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Table 1 Potential obstetric and offspring risks of morbid conditions associated with prior anticancer treatments including chemotherapy, radiotherapy, surgery, and/or hematopoietic stem-cell transplant

From: Obstetric and offspring risks of women’s morbid conditions linked to prior anticancer treatments

Morbid conditions associated with prior anticancer treatments

Potential obstetric and neonatal risksa

Potential long-term risks to offspringa

Endocrine disorders (for review, see Barnes and Chemaitilly [2]).

  

Hypothalamic-pituitary axis: hyperprolactinemia and deficiencies in growth hormone (GH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), and antidiuretic hormone (ADH).

- Obstetric complications are rare in hyperprolactinemic women treated or untreated with bromocriptine, although untreated hyperprolactinemia may be a risk factor for ectopical pregnancy (25 %, 4/78 vs. 5 %, 6/25 in bromocriptine-treated pregnancies (P = 0.017) [27].

 
 

- Hyperprolactinemia may lead to galactorrhea and nipple tenderness which are not suitable for breastfeeding (for review, see Du et al. [40]).

 
 

- Maternal hypopituitarism is associated with increased risk of abortion during early gestation, anemia, pregnancy-induced hypertension, placental abruption, premature birth, cesarean birth, and postpartum uterine inertia leading to postpartum hemorrhage (for review, see Du et al. [40]).

 

- Thyroid gland: primary hypothyroidism with elevated plasma TSH levels and either normal or low levels of free thyroxine (T4), hyperthyroidism, or autoimmune induced thyroid disease (note that the presence of thyroid antibodies does not necessarily lead to hypothyroidism in the context of hematopoietic stem-cell transplant).

- Pregnant women with subclinical hypothyroidism (elevated plasma TSH levels and normal free T4) have increased risk of miscarriage, gestational diabetes, preterm delivery, and placental abruption (for review, see Pearce [28]). Likewise, maternal overt hypothyroidism (elevated plasma TSH levels and low free T4) is associated with miscarriage, stillbirth, gestational hypertension, preterm delivery, and low birth weight (for review, see Pearce [28]).

- Maternal subclinical or overt hypothyroidism is associated with decreased child intelligence (for review, see Pearce [28]). Maternal hypothyroidism is also associated with increased risk of neonatal seizure [adjusted hazard ratio (HR):1.08, 95 % confidence interval (CI): 1.02-1.15], febrile seizure (adjusted HR: 1.21, 95 % CI: 1.10-1.32), and epilepsy (adjusted HR: 1.22, 95 % CI: 1.06-1.40); childhood autism spectrum disorders (adjusted HR: 1.30, 95 % CI:1.11-1.53); and adolescence and young adulthood psychiatric disorders (adjusted HR for use of antipsychotics: 1.22, 95 % CI: 1.03-1.44; and adjusted HR for use of anxiolytics: 1.23, 95 % CI: 1.03-1.48) (for review, see Andersen et al. [26]).

 

- Pregnant women with subclinical hyperthyroidism is not associated with adverse maternal or fetal outcomes (for review, see Pearce [28]). In contrast, uncontrolled overt hyperthyroidism during pregnancy is associated with increased risk of thyroid storm, maternal congestive heart failure, miscarriage, stillbirth, preterm delivery, pre-eclampsia, low birth weight, intrauterine growth restriction, and fetal/neonatal thyroid dysfunction (for review, see Pearce [28]).

- Maternal hyperthyroidism increases the risk of epilepsy (adjusted HR: 1.20, 95 % CI: 1.09-1.32) and attention-deficit hyperactivity disorder (adjusted HR: 1.18, 95 % CI: 1.03-1.36) (for review, see Andersen et al. [26]).

 

- Autoimmune hypo- or hyperthyroidism during pregnancy is associated with the same obstetrical and neonatal risks posed by non-autoimmune hypo- or hyperthyroidism (see above). In addition, euthyroid pregnant women with detectable thyroid autoantibodies display higher risk of miscarriage [in cohort studies, random effects odds ratio (OR):3.90, 95 % CI: 2.48-6.12; in case-control studies, random effects OR:1.80, 95 % CI: 1.25-2.60] and preterm delivery (in cohort studies, random effects OR: 2.07, 95 % CI: 1.17-3.68) (for systematic review, see Thangaratinam et al. [29]). Notwithstanding, treatment with levothryroxine reduces the risk of miscarriage [relative risk (RR):0.48, 95 % CI:0.25-0.92] and preterm delivery (RR: 0.31, 95 % CI: 0.11-0.90) (for systematic review, see Thangaratinam et al. [29]).

- Autoimmune hypo- or hyperthyroidism during pregnancy is associated with the same long-term risks to offspring posed by non-autoimmune hypo- or hyperthyroidism (see above). Furthermore, children of euthyroid pregnant women with elevated titers of thyroid peroxidase autoantibody (TPOAb) are at risk for transient hyperthyroxinemia one week after birth (the values of free T4 are, however, normalized after 15 days) [48] and impaired psychomotor development at 5 years of age (adjusted OR for the scores on the General Cognitive Scale: 10.5, 95 % CI: 3–34) (for review, see Dallas [49]). Transplacentally-transmitted TPOAb positivity at birth is also associated with increased incidence of autoimmune thyroiditis during childhood and adolescence (adjusted OR: 4.12, 95 % CI: 1.79-9.50) [50].

- Gonads: acute ovarian insufficiency (i.e., women do not experience a recovery of their ovarian function after finishing cancer treatments) or primary ovarian insufficiency (POI), previously called premature ovarian failure or premature or early menopause (i.e., women resume pubertal development or menstrual cycles after finishing cancer treatments but experience ovarian failure before the age of 40 years).

- In contrast to natural menopause, women diagnosed with POI may undergo unpredictable ovarian function leading to intermittent and unpredictable menses in 50 % of cases. Pregnancy and delivery in women with POI are unlikely and rare (for review, see Tarín et al. [41]).

 

- Body composition: survivors of acute lymphoblastic leukemia and brain tumors have higher risks of obesity and overweight.

- Pregnant women with obesity have higher risk of gestational diabetes (OR: 3.76, 95 % CI: 3.31-4.28 for women with body mass index (BMI) > 29.9 kg m−2), gestational hypertension (4.5-8.7 times more likely than normal weight women), pre-eclampsia (pooled RR: 2.68, 95 % CI: 2.40-3.00 for women with BMI 30–34.9 kg m−2), antenatal (OR: 1.43, 95 % CI: 1.27-1.61) and postnatal (OR: 1.30, 95 % CI: 1.20-1.42) depression, antenatal anxiety (OR: 1.41, 95 % CI: 1.10-1.80), instrumental-vaginal (OR: 1.17, 95 % CI: 1.13-1.21) and cesarean birth (ORs from 2.01, 95 % CI: 1.87-2.15 to 2.36, 95 % CI:2.15-2.59), and surgical site infection than pregnant women of healthy weight. In addition, maternal obesity is associated with higher risk of congenital anomalies, preterm birth (adjusted OR: 1.33, 95 % CI: 1.12-1.57 for women with BMI ≥ 35 kg m−2), large-for-gestational-age babies (above the 90th centile) (OR: 2.08, 95 % CI:1.95-2.23), miscarriage (pooled OR: 1.31, 95 % CI: 1.18-1.46 for women with BMI ≥ 28 kg m−2), fetal death (RR: 1.34, 95 % CI: 1.22-1.47 for women with BMI ≥ 30 kg m−2), stillbirth (adjusted OR: 1.6, 95 % CI:1.35-1.95 for women with BMI ≥ 30 kg m−2), birth over 41–42 weeks’ gestation, induction of labor, failure to progress in labor, post-partum hemorrhage, longer duration of hospital stay, neonatal intensive care unit admission, lower breastfeeding initiation incidence (ORs from 1.19 to 3.65), and shorter breastfeeding duration (HRs from 1.24 to 2.54) [42] (for systematic review, see Marchi et al. [43]).

- Maternal obesity is associated with cardiovascular and metabolic disorders, obesity, childhood asthma and wheezing, cognitive development deficits, attention-deficit hyperactivity disorder, cancer, and greater all-cause mortality (for review, see Wilson and Messaoudi [51]).

- Glucose metabolism: insulin resistance, metabolic syndrome, and diabetes mellitus.

- Maternal diabetes increases the risk of congenital anomalies affecting any developing organ system, although cardiovascular and neural tube defects are among the most frequent anomalies. Furthermore, it increases the risk of pre-eclampsia, preterm delivery, fetal macrosomia, low birth weight, and perinatal mortality [42].

- Children born to diabetic mothers tend to be overweight and taller, and have increased incidence of gross and fine motor abnormalities, attention deficit hyperactivity disorder, learning difficulties, likely autism spectrum disorder, and metabolic morbidity later in life (for reviews, see Hiersch and Yogev [31] and Ornoy et al. [30]).

 

- Pregnant women with insulin resistance display increased risk of miscarriage, pre-eclampsia, and fetal macrosomia, especially in pregnancies complicated by type 1 diabetes mellitus [44] (for review, see Gutaj et al. [45]). Moreover, maternal pregestational type 2 diabetes mellitus (insulin resistance) is associated with a higher prevalence of birth defects in offspring [adjusted prevalence ratio (PR): 4.51, 95 % CI: 2.46-8.29] including cardiovascular, genitourinary, and musculoskeletal defects [46].

 
 

- Women with metabolic syndrome have a higher risk of pre-eclampsia, preterm delivery or low birth weight (for review, see Malek [47]).

- Children of mothers with metabolic syndrome are likely to develop metabolic syndrome and cardiovascular disease (for review, see Malek [47]).

Adverse cardiovascular events (for reviews, see Travis et al. [3] and Ewer and Ewer [52]).

  

- Left ventricular systolic dysfunction, cardiovascular disease (pericardial disease, coronary artery disease, carotid artery occlusive disease, premature valvular calcification and dysfunction, conduction abnormalities, and cerebrovascular disease), cardiac arrhythmias, and cardiac ischemia.

- Pregnant women suffering from heart diseases have increased risk of maternal cyanosis, risk of bleeding due to anticoagulation treatment, placental hypoperfusion and/or cyanosis, fetal growth restriction, miscarriage, stillbirth, and prematurity (for review, see Emmanuel and Thorne [34]).

 

Pulmonary dysfunction in childhood cancer survivors, particularly in women treated with pulmonary-toxic chemotherapy and survivors treated with more than 20 Gy chest radiation [53].

  

- Restrictive lung disease with reduced lung volumes as a result of either decreased lung parenchyma or changes to the chest wall that may restrict lung parenchyma growth.

- The ability to increase the minute ventilation during pregnancy may be limited in pregnant women with restrictive lung disease. Consequently, they may have difficulty meeting the increased oxygen demands of late pregnancy putting the fetus at risk of hypoxic injury [54].

- Fetal chronic hypoxia induces fetal growth restriction and programs cardiovascular, metabolic, and endocrine dysfunction in the adult offspring (for review, see Giussani et al. [56]).

- Decreased pulmonary diffusion capacity.

- Cancer survivors with decreased pulmonary diffusion capacity are more likely to report respiratory symptoms, poor physical functioning, low energy and increased fatigue than survivors without diffusion defects [53]. These effects may be exacerbated during the third trimester of pregnancy when pulmonary diffusion capacity decreases compared to non-pregnant women especially in women living at high altitude [55].

 

Renal adverse effects (for systematic review, see Knijnenburg et al. [57]; for review, see Porta et al. [58]).

  

- Acute kidney injury, renal insufficiency, chronic kidney disease, impaired glomerular filtration rate, proteinuria, electrolyte disturbances, impaired phosphate tubular regulation, hypertension, and thrombotic microangiopathies.

- Pregnant women with chronic kidney disease and serum creatinine levels > 1.5 mg/dL have higher risk of gestational deterioration in renal function. In addition, there is a negative linear association between maternal proteinuria and infant birth weight as well as between the severity of maternal proteinuria and degree of renal dysfunction and fetal loss (for review, see Gyamlani and Geraci [59]).

 
 

- Treated chronic hypertension in pregnancy is associated with increased risk of pre-eclampsia (adjusted OR: 6.0, 95 % CI: 4.7-8.8), placental disorders (adjusted OR: 2.3, 95 % CI: 1.8-3.1), gestational diabetes (adjusted OR: 2.2, 95 % CI: 1.4-3.5), threatened abortion (adjusted OR: 1.9, 95 % CI: 1.7-2.1), preterm delivery (adjusted OR: 1.5, 95 % CI: 1.3-1.8), and low birth weight (adjusted OR: 2.3, 95 % CI: 1.8-2.7) (for review, see Czeizel and Bánhidy [32]). In addition, pregnancies complicated by chronic hypertension are at increased risk of congenital abnormalities, particularly cardiac malformations (adjusted OR in treated women: 1.06, 95 % CI: 1.4-1.9; adjusted OR in untreated women: 1.5, 95 % CI: 1.3-1.7) (for review, see Bateman et al. [33]).

 

Uterine damage (for reviews, see Lawrenz et al. [21], Wo and Viswanathan [60]; Wallace et al. [61], and Teh et al. [62]).

  

- Total-body, flank, abdomen, pelvis or direct uterine irradiation leads to changes in the uterus including reduced uterine volume, endometrial and myometrial atrophy, uterine fibrosis, loss of elasticity of the myometrium, and reduced blood flow.

- Radiotherapy-induced structural and functional changes to the uterus may adversely affect implantation and maintenance of pregnancy increasing the risk of placental attachment disorders (placenta acreta or placenta percreta), low birth weight (RR: 1.85, p = 0.03 in patients treated with pelvic irradiation, and ORs from 3.64, 95 % CI: 1.33-9.96 in survivors after abdominopelvic radiation up to 6.8, 95 % CI: 2.1-22.2 in patients treated with high-dose (>5 Gy) radiotherapy to the uterus), small for gestational age (OR: 4.0, 85 % CI: 1.6-9.8 in patients treated with high-dose (>5 Gy) radiotherapy to the uterus), preterm delivery (OR: 3.5, 95 % CI: 1.5-8.0 in patients treated with high-dose (>5 Gy) radiotherapy to the uterus), perinatal death, and fetal malposition (for review, see Wo and Viswanathan [60]).

 
 

- Surgical removal of the uterine cervix in cervical cancer patients is associated with increased risk of second trimester loss (10 % of pregnancies) and premature delivery in the third trimester (19 % of pregnancies) (for review, see Knopman et al. [4]).

 

Musculoskeletal deficiencies in survivors of childhood cancer (for reviews, see Wasilewski et al. [63], Barnes and Chemaitilly [2], and Wissing [64]).

  

- Low bone mineral density

- A deficit in bone mineral density is associated with increased susceptibility to fragility fractures in pregnancy or the puerperium that may result from the combination of abnormal skeletal microarchitecture prior to pregnancy and increased bone resorption during pregnancy (for review, see Kovacs [65]).

 
 

- During pregnancy and lactation, calcium homeostasis is overwhelmingly in favor of the fetus/neonate, and the fetal/neonatal calcium levels are maintained despite or even at the expense of maternal levels and health (for review, see Done [66]).

 
  1. aORs, HRs, PRs, or RRs to mothers and offspring of some morbid conditions linked to prior anticancer treatments are missing because of reviewed data come from literature narrative syntheses