrospective analysis of all patients treated in the ovulation induction clinic at the Middlesex Hospital, London, from May 1982 to January 1993. [193] A total of 200 anovulatory patients were included in the analysis, 103 with clomifene citrate-resistant PCOS, 77 with hypogonadotropic hypogonadism (HH), and 20 with weight-related amenorrhea (WRA). There was no difference in the mean age of the three groups. The cumulative conception rates (CCR) and cumulative live birth rates (CLBR) of the three groups in the first course of therapy and after 12 cycles of treatment are illustrated in The miscarriage rates were 16.5% in PCOS patients, 22.9% in HH patients, and 32.3% in WRA patients and, while not statistically significantly different, this resulted in comparable CLBRs between the three groups. Patients with amenorrhea secondary to weight loss respond well to ovulation induction therapy with normal or supranormal cumulative conception rates.[194-196]The miscarriage rate in these patients, however, was 32% and this resulted in a cumulative live birth rate that was similar to that of patients with PCOS and HH. Furthermore, women who conceived spontaneously and had a body mass i ndex (BMI) of less than 19.1 kg/m2 had twice the risk of delivering a low birthweight infant compared with women of normal weight (p < 0.005)[197] and they also had a higher incidence of preterm deliveries (p < 0.01). We have also reported previously that patients with WRA who conceive after treatment with pulsatile gonadotropin releasing hormone (GnRH) are more likely to deliver lighter babies than of normal weight (p < 0.001).[198] Our current approach is therefore to encourage weight gain and not to induce ovulation in women with a BMI of less than 19.5 kg/m2. VIRAL DISEASE AND ASSISTED REPRODUCTIVE TECHNIQUES HIV-positive women need to address a number of issues when planning to conceive. The HIV physician is best placed to provide pre -conceptual advice on HAART, self -insemination methods, and measures that will need to be put in place during pregnancy to reduce MTCT risk, as well as advising on any long -term health issues related to viral illness, which might be a contraindication to pregnancy. Relatively few antiretroviral medications (e.g., Efavirenz) are contraindicated during pregnancy due to potential teratogenic effects on the fetus [200]but it should be borne in mind that the evidence on the safety of most antiretrovirals during pregnancy is still incomplete. Folic acid should be given antenatally to minimize the risk of neural tube defects as antiretrovirals are known to have a folate antagonist International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 27 effect.There is increasing evidence to suggest that HIV -positive women have reduced fertility[201- 202]There are no data to suggest an increased incidence of cycle irregularity in positive women, but studies on positive women undergoing IVF suggest that HIV -positive women have lower IVF success rates than HIV-negative controls and require higher doses of gonadotropin stimulation [203-205]. IVF outcome does not appear to be affected in HIV -positive women undergoing ovum donation, pointing toward an effect of HIV and/or immunosuppression on ovarian response and ovarian reserve rather than on implantation [206]. Retrospective data from Sub -Saharan Africa [207 -208] and prospective data from the United Kingdom indicate an increased incidence of tubal infertility in positive women [201 - 202] of at least twice that of HIV- negative controls. On the basis of increased risk of low ovarian reserve and increased tubal infertility, HIV-positive women trying to conceive should be referred sooner rather than later for fertility evaluation and certainly if they have not conceived within six to 12 months of self- insemination. Referral should be early if there is a history of pelvic infl ammatory disease or in women over 35 years of age to assess tubal function and ovarian reserve. REDUCING RISK DURING ART IN POSITIVE WOMEN Minimizing risk in HIV -positive women lies primarily in reducing MTCT. There are no additional specific measures that can be taken during fertility treatment to further reduce this risk. There has been concern that invasive procedures such as IVF could increase the chances of the embryo becoming infected. The number of women treated so far is small and prospective data limited. A study of 10 women undergoing IVF or ICSI demonstrated that HIV was detectable in follicular fluid removed during vaginal egg collection in all patients with a detectable se rum VL and in 60% of those with an undetectable serum VL [209]. This raises the theoretical possibility of the embryo becoming infected at the laboratory stage of ART even before embryo transfer, although the likelihood is that viral infection would lead t o embryo death. Longitudinal studies are needed to monitor outcome of ART cyclesin positive women to identify if any such risk increases the chance of MTCT.Management of HIV- positive women should involve a multidisciplinary team comprising HIV physician, fertility specialist, and obstetrician with a special interest in HIV. The couple should have a sexual health screen for the same reasons as couples undergoing sperm washing. Likewise they should have a fertility screen in a similar way to HIV -negative cou ples (early follicular phase endocrine profile and pelvic scan, mid -luteal progesterone, and test of tubal function) and the male partner should have a semen analysis[210]. Couples concordant for HIV should be advised to conceive using sperm washing to prevent the risk of superinfection. MANAGING PATIENTS WITH HEPATITIS Hepatitis B (HBV) and Hepatitis C (HCV) viruses are major causes of chronic hepatitis, cirrhosis, and hepatocellular cancer. In cases where fertility treatment is required and one or both partners are HBV or HCV positive, samples should be treated as infectious and handled according to clinical and laboratory guidelines set out below.In the case of hepatitis B, vertical transmission accounts for over 40% of cases of chronic infection a nd the sexual transmission risk is twofold higher than for HIV and sixfold higher than for HCV. Unlike HIV or HCV, an effective vaccine is available for HBV and all healthcare workers and partners of known infected individuals should be vaccinated. Uninfec ted women should International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 28 only consider conception post -vaccination. Sperm washing should not be required as a means of reducing horizontal transmission risk unless a woman fails to develop adequate immunity through vaccination. If ART is required in HBV positive c ouples for fertility issues, similar clinical protocols to non-infected patients should be used. The Dutch view, as with HIV samples, is that if ART is required in a couple where the male is HBV positive, ICSI should be avoided due to the risk of introduci ng HBV into the oocyte [211]. There are no substantive data to support this view.Vertical transmission risk for an HBV positive woman during pregnancy is 2 –15% if she is only HBsAgpositive, and 80 –90% if she is also positive for HBeAg or is HBV DNA positive. Infection in the neonate can be minimized if immunoprophylaxis (HBV vaccination and one dose of Hepatitis B immunoglobulins) is given within 24 hours of birth with a further dose at one and six months. Breastfeeding does not appear to play a role in perinatal transmission.HCV infection is primarily transmitted by parenteral spread (blood products, shared needles, needlestick injury). Sexual transmission risk is very low unless the patient is co - infected with HIV [212]. There is no vaccine for HCV and sperm washing should be offered to HCVdiscordant couples where the male is infected. The principles of treatment are the same as in HIV - infected discordant couples[213,214] and sperm washing is as effective in reducing transmission risk to the female partner as in discordant cases of HIV. Patients who have expressed a desire to become parents, but who are in a high -risk group for infertility based on their age, should have a basic fertility evaluation and be referred to a specialist in a timely manner in order to maximize their fertility potentiaInfertility may work as a painful emotional experience[166 167]. It can cause a lot of psychological issues including stress, anxiety, depression, diminished self -esteem, declined sexual satisfaction, and reduced quality of life[168,169,170]. The resulted psychosocial issues affect the female gender adversely more than her spouse [171], especially in societies where there are prejudices against women[169 170 172] . As such, an infertile woman may show a relatively high level of frustration and anger which affect her relationship with family, friends and even her spouse. Likewise, infertile women are more likely to develop mental illnesses, marital dissatisfaction, and impaired quality of life compared to the individuals of fertile group[169, 172 173].

Many women have reported finding treatment for infertility stressful and a cause of relationship difficulties with their partners. The fear of failure was the most important barrier to treatment. The psychological support is fundamental to limit the possibility to drop -out from infertility treatment and reduce the distress level which is strongly associated with lower pregnancy rates. In addition some medications used in the treatment have several side effects which may be an important risk factor for the development of depression Many infertile women tend to cope with immense stress and social stigma behind their condition, which can lead to considerable mental distress.The long -term stress involved in attempting to conceive a child and the social pressures behind giving birth can lead to emotional distress that may manifest as mental disease.Women with infertility might deal with psychological stressors such as denial, anger, grief, guilt, and depressi on.There can be considerable social shaming that can lead to intense feelings of sadness and frustration that potentially contribute to depression and suicide.The implications behind infertility bear huge consequences for the mental health of an infertile woman because of the social pressures and personal grief behind being unable to bear children International Journal for Multidisciplinary Research (IJFMR) E-ISSN: 2582-2160 ● Website: www.ijfmr.com ● Email: [email protected] IJFMR22061060 Volume 4, Issue 6, November-December 2022 29

I express heartfelt gratitude to Dr. Rajesh Oswal and Prof Diksha Gupta, of Genba Sopanrao Moze College of Pharmacy , Wagholi for their full guidance and also for providing digital library.

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