Fertility Issues in Transfusion-Dependent Thalassemia Patients: Pathophysiology, Assessment, and Management


Number of pregnancies

Age (years)

Number (%) received ovulation induction

Ferritin (mean or range) μg/L

Delivery by CS (%)

Complications during pregnancy

Ref

Year

Prepregnancy

Post-pregnancy

3

23.6

0

736–1412

708–1160b

1 (33)

1 cardiac

89

2000

86

25.5–28.5

23 (27)

2000

2750

28 (32)

4 miscarriages

67

2004

2 stillbirths

24

19–38

12 (50)

1000–11,000

N/A

18 (75)

2 maternal deaths after delivery (cardiac failure)

68

2005

7 cardiac

2 miscarriages

1

28

0

3800

5800

1 (100)

None

90

2005

62a

N/A

0

N/A
 
12/45 (26)

5 cardiac

83

2006

12 miscarriages

1

38

0

67

1583

N/A

None

85

2008

5

31 ± 3.5

3 (60)

770–2100

N/A

4 (80)

1 GD, 1 cardiac arrhythmia

71

2008

1 renal colic, 1 stillbirth

11

N/A

11 (100)

2000

5000

7 (63)

1 thromboembolic episode

73

2009

Premature labor

58

29.5 ± 4.5

33 (57)

1463 ± 1,306

2692 ± 1,629

52 (89)

4 miscarriages

84

2010

5

23–29

1 (20)

500–1000
 
5 (100)

None

97

2011

1

35

0

2430

2260

1 (100)

GD

93

2011

28

27

22b(78)

N/A

N/A

N/A

4 GD

88

2013

4 cardiac

4

27.9 ± 3.7

1 (25)

236 ± 1258

336 ± 3054

3 (75)

1 miscarriage

96

2014

2

27

0

417

1196

0

None

94

2015


Two hundred ninety pregnancies were reported in prior ~15 years, 1985–2000 [14]

Cardiac complications: (1) cardiac death in patients who became pregnant despite preexisting cardiac dysfunction [68], (2) early congestive heart failure [89], (3) worsening measures of increase in LVEDD and LVESD, (4) decrease in SF and EF on echocardiogram

N/A not available, GD gestational diabetes

aNTDT patients possibly included

bIn two of the three pregnancies, the patient continued iron chelation with deferoxamine throughout the pregnancy and maintained stable low ferritin levels [89]



Earlier studies, presumably conducted in heavily iron-overloaded patients, suggest impaired oocyte function contributing to infertility. Extensive iron deposition in the ovary has been implicated as a cause of ovarian failure [12, 44]. In two successful pregnancies, inability to fertilize the thalassemia woman’s oocyte in vitro was alleviated by using donor oocytes and the husband’s sperm [72]. In a more recent study, ovarian volume was significantly reduced to the range of that of postmenopausal women. This reduction was probably due to the lack of gonadotropin stimulation, but could also have been a direct result of iron on the ovarian tissue, particularly in thalassemia women with long-standing iron overload [8]. Another study demonstrated hemosiderin in the endometrial epithelium of three TM women [45].



Ovarian Reserve and Fertility Preservation


An important part of care for TM women is providing them with information about their reproductive state and initiating an overall plan for a prepregnancy care (see below). FSH and estradiol levels in the follicular phase in TDT women are not reliable markers for gonadal function evaluation, and hormone stimulation tests to assess gonadal function did not yield consistent results [62, 73, 74]. More advanced methods such as hormonal profile along with ovarian reserve testing (ORT) in TM women of reproductive age are scarce. A more recent study utilized antral follicle count (AFC), a strong predictor of ovarian reserve, and found it to be lower in TM compared to normal controls, in particular in TDT women 30 years and older [8].

Anti-Mullerian hormone (AMH), another sensitive marker of ovarian reserve, is applied often in fertility clinics. It represents the early primordial follicle pool in the ovary, and is therefore independent of gonadotropin effect [7577]. It may therefore emerge as a more reliable marker for reproductive potential and predictor of success of assisted reproductive technology in thalassemia women. Two studies assessed AMH levels in TDT women, both describe low to a low-normal range compare to normal controls. However, a clear downward trend of AMH levels in older women, in the mid-30s and older, was noted [8, 77]. The two studies showed a reverse correlation between AMH and iron overload measures, NTBI or ferritin, that was independent of the patients’ age. It appears that fertility declines in older TDT women who may have a faster drop in their ovarian reserve pool than age-matched normal women (Figs. 14.1 and 14.2). This suggests that duration of exposure to iron may increase the deleterious effects and exhaust the ovarian reserve, possibly through direct ovarian tissue effect (as discussed in earlier sections of this chapter). Therefore, it is important to initiate assessment, discussion, and consultation regarding patients’ wishes and efforts to preserve fertility at a young age. Attempts to reduce iron overload through intensified chelation therapy may be helpful to restore some reproductive function in some cases. Notably, improvement in gonadal function was observed in one female who gave birth to two healthy children without hormonal stimulation after intense iron chelation treatment [3]. In addition, elective cryopreservation of oocytes or ovarian tissue should be considered, while the oocytes and tissue are still attainable.

A336217_1_En_14_Fig1_HTML.gif


Fig. 14.1
AMH levels and AFC in TM women and normo-ovulatory controls. (a) AMH levels in the thalassemia women, 25 years and older (n = 23, red circles), were compared with normal controls (●; n = 759), showing that the slopes of the regression lines against age were not statistically different (P = 0.56). The slope was significant for the normal controls (P < 0.0001; 95 % Cl, −1.867 to −1.406) and for the thalassemia patients (P < 0.03; 95 % Cl, −2.323 to −0.1142), implying an association with age. There was a 5.0pM (95 % Cl, 13.4–26.8) difference between the group means. The levels in the thalassemia women were in the low-normal range of normal and dropped to lower levels in women older than 30 years. (b) Age-dependent AFC in thalassemia women and normal controls. AFC number includes all counted follicles 2–10 mm in size, in thalassemia women, and in the cohort of normal controls (n = 769) (With permission from Singer, et al. Blood, 8 September 2011;118(10):2878–81)


A336217_1_En_14_Fig2_HTML.gif


Fig. 14.2
Iron overload is associated with low AMH in women with TDT. Scatter plot with fit line of the untransformed serum ferritin and AMH levels in 29 women with transfusion-dependent beta-thalassemia. Age-adjusted Spearman correlation coefficient is shown (With permission from Chang H, et al. BJOG. 2011;118:825–83)

Over the past decade, there has been increasing interest in methods to expand the reproductive options of patients facing gonadotoxic therapies for various types of malignancies [78, 79]. There is, however, very limited such information for thalassemia patients. A recent successful ovarian tissue cryopreservation was demonstrated both in an adolescent thalassemia patient [80] and in a TDT woman prior to receiving gonadotoxic preconditioning treatment for hematopoietic stem cell transplantation (HSCT). Reimplantation of ovarian tissue resulted in IVF pregnancy and delivery of a healthy baby [81].


Prepregnancy Planning in Transfusion-Dependent Thalassemia Women


Prepregnancy counseling and planning are essential in order to minimize risk to the pregnant thalassemia woman and to the fetus. Apart from subfertility, other systemic and endocrine disorders, primarily cardiac disease, liver dysfunction, diabetes mellitus, and chronic viral infections, hamper fertility ability and pregnancy. Ideally, a multidisciplinary team comprised of a hematologist, reproductive medicine specialist, obstetrician, and cardiologist should be involved. In many cases, a psychologist is helpful also. Partner screening for carrier status of a thalassemia syndrome is essential and genetic counseling may be needed. The safety of pregnancy for mothers with TDT has been discussed in several reports [68, 73, 8284]. A number of systems require prepregnancy evaluation and consideration during pregnancy:



  • Cardiac function. The cardiac load during pregnancy increases physiologically by about 25 %. In addition, most TM women require an increase in red blood cell transfusion to maintain high enough pre-transfusion hemoglobin levels. The increase in transfusion, coupled with discontinuing iron chelation throughout most of the gestational time due to concerns of teratogenicity can result in a significant increase in systemic and myocardial iron load (Table 14.1) [85]. In women with borderline cardiac function, these two factors can result in left ventricular dysfunction, serious cardiac complications, and even death. An evaluation of cardiac function by echocardiogram or by MRI and cardiac iron level by T2* MRI technology, if available, should be performed. The 2014 Thalassemia International Federation (TIF) guidelines for the management of TDT recommend having an ejection fraction >65 %, shortening fraction >30 % by echocardiogram, and T2* no less than 20 ms [86]. If cardiac function is low or cardiac iron load is high (T2* <20 ms), it is advised to intensify chelation to improve cardiac function before trying for a pregnancy. Occasionally, the use of iron chelation when faced with an increase in cardiac iron burden and cardiac failure during pregnancy is indicated.


  • Endocrinopathies. Patients need to be screened for early glucose intolerance or assure a well-balanced glucose range if diabetes mellitus has already developed. Screening for hypothyroidism and monitoring to assure a euthyroid state are important. Additionally, bone health and extent of osteopenia, osteoporosis, or chronic bone and joint pain need to be evaluated.


  • Viral infections. Screening for hepatitis B and C and HIV are important, and treatment for hepatitis C or HIV should be offered prior to pregnancy.


  • Psychological support. Thalassemia women face lifelong complications related to their disease that influence their self-esteem, sense of identity, social life, and family planning. TM women attempting to get pregnant have shown increased rates of anxiety and depression as compared to healthy pregnant controls [87]. Integrating psychological support in the multidisciplinary team that develops a program for a TM woman to become pregnant and follows her through her pregnancy is recommended.


Pregnancies: Management, Outcomes, and Complications



Cardiac Function Monitoring

Cardiac hemosiderosis reduces myocardial contractility, causing compensatory hypertrophy that can compromise cardiac performance during pregnancy as the cardiac output rises significantly. Though minimal transient cardiac function changes have been shown in a large report [84], other smaller case studies have shown a more pronounced increase in left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) in TDT women compared to the expected normal physiological changes in pregnancy. Some were accompanied by a fall in ejection fraction and shortening fraction, likely due to diminished contractility [83, 88, 89] or overt heart failure and subsequent death [68]. As an increased number of pregnancies may now be expected, careful monitoring of cardiac function is important, even with normal prepregnancy echocardiograms, as iron overload can develop rapidly with discontinuation of chelation [85, 90]. Regular cardiac monitoring every 3 months has been suggested [67].


Transfusion and Iron Chelation

Maintaining pre-transfusion hemoglobin of 10–11 g/dL through more frequent low volume blood transfusions is recommended. Data on the safety of iron chelation treatment during induction of ovulation treatment and during pregnancy is scarce. However, due to the concern of teratogenicity, a common practice is to discontinue chelation therapy during the ovulation induction days until the outcome is known, as well as during the first two trimesters of pregnancy (some patients chose to avoid chelation through the whole gestation period). In case reports, no teratogenicity with the use of deferoxamine was reported, and consideration should be given to offer it in second trimester or when a concern of change in cardiac function occurs [85, 89, 91, 92]. Withholding chelation with deferoxamine in such situations may result in further decline in cardiac function and possible heart failure during pregnancy or after delivery. There is limited data on newer oral chelators that are smaller molecules and may have a higher likelihood to cross the placenta. However, a case report of incidental use of deferasirox up to 22 weeks of gestation still resulted in the birth of a healthy baby [93].


Anticoagulation

Due to an increased risk of thromboembolism in TDT women who underwent splenectomy, it is advised to use low-dose aspirin during pregnancy and postpartum [71, 89]. In a larger study, low molecular heparin was administered peripartum subsequent to aspirin during gestation without any increased bleeding tendency [84]. More detailed recommendation can be found in the 2014 TIF guidelines for the management of TDT [86].

Based on the above, it seems that, irrespective of spontaneous or induced ovulation, the current outcome of attempted pregnancies in TDT women, with proper multidisciplinary guidance and care, is optimistic. More than 500 pregnancies in TDT women have been reported; the majority delivered healthy term babies, while preterm babies were reported in 13–35 %, some related to multiple pregnancies [94]. Complications included a higher frequency of miscarriage, intrauterine growth retardation (IUGR), and low birth weight. Cesarean section is most often the chosen delivery method due to concerns of cephalopelvic disproportion resulting from maternal short stature and skeletal deformities and normal fetal growth [68, 70, 84, 88, 9597]. Reports show a variable increase in iron load, which ranged from 10 to 100 % greater ferritin levels than preconception, likely related to the differences in the increase in blood transfusion during pregnancy. Some have noted a higher incidence of complications during pregnancy; these include: cardiac issues (compromised LV function, arrhythmias, and hypertension), gestational diabetes, impaired glucose tolerance, and renal colic (Table 14.1). There were no reports of increase in incidence of thrombosis or preeclampsia.



Fertility Issues in Thalassemia Men


While ovulation induction in TM women can result in successful pregnancies and births, successful paternity seems to occur less often in TM men, a discrepancy that is not well understood. It is estimated that more than one half of men with TM are affected by oligospermia, asthenospermia, and possibly compromised sperm quality [7, 17, 48, 62, 67]. However, great variability in TDT phenotypes in these studies likely affects these estimates. Additionally, emerging iron chelation treatments may positively impact this high prevalence. Infertility in TM men appears to have multiple causes, including HH, late-onset hypogonadism, abnormal spermatogenesis, and possibly nutrient deficiencies combined with an increase in oxidative stress that affects sperm qualities, as discussed above.


Assessment of Reproductive Potential



Hormonal Assessment


Several advances in diagnosis and treatment of male infertility have been made in recent years [98, 99]. In most sterile males in the general population, primary gonadal dysfunction will result in elevated LH and FSH levels; however, these are not useful predictors for fertility potential in thalassemia men, as their LH and FSH secretion will be compromised due to iron overload effects on the pituitary. Variable gonadotropin levels and age of onset of HH have been reported making the use of these hormone levels difficult for assessment of fertility potential [7, 17, 61]. Gonadal and fertility status is also difficult to predict by means of transfusion or chelation parameters, as no clear correlation was shown with HH [17, 100]. Levels of inhibin B, a hormone produced in sertoli cells in the testes that inhibits pituitary FSH secretion, seem to better reflect testicular function and spermatogenesis and show a more accurate predictive ability of male fertilization potential than FSH levels [101, 102]. Obtaining levels of inhibin B may have a better extrapolative value in TDT men, currently being studied.

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Sep 24, 2017 | Posted by in GYNECOLOGY | Comments Off on Fertility Issues in Transfusion-Dependent Thalassemia Patients: Pathophysiology, Assessment, and Management
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