Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0.74-34.40); early pregnancy loss (ORs, 1.40-6.25); late pregnancy loss (ORs, 1.31-20.09); pre-eclampsia (ORs, 1.37-3.49); placental abruption (ORs, 1.42-7.71) and intrauterine growth restriction (ORs, 1.24-2.92). Low-dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1.62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.2005.05847.x

Thrombophilia in pregnancy: a systematic review

The major function of the placenta is to transfer nutrients and oxygen from the mother to the foetus and to assist in the removal of waste products from the foetus to the mother. In addition, it plays an important role in the synthesis of hormones, peptides and steroids that are vital for a successful pregnancy. The placenta provides a link between the circulations of two distinct individuals but also acts as a barrier to protect the foetus from xenobiotics in the maternal blood. However, the impression that the placenta forms an impenetrable obstacle against most drugs is now widely regarded as false. It has been shown that that nearly all drugs that are administered during pregnancy will enter, to some degree, the circulation of the foetus via passive diffusion. In addition, some drugs are pumped across the placenta by various active transporters located on both the fetal and maternal side of the trophoblast layer. It is only in recent years that the impact of active transporters such as P-glycoprotein on the disposition of drugs has been demonstrated. Facilitated diffusion appears to be a minor transfer mechanism for some drugs, and pinocytosis and phagocytosis are considered too slow to have any significant effect on fetal drug concentrations. The extent to which drugs cross the placenta is also modulated by the actions of placental phase I and II drug-metabolising enzymes, which are present at levels that fluctuate throughout gestation. Cytochrome P450 (CYP) enzymes in particular have been well characterised in the placenta at the level of mRNA, protein, and enzyme activity. CYP1A1, 2E1, 3A4, 3A5, 3A7 and 4B1 have been detected in the term placenta. While much less is known about phase II enzymes in the placenta, some enzymes, in particular uridine diphosphate glucuronosyltransferases, have been detected and shown to have specific activity towards marker substrates, suggesting a significant role of this enzyme in placental drug detoxification. The increasing experimental data on placental drug transfer has enabled clinicians to make better informed decisions about which drugs significantly cross the placenta and develop dosage regimens that minimise fetal exposure to potentially toxic concentrations. Indeed, the foetus has now become the object of intended drug treatment. Extensive research on the placental transfer of drugs such as digoxin and zidovudine has assisted with the safe treatment of the foetus with these drugs in utero. Improved knowledge regarding transplacental drug transfer and metabolism will result in further expansion of pharmacological treatment of fetal conditions.

Drug transfer and metabolism by the human placenta

OBJECTIVES To assess the risk of clinical complications associated with thrombophilia in three high-risk patient groups: women using oral oestrogen preparations, women during pregnancy and patients undergoing major orthopaedic surgery. To assess the effectiveness of prophylactic treatments in preventing venous thromboembolism (VTE) and adverse pregnancy outcomes in women with thrombophilia during pregnancy and VTE in patients with thrombophilia, undergoing major orthopaedic surgery. To evaluate the relative cost-effectiveness of universal and selective VTE history-based screening for thrombophilia compared with no screening in the three high-risk patient groups. DATA SOURCES Electronic databases including MEDLINE, EMBASE, and four other major databases were searched up to June 2003. REVIEW METHODS In order to assess the risk of clinical complications associated with thrombophilia, a systematic review of the literature on VTE and thrombophilia in women using oral oestrogen preparations and patients undergoing major orthopaedic surgery; and studies of VTE and adverse obstetric complications in women with thrombophilia during pregnancy was carried out. Meta-analysis was used to calculate pooled odds ratios (ORs) associated with individual clinical outcomes, stratified by thrombophilia type and were calculated for each patient group. To assess the effectiveness of prophylaxis, a systematic review was carried out on the use of prophylaxis in the prevention of VTE and pregnancy loss in pregnant women with thrombophilic defects and the use of thromboprophylaxis in the prevention of VTE in patients with thrombophilia undergoing major elective orthopaedic surgery. Relevant data were summarised according to the patient groups and stratified according to the types of prophylaxis. A narrative summary was provided; where appropriate, meta-analysis was conducted. An incremental cost-effectiveness analysis was then carried out, from the perspective of the NHS in the UK. A decision analytical model was developed to simulate the clinical consequences of four thrombophilia screening scenarios. Results from the meta-analyses, information from the literature and results of two Delphi studies of clinical management of VTE and adverse pregnancy complications were incorporated into the model. Only direct health service costs were measured and unit costs for all healthcare resources used were obtained from routinely collected data and the literature. Cost-effectiveness was expressed as incremental cost-effectiveness ratios (ICERs); an estimate of the cost per adverse clinical complication prevented, comparing screening with no screening, were calculated for each patient group. RESULTS In the review of risk of clinical complications, 81 studies were included, nine for oral oestrogen preparations, 72 for pregnancy and eight for orthopaedic surgery. For oral contraceptive use, significant associations of the risk of VTE were found in women with factor V Leiden (FVL); deficiencies of antithrombin, protein C, or protein S, elevated levels of factor VIIIc; and FVL and prothrombin G20210A. For hormone replacement therapy (HRT), a significant association was found in women with FVL. The highest risk in pregnancy was found for FVL and VTE, in particular, homozygous carriers of this mutation are 34 times more likely to develop VTE in pregnancy than non-carriers. Significant risks for individual thrombophilic defects were also established for early, recurrent and late pregnancy loss; preeclampsia; placental abruption; and intrauterine growth restriction. Significant associations were found between FVL and high factor VIIIc and postoperative VTE following elective hip or knee replacement surgery. Prothrombin G20210A was significantly associated with postoperative pulmonary embolism. However, antithrombin deficiency, MTHFR and hyperhomocysteinaemia were not associated with increased risk of postoperative VTE. In the review of the effectiveness of prophylaxis, based on available data from eight studies, low-dose aspirin and heparin was found to be the most effective in preventing pregnancy loss in thrombophilic women during pregnancy, while aspirin alone was the most effective in preventing minor bleeding. All the studies on thrombophilia and major elective orthopaedic surgery included in the review of risk complications were also used in the review of the effectiveness of thromboprophylaxis. However, there were insufficient data to determine the relative effectiveness of different thromboprophylaxis in preventing VTE in this patient group. For the cost-effectiveness analysis, of all the patient groups evaluated, universal screening of women prior to prescribing HRT was the most cost-effective (ICER pound6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost-effective strategy (ICER pound202,402). Selective thrombophilia screening based on previous personal and/or family history of VTE was more cost-effective than universal screening in all the patient groups evaluated. CONCLUSIONS Thrombophilia is associated with increased risks of VTE in women taking oral oestrogen preparations and patients undergoing major elective orthopaedic surgery, and of VTE and adverse pregnancy outcomes in women with thrombophilia during pregnancy. There is considerable difference in the magnitude of the risks among different patient groups with different thrombophilic defects. In women who are on combined oral contraceptives, the OR of VTE among those who are carriers of the FVL mutation was 15.62 (95% confidence interval 8.66 to 28.15). However, in view of the prevalence of thrombophilia and the low prevalence of VTE in non-users of combined oral contraceptives, the absolute risk remains low. Significant risks for VTE and adverse pregnancy outcomes have been established with individual thrombophilic defects. Thrombophilic defects including FVL, high plasma factor VIIIc levels and prothrombin G20210A are associated with the occurrence of postoperative VTE in elective hip or knee replacement therapy. These associations are observed in patients who were given preoperative thromboprophylaxis and are, therefore, of clinical significance. Universal thrombophilia screening in women prior to prescribing oral oestrogen preparations, in women during pregnancy and in patients undergoing major orthopaedic surgery is not supported by current evidence. The findings from this study show that selective screening based on prior VTE history is more cost-effective than universal screening. Large prospective studies should be undertaken to refine the risks and establish the associations of thrombophilias with VTE among hormone users and in patients undergoing orthopaedic surgery. The relative value of a thrombophilia screening programme to other healthcare programmes needs to be established.

/pdf/screening-for-thrombophilia-in-high-risk-situations-3v1lws34ot.pdf

Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study

How strong is the association between maternal thrombophilia and adverse pregnancy outcome?: A systematic review

Drugs administered to mothers have the potential to cross the placenta and reach the fetus. Under particular circumstances, the comparison of the drug concentration in the maternal and fetal plasma may give an idea of the exposure of the fetus to the maternally administered drugs. In this review drugs are classified according to their type of transfer across the placenta. Several drugs rapidly cross the placenta and pharmacologically significant concentrations equilibrate in maternal and fetal plasma. Their transfer is termed ‘complete’. Other drugs cross the placenta incompletely, and their concentrations are lower in the fetal than in maternal plasma. The majority of drugs fit into 1 of these 2 groups. A limited number of drugs reach greater concentrations in fetal than maternal plasma. It is said that these drugs have an ‘exceeding’ transfer. The impression prevails that suxamethonium chloride (succinylcholine chloride) and doxorubicin do not cross the placenta. However, a careful analysis of the literature suggests that this impression is wrong and that all drugs cross the placenta, although the extent transfer varies considerably. The following parameters were considered as possible factors determining the extent of placental transfer: (i) the molecular weight of the drug; (ii) the pKa (pH at which the drug is 50% ionised); and (iii) the extent of drug binding to the plasma protein. Drugs with molecular weights greater than 500D have an incomplete transfer across the human placenta. Strongly dissociated acid drug molecules should have an incomplete transfer, but this does not seem to be an absolute rule. For example, ampicillin and methicillin transfer completely and they are strongly dissociated at physiological pH. The extent of drug binding to plasma protein does not influence the type of drug transfer across the human placenta.

Placental Transfer of Drugs Administered to the Mother

BACKGROUND Ovarian endometrioma is a frequent manifestation of endometriosis in women of reproductive age. Several issues related to its space occupying effects, local reactions and surgical removal continue to be actively debated today. The impact of ovarian endometrioma per se on ovarian reserve is still controversial and the effect of ovarian surgery is still actively discussed. Furthermore, the optimal biomarker of ovarian reserve estimation in women with ovarian endometrioma is still under examination. Additionally, there is no consistent agreement on the effect of endometrioma bilaterality on ovarian reserve. OBJECTIVE AND RATIONALE The objective of this systematic review and meta-analysis was to study the impact of unilateral versus bilateral ovarian endometrioma on ovarian reserve biomarkers before and after endometrioma cystectomy. SEARCH METHODS We performed an extensive electronic database search employing PubMed, EBSCO, Web of Science, ClinicalTrials.gov and the Cochrane Library, to identify published research articles published between January 2000 and October 2018. Search terms included endometriotic cyst OR endometrioma OR endometriomata, cystectomy OR resection OR stripping OR removal OR excision and infertility OR subfertility. Only prospective controlled studies that compared the impact of unilateral versus bilateral ovarian endometriotic cystectomy on ovarian reserve tests in the same setting were included. Studies which included cases with PCOS, ovarian failure, early menopause, oral contraception treatment, or prior chemotherapy and/or radiotherapy or ovarian surgery, were excluded from evaluation. We used the Newcastle-Ottawa Scale for assessing the quality of studies found eligible for meta-analysis. We registered the systematic review on PROSPERO and its number is CRD42018117170. OUTCOMES Twelve studies were eligible for meta-analysis including collectively 783 women: 489 and 294 in the unilateral and bilateral groups, respectively. The included studies had a low risk of bias. The pre-operative weighted mean difference (WMD) showed that serum AMH levels did not differ significantly between the groups. Conversely, AMH levels were significantly (P < 0.05) lower in bilateral groups than in unilateral groups at the early, intermediate and late post-operative periods, corresponding WMDs of 0.78 ng/ml (95% CI: 0.41-1.15), 0.59 ng/ml (95% CI: 0.14-1.04) and 1.08 ng/ml (95% CI: 0.63 to 1.52), respectively. Heterogeneity among eligible studies reporting on before the operation and at the early and intermediate post-operative periods was high. Pre-operative and post-operative AFC values were not significantly different between the groups. The heterogeneity among the studies reporting on AFC was high. Analysis of each of the unilateral and bilateral groups separately showed a significant and sustained serum AMH drop by 39.5% and 57.0%, respectively from baseline to after the operation. WIDER IMPLICATIONS Our results challenge the concept that endometrioma per se adversely affects ovarian reserve, whereas endometrioma cystectomy, especially as bilateral operation, has a deleterious and sustained effect on ovarian reserve. AMH seems to be a more appropriate biomarker of ovarian reserve than AFC in cases with endometrioma. Since low AMH implies a shorter reproductive lifespan, excision of endometrioma should be cautiously considered, especially in bilateral cases.

Impact of unilateral versus bilateral ovarian endometriotic cystectomy on ovarian reserve: a systematic review and meta-analysis

Postponement of child bearing and maternal age at first pregnancy are on the rise, contributing considerably to an increase in age-related infertility and the demand for assisted reproductive technologies (ART) treatment. This brings to the infertility clinics many women with low ovarian reserve and poor ovarian response (POR) to conventional stimulation. The Bologna criteria were released to standardize the definition of POR and pave the way for the formulation of evidence-based, efficient modalities of treatment for women undergoing IVF-ET. More than four years have passed since the introduction of these criteria and the debate is still ongoing whether a revision is due. Women with POR comprise several sub-groups with diverse baseline distinctiveness, a major issue that has fueled the discussion. Although antral follicle count (AFC) and anti-Mullerian hormone (AMH), are considered good predictors of ovarian reserve, their threshold values are still not universally standardized. Different definitions for sonographic AFC and diverse assays for AMH are held responsible for this delay in standardization. Adding established risk factors to the criteria will lead to more reliable and reproducible definition of a POR, especially in young women. The original criteria did not address the issue of oocyte quality, and the addition of risk factors may yield specific associations with quality vs. quantity. Patient’s age is the best available criterion, although limited, to predict live-birth and presumably oocyte quality. High scale studies to validate these criteria are still missing while recent evidence raises concern regarding over diagnosis.

/pdf/the-bologna-criteria-for-poor-ovarian-response-a-jv2n70inmf.pdf

The Bologna criteria for poor ovarian response: a contemporary critical appraisal

Johnny S.Younis1,4, Gonen Ohel2, pregnancy, had a 90% chance of fetal loss (Rai et al., 1995a). However, APS has been found in no more than 5–10% of all Benjamin Brenner3 and Moshe Ben-Ami1 patients with recurrent pregnancy loss. Moreover, as many as 1Unit of Reproductive Medicine, Department of Obstetrics 50% of cases with repeat fetal loss are invariably unexplained and Gynecology, Poriya Hospital, Tiberias, 2Department of with no obvious discernible causes (ACOG, 1995; Bulleti Obstetrics and Gynecology, Bnai-Zion Hospital, Haifa, and et al., 1996; Christiansen, 1996). 3Thrombosis and Homeostasis Unit, Rambam Hospital, Haifa, Israel Until recently, primary hypercoagulable states or inherited thrombotic disorders, were responsible for less than 10% 4To whom correspondence should be addressed of cases presenting with documented episodes of different thrombotic phenomena. These inherited thrombotic disorders, This debate was previously published on Webtrack, March termed today ‘familial thrombophilia’, are the result of specific 18, 1997 defects in the genes for plasma coagulation proteins involved in heparin-antithrombin III and protein C anticoagulant pathways. Deficiencies of antithrombin III, protein C and protein S are As many as 5% of all couples attempting to conceive have rare familial disorders that are usually inherited as autosomal two successive pregnancy losses, and 1% have three or more dominant disorders (Bauer, 1995). The homozygous variety of consecutive losses. Uncertainties regarding the aetiology and these disorders is often fatal in the neonatal period. Heterozygcontroversies surrounding management of repeat fetal demise ous patients have an age related risk for thrombosis and it is are two reasons that keep this issue a particularly frustrating estimated that up to 70% of them will develop a thrombotic challenge for physicians and patients. There is a general event by age 50 (Bauer, 1995). agreement today in regard to genetic, endocrine, uterine and Lately, the situation has changed dramatically with the autoimmune factors being associated with repeat fetal loss. discovery of a novel genetic defect associated with thrombotic However, there is still considerable disagreement in regard to disorders. In 1993, Dahlback et al. (1993) reported a new other potential conditions associated with consecutive losses, mechanism for familial thrombophilia characterized by an such as infectious, alloimmune, environmental, psychological inherited resistance to activated protein C (APC). Subsequent and other factors (Berry et al., 1995). studies revealed that APC-resistance is almost always caused For several decades now clinicians have presumed that a by a single point mutation of G to A at nucleotide 1691 in significant proportion of women suffering from repeat pregthe factor V gene, which destroys one of the APC-cleavage nancy loss have a homeostatic disturbance in the placental sites by the substitution of glutamine for arginine at amino bed, but neither actual evidence nor methodical documentation acid 506 in factor V (Arg 506 Gln) (Bertina et al., 1994). This have been presented. The assumption is that microthrombi of new mutation of factor V has been termed factor V Leiden the placental bed vessels could lead to multiple placental and it is inherited as an autosomal dominant. Moreover, it has infarctions that adversely affect the feto–maternal circulatory been revealed that this point mutation increases the risk for system leading eventually to fetal death. Several empirical thrombosis by 5–10-fold in heterozygous and by 50–100-fold antithrombotic treatments, such as aspirin, dipyridamole and in homozygous patients. Most importantly, several studies heparin have been advocated in the past but without any have shown that factor V Leiden is a very common finding in scientific validation or medical proof of efficacy. patients with venous thrombosis and that this derangement is The introduction of the antiphospholipid syndrome (APS), a widespread mutation with an estimated prevalence of 2–7% in the early 1980s, as an aetiological cause for recurrent in different populations (Bauer, 1995). pregnancy loss, has substantiated the ‘thrombosis theory’ of With the discovery of this new genetic risk factor for repeat fetal loss. A necrotizing decidual vasculopathy has been thrombosis, a major step forward has been made in understandfound in the placentas of women with APS presenting with ing the clustering of thrombophilia in selected families and/or fetal death, providing strong evidence for a thrombotic basis young patients. Especially the fact that, in contrast to other of fetal loss (Silver and Branch, 1994). Although the pathoknown rare hereditary thrombophilias, APC resistance is a physiology of APS-associated thrombosis is still not well very common disorder which is responsible almost for 50% characterized, antithrombotic treatments employing aspirin of cases with familial thrombophilia (Bertina et al., 1995). and/or heparin have proved to be effectual in these women. This new finding has led some groups of investigators to explore whether a relationship could be found between this Moreover, APS patients who declined treatment in their next

Familial thrombophilia--the scientific rationale for thrombophylaxis in recurrent pregnancy loss?

Insufficient transplacental digoxin transfer in severe hydrops fetalis

The viral pandemic of the coronavirus disease 2019 (COVID-19), generated by a novel mutated severe acute respiratory syndrome coronavirus (SARS-CoV-2), has become a serious worldwide public health emergency, evolving exponentially. While the main organ targeted in this disease is the lungs, other vital organs, such as the heart and kidney, may be implicated. The main host receptor of the SARS-CoV-2 is angiotensin converting enzyme 2 (ACE2), a major component of the renin-angiotensin-aldosterone system (RAAS). The ACE2 is also involved in testicular male regulation of steroidogenesis and spermatogenesis. As the SARS-CoV-2 may have the potential to infect the testis via ACE2 and adversely affect male reproductive system, it is essential to commence with targeted studies to learn from the current pandemic, with the possibility of preemptive intervention, depending on the findings and time course of the continuing pandemic.

https://journals.physiology.org/doi/pdf/10.1152/ajpendo.00183.2020

Johnny S. Younis

Papers

Impact of unilateral versus bilateral ovarian endometriotic cystectomy on ovarian reserve: a systematic review and meta-analysis

The Bologna criteria for poor ovarian response: a contemporary critical appraisal

Familial thrombophilia--the scientific rationale for thrombophylaxis in recurrent pregnancy loss?

Insufficient transplacental digoxin transfer in severe hydrops fetalis

Is there an impact of the COVID-19 pandemic on male fertility? The ACE2 connection.