• 1.
  

  a) F b) F c) F d) T e) F

Most immunosuppressive drugs are able to reach the Fetal circulation by crossing the placental barrier. However, due to an extensive first pass metabolism in the Fetal liver, the drug concentration of Cyclosporine, Tacrolimus and Mycophenolate Mofetil in the Fetal blood was shown to be lowered as compared to non-pregnant women. Neither Cyclosporine (4.9%) nor Tacrolimus (4.2%) have shown an increased rate of birth defects in comparison to the general US population (3% to 5%). There are several reports on Azathioprine medication in pregnant women. While there is no increase in birth defects caused by this drug, a neonatal leukopenia has frequently been observed, but this usually normalizes within one year. The use of Mycophenolate Mofetil is contraindicated in pregnant women. This drug has been associated with an increased risk of miscarriage during the first trimester and several possible malformations, including ears, limbs, heart, oesophagus, kidneys or deformations in the upper oral tract such as cleft lip and palate.

• 2.
  

  a) F b) T c) F d) F e) F

CT is rarely used in pregnancy, particularly early pregnancy, due to its high radiation dose. Due to an extensive first pass metabolism in the Fetal liver, the drug concentration of Cyclosporine and Tacrolimus has been shown to be lowered as compared to non-pregnant women – levels therefore need to be measured more frequently and doses increased as necessary. Rejection and transplant organ failure does not appear to have a relationship with time from transplant once the patient is stable. There is currently limited knowledge about potential side effects of Sirolimus or Everolimus in pregnancy.

• 3.
  

  a) F b) F c) F d) T e) F

The mode of delivery should be determined by standard obstetric decisions or when organ function decline necessitates rapid delivery – as long as mother and baby remain well there is no specific indication favouring vaginal or abdominal delivery. Vitamin D is recommended as transplant recipients have higher levels of deficiency as both the liver and kidney are involved in vitamin D metabolism and stores are often reduced. Term delivery is safe and preferred as long as mother and baby both remain well – preterm delivery is only necessary for obstetric indications or significant accelerated organ dysfunction. Vomiting will indeed potentially reduce serum immunosuppressive levels if significant as with most oral medications. Antibiotics should only be prescribed in the presence of proven infections or where the clinical picture warrants it – there is no indication for routine prophylaxis.

• 4.
  

  a) F b) F c) T d) T e) T

The rate of malformations is not any higher in women using anti-suppressive medication except for Mycophenolate Mofetil which is avoided. Rejection has been shown to be higher in liver transplant patients than kidney recipients. Clarithromycin should not been used as this antibiotic might increase the levels of Tacrolimus or Cyclosporine with potentially severe consequences such as drug induced development of haemolytic uraemic syndrome. Viruses of special relevance in the context of pregnancies in transplant recipients are the herpes family of viruses as they show life-long latency after the first infection. In patients with immunosuppressive therapy they can reactivate and cause symptomatic illness or even graft damage, especially CMV, which is also well known to cause fetal abnormalities. With modern management the outcome for pregnancies in organ recipients is indeed about comparable to the outcome of pregnancies in healthy women and their organs are only usually minimally affected.

• 5.
  

  a) F b) F c) T d) T e) T

Birth control is crucial, since unplanned pregnancies often bear several risks to transplanted women. Estradiol containing contraceptives may increase hypertension and the risk of thrombosis in these patients, and their use is generally to be avoided since there is a concern that drug interaction through the cytochrome 450 system may decrease the efficacy of immunosuppressive medications and hormonal contraception. Therefore, estrogen-related problems combined with an 8% failure rate with typical use make combined hormonal methods less than ideal in transplanted women. Depot-medroxyprogesterone-acetate (Depo-Provera) is contraindicated in patients with active liver disease and therefore not suitable in LTRs and has been shown to have a depressing effect on bone density, and although reversible is not favourable in transplanted patients with an already decreased mineralization (usually due to long term steroid use). Intrauterine devices (IUDs – copper or LNG-IUD) are mostly used as long as there is careful infectious screening since the milieu of the vagina may be altered by the use of immuno-suppression, which might favour bacterial infections or mycosis. Condoms are uncomplicated but as this method is not as reliable women need to be aware of the need for proper use.

• 6.
  

  a) T b) T c) F d) F e) F

Anaemia (haemoglobin ≤ 10.5 g/dl) and elevated haemoglobin levels (haemoglobin ≥13.2 g/dl) have been defined for pregnancy according to the WHO criteria. Iron deficiency is quite common in healthy pregnant women and is recorded in about 15% of all pregnancies in the Western World. The rate of iron deficiency in transplanted pregnant women is even higher. Furthermore, pregnant KTRs with a decreased renal function in comparison to healthy pregnant women only have limited ability to adapt their haemoglobin level to the value needed since the synthesis of endogenous erythropoietin is not optimal. In patients with renal insufficiency, there are clear guidelines concerning the therapeutic goal for the treatment of anaemia. According to these, a haemoglobin value of 10-12 g/dl has to be achieved and this is also recommended in KTRs. Many different erythropoietin stimulating agents (ESA) are used and a sufficient availability of iron for haemoglobin synthesis has to be assured. Careful use of ESA is not therefore contraindicated in pregnancy. High dose ESA-therapy is associated with an accentuation of hypertension and should be avoided.

• 7.
  

  a) F b) T c) T d) T e) T

After 1 year post-OLT recipients are receiving lower doses of immunosuppression and are at decreased risk of developing rejection. Recipients have usually achieved optimal liver graft function and are on a stable immunosuppressive regimen by the end of the first year. The incidence of viral infections, specifically cytomegalovirus (CMV), which are associated with a high incidence of graft failure and maternal mortality, commonly occur within the first 3-6 months post-OLT. Recipients would also have achieved stable renal function with well controlled hypertension or diabetes by one year.

• 8.
  

  a) T b) T c) T d) T e) T

Tacrolimus – Category C

Cyclosporine – Category C

Prednisone – Category B

Mycophenolic acid- Category D

Azathioprine- Category D

• 9.
  

  a) F b) F c) F d) T e) F

Autoimmune hepatitis represents the most common cause of liver disease in female OLT recipients, and this is probably related to the higher occurrence of autoimmune hepatitis in women of reproductive age.

• 10.
  

  a) T b) T c) T d) T e) T

The incidence of structural malformations in the newborn of female OLT recipients is 4.4% which is similar to the rate of 3-5% reported in the US general population. The most frequent maternal complication is pregnancy-induced hypertension occurring in 14-44% of OLT recipients, which is significantly higher than the rates of 4-10% reported in the general population. The frequency of Caesarean Section among OLT recipients of 30-63% is relatively higher than the rate of 20-25% observed in the general population. Most were performed for standard obstetric complications (i.e., severe pre-eclampsia), which reflects the higher incidence of preterm delivery among transplant recipients. Pregnancy-related maternal death in OLT recipients is uncommon. NTPR data reported 7 maternal deaths mostly from recurrent liver disease i.e. recurrent hepatitis.

• 11.
  

  a) T b) T c) T d) F e) F

Mycophenolate and sirolimus use during pregnancy are both associated with congenital malformations and should therefore be discontinued at least 6 weeks before conception. Cyclosporine or Tacrolimus should be continued to maintain stable graft function in transplant recipients. The prevalence of fetal structural anomalies after in utero exposure to these drugs is relatively low and comparable to the general population. Although in utero exposure of azathioprine has been associated with reports of isolated fetal immunodeficiency, thymus atrophy and congenital malformations, azathioprine should preferably not be discontinued, but dosing should be kept as low as possible during pregnancy (< 2 mg/kg/day). No studies have demonstrated an increased incidence of other fetal congenital malformations with maternal corticosteroid use.

• 12.
  

  a) T b) F c) T d) T e) F

In general, transplant recipients are advised to wait 1 to 2 years after transplant before becoming pregnant. This allows recovery from the surgery and allows time to ensure stable graft function with a lower risk for acute rejection. Additionally, delaying conception allows time for immunosuppressive agents to be at lower maintenance levels, to complete postoperative treatment of opportunistic infections and for associated medical conditions (hypertension, diabetes) to be under good control. Genetic counselling is only required for transplant recipients in whom the original diagnosis may be genetically inheritable (e.g. congenital heart disease, mitochondrial cardiomyopathy, cystic fibrosis, etc.). Screening for chronic infections (e.g. HIV, HBV, HCV, CMV, HSV, HPV, syphilis, rubella, varicella and toxoplasmosis) and assessment of vaccination status should be performed in all transplant recipients who pursue pregnancy and vaccinations should be completed before conception (i.e. rubella, tetanus, HBV, influenza, pneumococcus). There are no clear guidelines for assisted reproductive technologies in transplant recipients who want to become pregnant, however, there are no strict contra-indications in this population.

• 13.
  

  a) T b) F c) F d) F e) F

Data from post-marketing surveillance and from the NTPR showed a significant increase in the rate of spontaneous miscarriage and birth defects, as well as a pattern of birth defects, when pregnant women took mycophenolic acid based products during their pregnancy.

Although uncontrolled hypertension during pregnancy is associated with poorer outcomes, and a more common side effect of MPA is an increase in blood pressure, it has not been shown that there is an increased risk of superimposed pregnancy-induced hypertension while taking MPA. MPA levels are not often monitored due to unreliable systems of measurement and as such, the dose of these products is not adjusted based on trough levels. Studies of MPA levels during pregnancy are not feasible. Although gestational diabetes during pregnancy is associated with prednisone, MPA has not been shown to cause an increase in blood sugar.

• 14.
  

  a) T b) T c) T d) T e) F

Each of the first four classes of medications acts to suppress the immune system. Granulocyte-colony stimulating factors are used to combat infections during chemotherapy by stimulating neutrophil production thereby theoretically enhancing the immune system.

• 15.
  

  a) T b) F c) T d) F e) T

Hypertension during pregnancy in kidney transplant recipients is a common occurrence. There is a low incidence (1-4%) of rejection reported during pregnancy in kidney transplant recipients. The live birth rate among kidney transplant recipients is approximately 70-80%. The rate of prematurity is about 50% among the offspring of kidney transplant recipients. The rate of pre-eclampsia reported in kidney transplant recipients is approximately three times that of the general population.

• 16.
  

  a) F b) T c) F d) F e) F

Within couples, female factor subfertility corresponds to approximately 35 % with a uterine factor making up approximately 3-5 %.

• 17.
  

  a) T b) T c) T d) T e) F

Uterine factor related infertility (UFI) has many causes and is either congenital or acquired, and can be absolute or relative. Absolute uterine factor infertility (AUFI), affects around 1 in every 500 women of fertile age, corresponding to around 200 000 women in Europe and 85 000 in the US respectively. Absence of a uterus is seen in the Mayer – Rokitansky – Küster – Hauser (MRKH) syndrome and Androgen insensitivity syndrome (AIS). Both conditions are characterized by Müllerian duct aplasia, resulting in lack of uterus and the upper two-thirds of the vagina but MRKH has a 46XX karyotype with normal ovaries and AIS has a 46XY karyotype with testes.

• 18.
  

  a) T b) F c) F d) T e) T

Myomas do not always affect the fertility, yet they may represent the most common cause of acquired UFI. Around 10 % of the population between 33 and 40 years have myomas and the incidence increases with age, as does subfertility. Corrective surgery is the primary option for a woman of fertile age but effectiveness on infertility is dependent on the position, number and size of the myomas and data on improvement rates is of low quality. Intrauterine adhesions can cause both infertility and recurrent miscarriage. Adhesions can occur secondary to intrauterine infections, surgical abortions or genital tuberculosis, with the latter cause being more common in third-world countries. Even despite adhesiolysis, around 50% of women with adhesions remain infertile. Fertility-sparing surgery (trachelectomy) for cervical cancer is restricted to tumours with an invasion less than 10 mm and a diameter not exceeding 20 mm. Half of the group with cervical cancer <40 years are suitable for this type of intervention. The remaining group of women is treated with radical hysterectomy with preservation of the ovaries.

• 19.
  

  a) F b) T c) F d) T e) F

The uterus recipient has to be thoroughly investigated prior to the transplantation both regarding the physical and psychological ability to handle the transplantation itself and the aftercoming treatment and pregnancy. Today there is a known shortage of multi-organ donors. In the case of UTx the number of potential deceased donors will at least be reduced to 50%. In most cases organ survival and function will be better with an increased HLA-match. Use of a uterus from a close relative may result in sharing some of the HLA- antigens. Rejection, modification of appropriate immunosuppression for pregnancy and recovery from surgery all dictate that waiting a year from the transplant is recommended before embryo transfer. Pregnancy following natural mating failed to occur in baboon UTxs. Post-mortem analysis revealed tubal blockage as a likely cause.

• 20.
  

  a) F b) F c) F d) F e) F

According the United States Medical Eligibility Criteria for Contraceptive Use (USMEC), all contraceptive methods can be used in women with a history of solid-organ transplantation. Women with a history of solid-organ transplantation often have additional medical comorbidities that would make estrogen-containing methods (pill, patch ring) relatively or absolutely contraindicated. These include lupus, diabetes and hypertension but this will be on an individual patient risk basis.

• 21.
  

  a) T b) T c) T d) T e) T

Medical conditions such as migraine with aura, hypertension, diabetes, lupus, or smoking increase a woman’s thromboembolic risk. Thromboembolic risk is additive in the case of estrogen-containing contraceptives, which are the combined hormonal pill, patch, and ring. Over 35 plus one other cardio-vascular risk factor is a contra-indication to estrogen containing contraception.

• 22.
  

  a) T b) T c) F d) T e) T

IUDs are rarely contraindicated. One of the few contraindications to their use is active uterine infection.

• 23.
  

  a) F b) F c) T d) F e) F

Metabolic disturbances are common in patients with renal dysfunction and account in part for the menstrual irregularities, although they seem not to be primary. There is no data on corticotrophin and menstrual dysfunction in renal patients. Even though therapy in patients with ESRD on long-term peritoneal dialysis and haemodialysis see an improvement in their general health and longevity and partial amelioration in the HPO-axis, there are several hormonal abnormalities that commonly contribute to menstrual irregularities such as reduced GnRH pulsatile secretion with absent mid-cycle LH surge. The HPO-axis abnormalities seem to be time dependent in relation to the CRF onset. Immunosuppression does not seem to be related to menstrual dysfunction. Hyperprolactinaemia is secondary to the increase in lactotroph pituitary secretion, decrease of its clearance and a decrease in dopaminergic inhibition sensitivity. It can disrupt the HPO-axis but usually results in oligo-amennorrhoea.

• 24.
  

  a) F b) F c) T d) T e) F

In most instances, pregnancy is recommended at least 1 to 2 years post transplantation assuming good graft function, well-controlled co-morbidities, no recent evidence of organ rejection, that there are no contraindications and that the patient is properly informed of potential outcomes. It is equally important for the partner to be evaluated and a combined assessment is recommended. Moreover, the patient has not been able to attain desired fertility after 12 months and should seek an infertility specialist as soon as possible. Even though the patient may first seek her primary caretaker, it would be recommended that a specialist in reproductive endocrinology should have also evaluated the patient.

• 25.
  

  a) T b) T c) T d) T e) F

Currently it is recommended to counsel all young OTr males for fertility cryopreservation. It is important that patients undergoing potentially gonadotoxic therapy (i.e. chemotherapy, radiation) undergo a comprehensive fertility evaluation. This assessment may start with the primary caretaker (oncologist) and/or urologist to evaluate and counsel for potential fertility preservation techniques. In-vitro-fertilization and the addition of ICSI seem to be adequate choices in males with poor quality sperm samples. It would be inappropriate for the patient to undergo fertility preservation only after chemotherapy and radiation therapy, known to be highly gonadotoxic. In cases where this therapy is unavoidable, all efforts should be made for fertility preservation prior to its start.

• 26.
  

  a) T b) T c) T d) T e) F

Anxiety and depression may be associated with fear of organ rejection, frustration regarding future deterioration and immunosuppressant side effects such as weight gain fluctuations, heart burn, and persistent fatigue. Family and marital strain may be due to disapproval of the pregnancy due to the perception that it may threaten the recipient’s life. Marital strain may result from role adjustment and increased transplant-related financial responsibilities. Newer immunosuppressive agents are not recommended by the National Transplantation Pregnancy Registry. The NTP reported information on 1,909 pregnancies following kidney, liver and a smaller number of other organs. Co-morbidities must be considered, but outcomes were favourable for the mother and newborn with older immunosuppressant exposure. Graft survival for kidneys and livers range from 9 to 13 years depending on the type of donor. Approximately 75% of heart recipients’ grafts survive 5 years. Most transplant recipients experience no major issues regarding mode of delivery.

• 27.
  

  a) T b) T c) T d) F e) T

Descriptive accounts of recipients’ experiences with pregnancy and child-rearing, the delineation of their hopes and fears in these situations, and the specificity of their social and cultural situations expand our understanding of what constitutes ‘ethical’ approaches to counselling and caring for this population. Ethics, informed by the social sciences, exceeds the ethically fraught moment of decision (to advise for or against pregnancy) to encompass the dynamics of families and communities, the interplay of gender and socioeconomic status and the full scope and duration of patients’ lives. Social studies research, particularly through the use of qualitative methods, longitudinal studies, and quality of life analysis, can illuminate ethical questions, clinical concerns, and the links between them. Static, and individualist, application of ethical principles such as beneficence, non-maleficence, and patient autonomy do not capture the full range of moral concerns that preoccupy pregnant transplant recipients. Anxiety about their technological pregnancy is informed by cultural currents that champion ‘natural’ birth as a particular moral identity for women; this anxiety may not be simply superseded by rationalistic calculation of the risks and benefits of discontinuing immunosuppressant drug regimens. Social studies research can provide both qualitative and quantitative empirical data that illuminate the experience of pregnancy after transplant. Such data enable clinicians to explore the full range of reproductive options and their clinical, social, ethical and psychological ramifications with their patients. Such empirical data will certainly make women’s choices better informed. However, such data cannot tell them what choice to make. The lack of attention to gender-specific issues such as pregnancy, labour, delivery, mothering, the menopause, effective contraceptive methods, intimacy issues and breastfeeding in studies of transplants is indicative of the importance of seeing ‘ethics’ through a sociological lens. Race, gender, socioeconomic status, varying ideological convictions, and distinct moral traditions all impact the ethical questions asked, the ethical calculus used, and the moral identity sought. Attending to patients’ social contexts and conditions will open up the fullest exploration of the bioethical considerations of pregnancy after transplant.

• 28.
  

  a) F b) F c) F d) T e) F

Based on data from the NTPR, approximately 70% of post-transplant pregnancies result in successful live birth. These data come mostly from kidney transplants, followed by liver and heart. Not only do most of these pregnancies not significantly alter graft function but also by the measure of live births, these pregnancies are comparable to population wide statistics.

• 29.
  

  a) T b) T c) T d) T e) T

NMSC occur on sun exposed areas like the head, neck or upper extremities; risk rises with the degree of sunshine and cumulative UV exposure and is higher in light-skinned individuals. For this reason NMSC are more frequently found in transplant recipients in Nordic Countries like Norway or Sweden with pale skin and even more in Countries with an elevated sun exposure like Australia, where moreover most of the population is of Anglo-Saxon origin.

• 30.
  

  a) F b) F c) T d) F e) T

Although the level at which hypertension should be treated pharmacologically in pregnancy is disputed internationally the general opinion is that BP should be maintained close to normal. Moreover, in the placental bed, vascular lesions including obstructive atherosclerosis are clearly more severe than in any other organ. This is associated with fetal growth restriction from the early stage of pregnancy and risk of fetal death. There can be a marked increase in proteinuria unrelated to parenchymal disease. This relates to the large increases in circulating sFlt1, which deletes podocytes of vascular endothelial growth factor. Thus, when dealing with pregnant women, considering fetal concerns, the treatment with acceptable oral antihypertensive agents should be started form the earliest stage. Age and parity are not in themselves relevant.