The experience with management of pregnancy in women after solid organ transplantation in multidisciplinary hospitals
M.A. Lysenko1, L.Yu. Artyukhina1, I.Yu. Kokaya1, P.V. Kozlov2, I.P. Osokin1
1City Clinical Hospital No. 52, Moscow, Russian Federation
2Pirogov Russian National Research Medical University, Moscow, Russian Federation
Worldwide diffusion of transplantation technologies provides both the recovery of impaired organ functions and the realization of reproductive function. Much experience with the management of these women resulting in the positive perinatal outcome has gained worldwide. However, immunosuppressive therapy, prevention of gestational complications, and the choice of delivery terms and methods are still disputable. This paper summarizes the experience with the management of pregnancy and childbirth in women after solid organ transplantation. The principles of pre-pregnancy planning, the management of pregnancy, and specific medical treatment are addressed considering international and authors’ findings. Potential prolongation of pregnancy until term which requires multidisciplinary approach to the management and delivery and specialized multitype hospital having specialists in the management of patients after transplantation to provide high-tech diagnostic and treatment care is quite possible. Until recently, adequate delivery terms, the need for delivery induction, delivery methods, and the safety of breastfeeding in women after transplantation are still disputable.
Keywords: solid organ recipients, transplantation, pre-pregnancy planning, pregnancy, delivery, management, medical treatment, effects to the fetus.
For citation: Lysenko M.A., Artyukhina L.Yu., Kokaya I.Yu. et al. The experience with management of pregnancy in women after solid organ transplantation in multidisciplinary hospitals. Russian Journal of Woman and Child Health. 2020;3(1):–30. DOI: 10.32364/2618-8430-2020-3-1-26-30.
Modern transplantation technologies are the most advanced treatment modalities for end-stage chronic diseases of vital organs as they optimize rehabilitation, significantly improve survival, quality of life, and chances of having a healthy child. Many of solid organ transplant recipients are women of reproductive age in whom the restoration of fertility is an essential step in medical and social rehabilitation. To date, more than 14,000 childbirths in women after organ transplantation are reported . Considering this, the principles of pregnancy planning as well the management of pregnancy and delivery in these women are an important issue.
65% to 92% of women after solid organ transplantation have successful pregnancy outcomes. However, given comorbidities and the need for permanent immunosuppressive drugs, the risk of obstetrical adverse events (including preeclampsia, intrauterine growth restriction, and preterm birth) is significantly higher than in general population .
Immunosuppressive therapy. Permanent maintenance immunosuppressive therapy is required to provide maximum transplant functions as defined by adequate suppression of alloimmune response, from the one hand, and minimum risks of immunosuppressant adverse effects, from the other hand. Optimal regimen of immunosuppressive therapy is provided by therapeutic drug monitoring that ensures drug therapeutic range. The most common immunosuppressive drugs prescribed in pregnancy are cyclosporine and tacrolimus and their derivatives (calcineurin inhibitor, tacrolimus, is characterized by more labile pharmacokinetics as compared with cyclosporine).
Breastfeeding in solid organ transplant recipients. Breastfeeding safety in transplant recipients is understudied. Breastfeeding is not recommended for women receiving immunosuppressive drugs (including sirolimus, everolimus, and belatacept). Nevertheless, there are numerous reports on breastfeeding in these women in the last 25 years worldwide. In 2014, data on the safety of breastfeeding and rapid decrease in blood concentrations of immunosuppressive drugs in infants born to transplant recipients who received standard doses of prednisolone, azathioprine, cyclosporine, and tacrolimus were published . Any immunosuppressant is potentially unsafe for a newborn. However, relatively low level of drug transferred into breast milk and low rate of side effects (reported in few publications only) demonstrate that favorable effect of breastfeeding is superior to theoretical risks of negative effects of immunosuppressive drugs .
Kidney transplantation & pregnancy
Published data on several thousands of pregnancies in kidney transplant recipients (including kidney transplant for lupus nephritis) are available. About 90% of these women have successful pregnancy outcomes. However, a variety of pathological conditions of kidney transplant requires careful pregnancy management, monitoring of clinical and laboratory tests, differential diagnosis of pregnancy complications, and, if necessary, early etiologically or pathogenetically oriented treatment. Kidney diseases are an aggravating factor, however, the prognosis mainly depends on the condition directly associated with pregnancy, i.e., preeclampsia, eclampsia, or HELLP syndrome. The most common comorbidities in kidney transplant recipients are high blood pressure, low glomerular filtration rate, and renal failure that often make it challenging to diagnose severe pregnancy complications (including preeclampsia) early [2, 5-7].
Case history 1
Medical history. A 31-year-old woman has received pathogenetically oriented treatment with corticosteroids (oral prednisolone 60 mg) for manifestations of vasculitis with skin and renal involvement since 2000. Hemodialysis for end-stage renal disease was initiated since 2009. In 2013, mother-to-daughter kidney transplantation was performed. Since 2013, hemodialysis for rapidly progressing renal failure resulted from chronic glomerulonephritis exacerbation (IgA nephropathy) after acute respiratory infection was reinitiated. No transplantectomy was performed. In 2014, kidney retransplantation was performed. In 2015, the woman was successfully treated with methylprednisolone pulse therapy (1,500 mg) for IgA nephropathy. In 2017, ACE inhibitors and mycophenolate mofetil were discontinued due to pregnancy planning. Immunosuppressive treatment with azathioprine was started. In 2017, the woman was diagnosed with pregnancy.
Pregnancy and childbirth. The woman was followed up in antenatal outpatient department since 10-11 weeks of pregnancy by obstetrician-gynecologist and nephrologist. Blood parameters related to nitrogen, blood tacrolimus (see Fig. 1 and 2), and preeclampsia markers (i.e., placental growth factor/PLGF and soluble fms-like tyrosine kinase/SFLT) were measured. Routine caesarean section was performed by multidisciplinary team (obstetricians and urologists) at 38-39 weeks of pregnancy. Alive full-term boy (weight 2,730 g; height 49 cm; Apgar score 7-9) was delivered. The infant has received bottle feed. No transplant dysfunction was revealed within the next months.
Liver transplantation & pregnancy
In general, pregnant women with liver transplants are highly tolerant to pregnancy complications (in particular, to preeclampsia) and have more favorable perinatal outcomes as compared with kidney transplant recipients. In addition, these women are characterized by more favorable immunosuppressive profile as they usually receive just one medication (thereby reducing the risk of infectious complications). Liver transplantation for hepatitis B is associated with potentially higher risks of liver transplant dysfunction and poor perinatal outcome.
Pregnancy in liver transplant recipients can be accompanied by thrombocytopenia, moderately elevated transaminases and bilirubin, and low albumin. The most common pregnancy complication in liver transplant recipients (as compared with other organ transplant recipients) is intrahepatic cholestasis of pregnancy [8-10].
In 2018-2019, two babies were born to liver transplant recipients in City Clinical Hospital No. 52. No complications during pregnancy or delivery were reported.
Case history 2
Medical history. A 37-year-old woman has experienced noninfectious jaundice for the first time that was successfully treated with 1-month infusions and hormonal therapy. In 1991, type 1 diabetes was diagnosed. In 1995, cirrhosis (as a result of autoimmune hepatitis), portal hypertension stage 3, hepatosplenomegaly, hypersplenism, thrombocytopenia, type 1 diabetes, iatrogenic Cushing’s syndrome (after long-term corticosteroid use), and osteopenia were diagnosed. In 2013, orthotopic liver transplantation with retrohepatic vena cava preservation was performed.
The first pregnancy (2003) was terminated at 7-8 weeks for medical reasons. The second pregnancy (2006) has ended in premature birth at 34 week by caesarean section for severe preeclampsia. Alive preterm girl (weight 2,000 g; height 45 cm) was born. Postnatal outcome was favorable. In 2003-2007, ligation of esophageal veins for bleeding was performed. The third (desired) pregnancy has occurred immediately after barrier contraception discontinuation.
Pregnancy and childbirth. The woman was followed up by obstetrician-gynecologist and liver specialist of V.I. Kulakov Scientific Center for Obstetrics, Gynecology, and Perinatology and endocrinologist of City Clinical Hospital No. 52. Careful dynamic monitoring and regular control of clinical laboratory tests were performed. The woman has received tacrolimus 7 mg daily under the measurements of its blood concentration and insulin therapy.
No pregnancy complications were reported. Routine caesarean section was performed at 37 weeks of pregnancy. Alive full-term boy (weight 3,160 g; height 50 cm) was delivered. The mother and the child were discharged at day 7 in fair condition.
Lung transplantation & pregnancy
Lung transplantation has become an accepted treatment option for end-stage lung diseases that do not respond to medications including idiopathic pulmonary arterial hypertension (IPAH).
IPAH (Ayerza’s disease; Escudero’s syndrome; black cardiac) is a disease of unknown origin characterized by significantly increased pulmonary vascular resistance and pulmonary arterial pressure, progressive course, rapid development of right ventricular failure, and poor prognosis. According to the World Health Organization, IPAH is one of the rarest cardiovascular disorders worldwide (1-2 cases per million per year) and ranks 7th among indications for lung transplantation. IPAH may develop irrespective of age or sex. In women, IPAH onset commonly occurs between 20 and 30 years of age. The most common causes of death are right ventricular heart failure in 47% and sudden cardiac arrest in 26%.
In 1996-2016, the rate of lung transplantation has increased from 1,297 to 4,661 per year worldwide. Pregnancy after lung transplantation is an important issue as one-third of lung recipients are women; of them, 75% are women of reproductive age. Lung transplantation has improved their survival, quality of life, and chances for successful pregnancy. In 1991-2017, 44 pregnancies (including multiple pregnancies) were delivered, 46 infants were born [11, 12].
Pregnancy after lung transplantation is associated with higher risks of maternal and perinatal morbidity and mortality and requires multidisciplinary approach to the management of pregnancy and childbirth. The rate of lung graft rejection in pregnant women is 16-36% that is significantly higher as compared with the rate of other transplant rejection, e.g., heart (9-20%), liver (4.5-10%), and kidney (1-9%). As to pregnancy complications in lung transplant recipients, spontaneous abortion occurs in 28%, gestational arterial hypertension in 53.3%, and preterm birth (on average, at 33.9 weeks of pregnancy) in > 50%. The risk of maternal mortality is more than 16% .
Case history 3
Medical history. In 2013 (one year after the first pregnancy), a 27-year-old woman was diagnosed with IPAH. Medical treatment (sildenafil) was ineffective. In 2015, lung transplantation was performed. Postoperative period was complicated by severe primary transplant dysfunction, acute kidney failure, and right-sided pleural effusion that required rethoracotomy, pleural cavity drainage, and hemodialysis. Lifelong immunosuppressive therapy was prescribed.
The first pregnancy (2010) has resulted in missed miscarriage. Medical abortion was performed at 6-7 weeks of pregnancy; no complications were reported. The second pregnancy (2013) has ended with a birth of full-term boy (weight 3,400 g; height 52 cm); no complications were reported. The third pregnancy (2017) was terminated before 12 weeks for medical reasons (the woman has received Certican, immunosuppressive drug known to have teratogenic effects).
In 2018, a desired pregnancy has occurred.
Pregnancy and childbirth. The woman was followed up in antenatal outpatient department of the City Clinical Hospital No. 52 since 7-8 weeks of pregnancy by obstetrician-gynecologist, transplant surgeon, nephrologist, and general practitioner. In the first trimester, threatened miscarriage and mild anemia have occurred. Pregnane derivatives, antianemic drug, and complex immunosuppressive therapy (methylprednisolone 4 mg daily and tacrolimus 4 mg daily) were prescribed. Immunosuppressive therapy was adjusted based on blood concentration of tacrolimus (see Fig. 3). Target concentration of tacrolimus was 8-10 ng/ml.
At 32-33 weeks of pregnancy, the woman has experienced acute respiratory infection and left-sided otitis that have resulted in dyspnea on mild exertion.
Reduced forced expiratory volume in the first trimester of pregnancy and its progressive decrease at 38 weeks of pregnancy (3.4% from baseline) were revealed by pulmonary function test.
Myocardial dysfunction (but no signs of pulmonary hypertension) was revealed by transthoracic echocardiography.
Considering full-term pregnancy and well-functioning transplant, a panel of obstetrician-gynecologists, transplant surgeons, anesthesia & resuscitation specialists, and neonatologists has decided to perform caesarean section at 37-38 weeks of pregnancy. Spinal and epidural anesthesia was performed. Alive full-term girl (weight 2,590 g; height 48 cm; Apgar score 8-9) was delivered. No complications of early neonatal period were reported. The infant has received bottle feed. Blood level of tacrolimus in the infant has reduced more than 3 times within the first 5 days of life (see Fig. 4).
Considering high risk of graft failure, the dosage of immunosuppressive drug (i.e., tacrolimus) was adjusted in the postnatal period. The mother and the child were discharged at day 7 in fair condition.
International and authors’ experience with the management of pregnancy in organ transplant recipients demonstrates that favorable pregnancy outcome is possible with careful monitoring of transplant functioning as well as the health of solid organ transplant recipient and the child throughout the pregnancy. One of the most important criteria of successful pregnancy and favorable perinatal outcome after solid organ transplantation is at least 1-year interval between the transplantation and pregnancy. This interval is required to achieve optimal immunosuppression that provides stable transplant functioning, minimal or no dysfunction of other organs, and minimal risks of infectious complications. Transplant recipients often receive 2 or 3 immunosuppressive drugs. As a result, reducing immunosuppressants and discontinuing teratogenic agents should be considered during pregnancy planning. Regular monitoring and early dose adjustment of immunosuppressants are required during pregnancy. Blood levels of calcineurin inhibitors (i.e., cyclosporine and tacrolimus) are reduced as pregnancy progresses to prevent graft dysfunction or failure. During pregnancy, continuous dose adjustment of immunosuppressants based on their blood levels is recommended.
Hence, the conclusions may be summarized as follows:
1. Contraception and pregnancy planning are required after organ transplantation.
2. Stable transplant functioning for 1-2 years is crucial for planning a pregnancy.
3. A pregnancy may be deemed high risk due to transplantation that requires multidisciplinary approach to the management and delivery and specialized multidisciplinary hospital having specialists in the management of patients after transplantation to provide high-tech diagnostic and treatment care.
4. Pregnancy is not contraindicated in kidney transplant recipients under the following conditions: (1) minimal or no proteinuria; (2) controlled arterial hypertension; (3) no urodynamic abnormalities of kidney transplant; (4) normal glomerular filtration rate (blood creatinine < 2.0 mg/dl, optimally < 1.4 mg/dl); (5) low doses of immunosuppressive drugs (prednisolone ≤ 15 mg/day, azathioprine ≤ 2 mg/kg/day, cyclosporine < 5 mg/kg/day).
5. Adequate immunosuppressive therapy during pregnancy has no teratogenic effects on the fetus, does not cause intrauterine growth restriction, provides good transplant functioning, and does not increase the risk of graft rejection.
6. In solid organ transplant recipients without any signs of graft dysfunction, pregnancy should be prolonged until term.
7. Until recently, adequate delivery terms and methods, the need for delivery induction, and the safety of breastfeeding in women after organ transplantation are still disputable matters.
About the authors:
1Mariana A. Lysenko — MD, PhD, the Head Doctor, ORCID iD 0000-0002-2636-2558;
1Ludmila Yu. Artyukhina — MD, PhD, Head of the Department of Nephrology, ORCID iD 0000-0003-3353-1636;
1Inga Yu. Kokaya — MD, PhD, Head of the Maternity Hospital, ORCID iD 0000-0002-0637-1537;
2Pavel V. Kozlov — MD, PhD, Professor of the Department of Obstetrics and Gynecology, ORCID iD 0000-0002-9916-6128;
1Ivan P. Osokin — MD, Head of the Department of Pathological Pregnancy, ORCID iD 0000-0003-2957-7236.
1City Clinical Hospital No. 52. 3, Pehotnaja str., Moscow, 123182, Russian Federation.
2Pirogov Russian National Research Medical University. 1, Ostrovitianov str., Moscow, 117997, Russian Federation.
Contact information: Pavel V. Kozlov, e-mail: firstname.lastname@example.org.
Financial Disclosure: no authors have a financial or property interest in any material or method mentioned. There is no conflict of interests. Received 25.10.2019.
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