Triplet and higher-order multiple pregnancies can carry increased fetal and maternal complications. Reports of triplet pregnancies after kidney transplant are scarce and have been associated with perinatal complications. Presence of diabetes in such cases worsens both fetal and maternal outcomes. Here, we present a triplet pregnancy in a kidney transplant recipient with diabetes. We also reviewed the literature for causes, prevalence, and outcomes in association with chronic kidney disease, kidney transplant, and diabetes mellitus. The patient, a 31-year-female who received a living-donor kidney transplant, had a first-time pregnancy 6 years after transplant. Pregnancy was complicated by gestational diabetes, preeclampsia, and miscarriage. She continued to have postpartum-impaired glucose tolerance. She became pregnant again after 6 months but required insulin therapy during her third trimester. Pregnancy was terminated by cesarean section for a viable small boy. Two years later, she had triplet pregnancy after ovulation induction with clomiphene. Glycemic control was maintained using intensive insulin therapy guided by frequent home blood glucose monitoring (HbA1c was 5.8% at 22 wk). Both gynecologic care and nephrologic care were carried out through outpatient follow-up. Pregnancy was complicated by hypertension and mild renal dysfunction without proteinuria and ended in elective premature cesarean section at 32 weeks of gestation. She had 3 male babies with low birth weights (1320, 1380, 1275 g), with the largest baby developing sepsis and requiring an intensive care unit stay and then incubator for 49 days. The other 2 required incubators for 36 days. Their weights after 22 months were 9, 16, and 11 kg. The mother is now normotensive with normal renal function and impaired glucose tolerance. Care of diabetic kidney recipients with triplet pregnancy constitutes a special challenge requiring a multispecialty skilled team to ensure the best outcome.
Key words : Chronic kidney disease, Diabetes mellitus, Kidney recipient, Multiple pregnancy, Outcome
Advancing maternal age and assisted reproductive technology are considered the leading factors behind increased incidences of multiple pregnancies in the developed world.1 The rate of triplet and higher-order multiple births in the United States was 148.9 per 100 000 total births in 2007 compared with 70 per 100 000 total births in 1990.2 With recent changes in assisted reproductive technology, this rate has been reduced to 119.5 per 100 000 births in 2013.3
The associated maternal morbidity and obstetric complications are significantly higher in multiple compared with twin pregnancies in a dose-response relation.4 A multiple pregnancy is associated with increased incidence of gestational diabetes in up to 3% to 6% of twin pregnancies and in 22% to 39% of triplet pregnancies.5 Diabetes mellitus with pregnancy carries a higher risk of several adverse maternal and neonatal outcomes.6 Maternal glycemic levels even less so than overt diabetes are associated with adverse maternal outcomes (primary cesarean delivery and preeclampsia) and neonatal outcomes (clinical hypoglycemia, premature delivery, birth injury, shoulder dystocia, hyperbilirubinemia, and intensive neonatal care) in continuous linear associations with fasting as well as in 1- and 2-hour plasma glucose levels according to the 75-g oral glucose tolerance test.7
Kidney transplant is vital in reversing fertility by improving gonadal function and stabilizing the hormonal cycle. This fact is reflected by the success rate of pregnancy after first trimester, which has now exceeded 90%.8 Pregnant women with kidney transplants are usually at risk of pregnancy-related complications and renal graft dysfunction. Preexisting hypertension and/or proteinuria may confuse the diagnosis of preeclampsia, which can develop in one-third of patients.9 Prematurity, intrauterine growth retardation, and low birth weight are frequent fetal complications in women after kidney transplant.10
Medications required for transplant recipients are crucial when pregnancy is considered because some medications could be contraindicated or need to be withdrawn before pregnancy. All immunosuppressive medications can cross the maternal-placental-fetal barrier. These undergo additional metabolism by placental and fetal hepatic enzymes, necessitating frequent dose adjustment.11 Here, we present a female patient with kidney transplant who had a triplet pregnancy and diabetes. We analyzed various aspects of her condition in view of the available literature.
A 31-year-old female patient, with renal failure at 20 years old secondary to a recessive type of polycystic kidney disease, remained normotensive and normoglycemic, although she had a positive family history of diabetes. She underwent a successful living unrelated renal transplant somewhere abroad using daclizumab (Zenapax, Hoffmann-La Roche Pharmaceutical, Basel, Switzerland) as induction immunosuppression and prednisolone, mycophenolate mofetil (CellCept, Hoffmann-La Roche Pharmaceutical), and cyclosporine (NEORAL, Novartis Pharmaceuticals, Basel, Switzerland) as maintenance immunosuppression. She had stable renal function posttransplant except for biopsy-proven cyclosporine toxicity, which responded to dose reduction. She developed cytomegalovirus pneumonia early after transplant and received parenteral and then oral ganciclovir for 3 months with full clinical, radiologic, and laboratory recovery. A perigraft collection compressing the renal pelvis was drained surgically to the peritoneal cavity at 3 months after transplant. After that, she maintained normal renal function and underwent regular follow-up in the outpatient department.
At 6 years after transplant, she married and had her first planned pregnancy 3 months later. Mycophenolate mofetil was converted to azathioprine. Despite normal progression of pregnancy through the first and second trimesters, she developed preeclampsia and intrauterine fetal death. Her pregnancy was terminated at 28 weeks by vaginal delivery. She had normal blood glucose levels during pregnancy except for elevated postprandial glucose (8-10 mmol/L) near the time of termination. She had persistent renal dysfunction for 2 months due to biopsy-proven chronic cyclosporine toxicity. Cyclosporine dose was initially reduced and then converted to tacrolimus (Prograf, Astellas Pharma, Deerfield, IL, USA), and renal function returned back to normal.
Six months later while on azathioprine, she had her second pregnancy. At that time, her blood pressure was controlled on labetalol, and she was normoglycemic and on a normal diet. She developed impaired glucose tolerance during her first and second trimesters. Despite diet control, she required insulin during the third trimester. She had fetal growth retardation (1.1 kg by 29 weeks) with occasionally absent end-diastolic flow of the umbilical artery that was not worsening. She was started on low-molecular-weight heparin for 3 weeks, and then she was admitted to the hospital at 32 weeks with thrombocytopenia (platelet count of 92 000), a slightly elevated gamma glutamyl transpeptidase level, and a raised serum creatinine level (150 μmol/L) with normal blood pressure. Pregnancy was terminated by elective cesarean section to give birth to a viable boy who weighed 1.4 kg. Renal function came back to normal, and she did not require insulin after delivery, although she continued to have impaired glucose tolerance for some time before she was diagnosed with diabetes.
After 15 months of stable renal function, she was reassessed for a third pregnancy but was found to have secondary infertility due to anovulatory menstrual cycles with extremely low progesterone levels (< 3 ng/mL at 21 days of the cycle) and normal gonadotropin and prolactin levels. Her glycemic control was abnormal (HbA1c = 7.9%), and she was asked to adopt a strict lifestyle modification as she refused to start on pharmacologic therapy. A trial of ovulation induction using clomiphene citrate (Clomid, Sanofi-Aventis, Bridgewater, NJ, USA) at 50 mg daily for 5 days was given after lowering her HbA1c level to 7.6%. She became pregnant from the first trial and was found to have triplet pregnancy with separate upper placentae (trichorionic) and amniotic sacs (triamniotic). Follow-up anomaly scan showed normal fetal anatomy. There was intrauterine growth restriction of the triplet. Follow-up Doppler ultrasonography scans of umbilical arteries were normal.
The patient received regular follow-up every 2 weeks by a team of specialists (gynecologist, endocrinologist, and nephrologist) in addition to a dietitian and diabetes educator. Blood glucose was controlled using twice-daily intermediately acting insulin (Insulatard, Novo Nordisk, Denmark) and premeal short-acting insulin (NovoRapid, Novo Nordisk, Malov, Denmark). HbA1c had decreased to 5.8% by the third trimester. Her blood pressure levels remained within normal ranges without medications throughout the pregnancy. Tacrolimus dose was progressively increased to 5 times the prepregnancy dose to keep the target blood level around 5 ng/mL. She had 2 episodes of urinary tract infection, which were treated with oral antibiotics. She also had normocytic normochromic anemia that required subcutaneous erythropoietin injections.
At 30 weeks gestation, she was admitted to the hospital because of abdominal pressure symptoms, elevated blood pressure, and mild deterioration of renal graft function without proteinuria. Elective low transverse cesarean section was done at 32 weeks. She delivered 3 boys weighing 1320, 1380, and 1275 g each (Table 1). Her blood pressure and renal function improved, and she was able to leave the hospital after several days, but she continued to have impaired glucose tolerance. The 3 babies had Apgar scores of 7 to 9. They had respiratory distress syndrome due to hyaline membrane disease that was managed by aminophylline and continuous positive airway pressure for 8, 6, and 1 day. They had nonhemolytic neonatal jaundice that was treated with phototherapy for 3 to 4 days. The 3 infants received prophylactic antibiotics for 7, 3, and 7 days. Blood transfusion was required 6 times for the first and twice for the second and third babies. Oral feeding commenced at days 4, 3, and 6 of life. It was tolerated well by the second and third babies but was held for the first baby as sepsis was suspected due to prenecrotizing early colitis. The first infant thus required an antibiotic course for 1 week. The infants were discharged from the neonatal intensive care unit after 49, 36, and 36 days with body weights of 1880, 2100, and 2000 mg. After 12 months, these weights were 8, 11, and 10 kg. The infants had normal mental and physical growth on follow-up. At 24 months, their reported weights were 9, 16, and 11 kg (Table 1). The first one developed asthma and required inhaled steroids and bronchodilators.
Female fertility with chronic kidney disease
Sexual dysfunction is a known complication in both male and female patients with chronic kidney disease (CKD). Although erectile dysfunction is a common presenting symptom in men with CKD, irregular menstrual cycle is a usual complaint among affected women. Decreased libido and infertility are common in both sexes.12 Uremic women have abnormal hypothalamic-pituitary-gonadal axes leading to anovulatory cycles.13,14 In normal menstrual cycle, follicular maturation is stimulated by the secretion of follicle-stimulating hormone from the anterior pituitary. Follicle-stimulating hormone exhibits typical negative feedback with increasing levels of estrogen secreted by the ovary. Whereas luteinizing hormone (LH) secretion is suppressed maximally with low levels of circulating estrogen, the sustained rise in estradiol produced by the maturing follicle stimulates the surge of LH through a positive feedback leading to ovulation. After ovulation, progesterone production by the corpus luteum increases, leading to transformation of the endometrium into the luteal phase. In uremic women, the increase in estradiol concentration and the preovulatory surge of LH is frequently absent. Failure of exogenous estrogen to stimulate LH release suggests disturbance of gonadotropin production by the hypothalamus.13,14 Increased endorphin and prolactin levels in women with CKD have been suggested as a cause for gonadotropin suppression.13 A possible role for recombinant erythropoietin use in women with CKD in improving hypothalamic function was attributed to reduction in prolactin levels.13 Clomiphene is a selective estrogen receptor modulator that has been widely used as treatment for infertility due to oligoovulation or anovulation. It acts through binding to hypothalamic estrogen receptors, thereby blocking the negative feedback effect of circulating endogenous estrogen.15 The use of clomiphene is found to be associated with increased incidence of multiple pregnancy.1
Our patient had spontaneous pregnancy twice after kidney transplant. She lost her first pregnancy due to preeclampsia for unclear causes at the time of delivery. With retrospective analysis, we assumed that cyclosporine toxicity may have precipitated the condition through placental vasoconstriction despite having therapeutic trough levels. This possibility was considered during her second pregnancy as cyclosporine was changed to tacrolimus with levels kept at a relatively lower therapeutic range and Doppler ultrasonography monitoring performed regularly. Low-molecular-weight heparin was used during her last 3 weeks of pregnancy. It was not clear why the patient developed secondary infertility later despite normal gonadotropin and prolactin levels and normal ultrasonography of the ovaries. Measurement of progesterone at the midluteal phase was repeatedly low (day 21 of the cycle), which denotes anovulatory cycles. With the above data, the use of clomiphene was justified, and she became pregnant after the first trial.
A multiple pregnancy is more likely to occur with assisted reproductive technologies and in older mothers who may delay pregnancy.3 The use of clomiphene for ovulation induction is associated with 0.3% to 0.5% rate of triplet pregnancies.16 It is clear that morbidity and mortality associated with multiple pregnancies can be high. In a practice bulletin by the American College of Obstetricians and Gynecologists, low birth weight (1687 g), premature delivery (32.2 weeks), growth restriction (50%-60%), need for neonatal intensive care unit with average stay of 30 days (75%), and risk of death by age 1 year (20% higher than singleton) were average complication data associated with triplet pregnancy.17 The adjusted odds ratios for maternal complications were 1.22 to 1.27 for pregnancy-associated hypertension, 1.5 to 2.22 for excessive bleeding, and 6.55 to 7.38 for delivery by cesarean section.18 Our patient had medical reasons to receive ovulation induction. The pressures of local society and its traditions coupled with her receiving a successful kidney transplant with normal graft function were the major factors behind her eagerness to get pregnant before any possible future kidney dysfunction. Her rapid response to ovulation induction precluded the need for ultrasonographic monitoring of mature follicles to take the possible precautions to avoid triplet pregnant. Fetal reduction was not considered for the same reasons, as future chances to get pregnancy were not clear. The course of pregnancy was relatively stable, and cesarean section delivery was indicated. Fetal complications were anticipated; however, morbidity was minimal and there was no mortality.
Diabetes and pregnancy
Glucose intolerance with onset or first recognition during pregnancy is known as gestational diabetes mellitus, whereas presence of diabetes (type 1 or 2) before conception is referred to as pregestational diabetes.19 Gestational diabetes mellitus is the most common type among pregnant women, with prevalence around 88% compared with 12% for pregestational diabetes.20 The relation between the order in multiple pregnancies and the development of gestational diabetes mellitus has been well described in the literature, with a suggested dose-response relation.4 Fetal reduction from triplet to twin pregnancy has been associated with less incidence of gestational diabetes mellitus.21 It is not clear from the literature whether diabetes-related complications are similar in multiple versus singleton pregnancies. Pregestational diabetes, although less prevalent, carries a high risk of both fetal and maternal complications. In a population-based study from Sweden, the obstetric and perinatal outcomes were assessed in 5089 type 1 diabetic pregnancies compared with a control group of 1 260 207 normal pregnancies. The odds ratios for preeclampsia, delivery by cesarean section, stillbirth, shoulder dystocia, perinatal mortality, major malformations, and fetal macrosomia were significantly higher in diabetic pregnancies.6 Hyperglycemia is a detrimental factor for macrosomia, spontaneous abortion, and congenital malformations. Intensive insulin therapy in the group who became pregnant during a diabetes control and complication trial showed lower rates of spontaneous abortion and congenital malformation, with rates similar to those in a nondiabetic population.22
The effects of maternal hyperglycemia on infants may extend into adult life by increasing the risk of being overweight and metabolic syndrome.23 Good glycemic control before and during pregnancy can be achieved through frequent self-monitoring of blood glucose (SMBG), dietary adjustment, and titration of insulin therapy targeting euglycemia. Blood glucose monitoring is considered the standard method for better glycemic control. Women planning for pregnancy should have their own blood glucose monitor. Those on multiple insulin regimens should perform SMBG at least 3 times per day.24 Postprandial blood glucose monitoring is associated with fewer complications compared with preprandial.25 The use of 1-hour glucose levels is preferred.26 Continuous glucose monitoring, if available, provides extra advantages by highlighting periods of unexpected hypoglycemia or hyperglycemia.27 The International Diabetes Federation28 has suggested an easy way to remember the target blood glucose values for control of diabetes during pregnancy as < 100, 140, and 120 mg/dL for fasting, 1-hour postprandial, and 2-hour postprandial blood glucose (or < 5.5, 8.0, and 7.0 mmol/L in SI units) (Table 2).
Testing for ketonemia or ketonuria is required for patients with type 1 diabetes mellitus when patients become ill or have high glucose readings. HbA1c may show some variability due to the physiologic changes in blood during pregnancy. This fact was assessed retrospectively in 94 patients who had 7-point glycemic profiles throughout pregnancy compared with their corresponding HbA1c levels. It was found that HbA1c closely correlated with SMBG.29 However, variations in HbA1c monitoring can be overcome by doing it at shorter intervals (eg, 4-8 weeks).29 The National Institute for Health and Clinical Excellence guidelines30 suggested HbA1c < 6.1% preconception and during the first trimester and did not recommend the use of HbA1c routinely for assessing glycemic control in the second and third trimesters. Target HbA1c by the American Diabetes Association24 and American College of Obstetricians and Gynecologists31 is < 6.0% (Table 2). Observational and randomized control studies have shown that mildly increased HbA1c is associated with increased incidence of macrosomia,28 fetal malformations,32 and preeclampsia.33
Insulin is the recommended pharmacologic therapy during pregnancy. Although guidelines differ, the safety and efficacy of metformin34 and glyburide (glibenclamide)35 have been documented in gestational diabetes and considered as treatment options by the National Institute for Health and Clinical Excellence.30 These are also approved for use by the International Diabetes Federation28 in poorly resourced areas of the world. Their use in patients with CKD is guided by creatinine clearance levels. Insulin therapy for pregnant women can be delivered as multiple daily injections or continuous subcutaneous insulin infusions. Intermediate-acting insulin as single or twice daily doses together with premeal rapid-acting insulin is the standard therapy for multiple daily injections, whereas rapid-acting insulin is the one used for continuous subcutaneous insulin infusion. There is sufficient evidence for the use of rapid-acting analog insulin (lispro or aspart) with good outcomes,36 whereas evidence is lacking for long-acting analogs (detemir or glargine).
Our patient was permitted to get pregnant at a higher HbA1c level than what is recommended. This could have put her at risk of fetal malformations. Fortunately, she had healthy offspring. Her eagerness to get pregnant, the unexpected rapid response to clomiphene, and her enthusiasm to control diabetes pushed the team to accept the idea and support her pregnancy. HbA1c was brought to near target levels with the start of her second trimester, with target levels achieved throughout the third trimester until delivery. She did not have any of the major complications of diabetes with pregnancy apart from premature labor.
Kidney transplant and pregnancy
An improvement in fertility after kidney transplant is considered one of the major benefits in women who are in their childbearing period. The reported rate of pregnancy for women on dialysis was 0.44% versus 22.7% after transplant.37 However, pregnancy rate during the first 3 years posttransplant was only 30 per 1000 women compared with 100 per 1000 women in the general population, with overall live birth rate of 19 per 1000 in transplanted women versus 70 per 1000 in the general population.38 Timing for pregnancy after transplant depends on stability of renal function and presence of proteinuria (< 1 g/day).39 The 2009 Kidney Disease Improving Global Outcomes39 guideline has suggested delaying pregnancy for at least 1 year after transplant to avoid the risk of heavy immunosuppression, rejection, and infections.
The effects of pregnancy after kidney transplant on graft survival outcomes are somewhat uncertain. Although some have reported decreased rates of allograft survival in women who gave birth compared with others who did not,40 reports from the United Kingdom and European Dialysis and Transplantation Association showed favorable outcomes.41,42
The use of immunosuppressive medications during pregnancy is guided by the patient’s fetomaternal toxicity. Medications used by the mother pass through the maternal-placental-fetal barriers. Placenta is considered the first pass for drug metabolism. Drugs that pass the placental barrier can still be filtered by the fetal liver before reaching the fetal circulation.11,43 Steroids are efficiently metabolized in the placenta and rarely cause suprarenal suppression in the fetus.44 Azathioprine is widely accepted for use during pregnancy due to the long experience with the drug and lack of fetal enzyme inosinate pyrophosphorylase required for converting azathioprine into its active form.45 Mycophenolate mofetil is listed as category D by the US Food and Drug Administration, with advised conversion to azathioprine for at least 6 weeks before pregnancy.39 The calcineurin inhibitors are cornerstones of immunosuppression. They readily cross the placenta with detectable levels in fetal blood. They can cause T-cell inhibition in newborns.46 Calcineurin inhibitors do not appear to be teratogenic.47,48 Frequent drug level monitoring is required during pregnancy. Sirolimus and everolimus, the mammalian target of rapamycin inhibitors, are contraindicated during pregnancy. They should be discontinued at least 12 weeks before pregnancy.49
The prevalence of multiple pregnancies in transplant is not known. Case reports are the only sources of information.50,51 Few cases of triplet pregnancy have been reported with fair outcomes.52-55 Our case may shed some light on triplet pregnancy outcomes. Our patient had a stable pregnancy course. Tacrolimus dose was increased by 5 times compared with levels before pregnancy to keep blood trough levels around 5 ng/mL. Her blood pressure was well controlled without medications.
Kidney transplant has a favorable outcome on female fertility. Pregnancy rates after transplant, although less than the general population, is much higher than on dialysis. Assisted reproductive technologies are associated with increased incidence of multiple pregnancies. The literature is deficient in reporting cases of triplet pregnancy posttransplant. Proper glycemic control is essential for favorable pregnancy outcomes.
Volume : 15
Issue : 1
Pages : 139 - 146
DOI : 10.6002/ect.mesot2016.P23
From the 1Nephrology Department, Hamed Al-Essa Organ Transplant Center, Kuwait;
the 2Obstetric and Gynecology Department, Royal Hayat Hospital, Kuwait; and the
3Radiology Department, Ibn Sina Hospital, Kuwait
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Tarek Said Hamed Mahmoud, PO Box 993, Hawally (32010), Kuwait
Phone/Fax: +965 6669 2074
Table 1. Infant Characteristics
Table 2. Glycemic Targets During Pregnancy