Journal of Perinatology (2007) 27, 62–64 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07 $30 PERINATAL/NEONATAL CASE PRESENTATIONNeonatal anemia and hydrops fetalis after maternal IFA Tjeertes, DET Bastiaans, CJLM van Ganzewinkel and SHJ Zegers Department of Neonatology, Isala Klinieken, Zwolle, The Netherlands remaining live-birth pregnancies: ear malformations, cleft lip, After admitting a patient to our Neonatal Intensive Care with a severe hypoplastic nails and clinodactyly of the fifth finger.
anemia and an ear malformation, we ruled out any other cause than maternal medication use. Knowing she used mycophenolate mofetil during pregnancy, we looked for related articles. Two articles were found describing ear malformations, but no article was ever written about anemia caused We present a neonate born prematurely at a gestational age of 35 by this medication. Consulting the international registers of drug effects weeks by emergency cesarean because of fetal distress. The mother, through the National Institute for Public Health and the Environment, who is 36 years old, has a history of three early spontaneous we found out that the anemia was never seen or reported before.
abortions, and a preterm vaginal delivery who is now a healthy Journal of Perinatology (2007) 27, 62–64. doi:10.1038/ 10-year old girl. The pregnancy was uncontrolled until 20 weeksgestation, because the mother still had regular monthly blood loss Keywords: neonatal anemia; hydrops; mycophenolate mofetil;immunosupperession and therefore did not know that she was pregnant. Medicationsused throughout the current pregnancy were mycophenolatemofetil and prednisolone, both as immunosuppressant therapyafter a renal transplantation 4 years ago. The maternal terminal renal failure was caused by vesico-uretral reflux. Her first Mycophenolate mofetil (Cellcept) is an immunosuppressive drug, four pregnancies were before her renal transplant. Since the used mainly after organ transplantations. It is a prodrug and is transplantation, the mother suffered from psychoses, which became converted to biologically active mycophenolic acid after oral more severe during pregnancy. Before this pregnancy, the mother administration. Mycophenolic acid inhibits the lymphocyte used antipsychotic (olanzapine) and hypnotic medication (nitrazepam). During her pregnancy, she was admitted to the Although it has already been associated with teratogenic effects psychiatric ward of our hospital, and was prescribed diazepam and in humans, literature about these effects is limited: only two case haloperidol from the fourth month of pregnancy. In the last reports have been published.1–4 The first describes a live-birth months of the pregnancy, she also received darbepoetin alfa following a pregnancy in which mycophenolate mofetil, prednisone because of anemia, and the antihypertensive methyldopa.
and tacrolimus were administered. The teratogenic effects Detected Structural fetal ultrasounds were normal at 20 and 30 weeks were hypoplastic nails and short fifth fingers.1 The second case gestational age. Neither were there any signs of hydrops in utero, report describes ‘major fetal malformations’ resulting in the nor was the malformation of the ear recognized.
decision to terminate pregnancy at 22 weeks of gestation.
Apgar scores were 5, 8 and 8 after respectively, 1, 5 and 10 min.
During the first trimester, our patient’s mother received Birth weight was 2330 g, median for this gestational age. At mycophenolate mofetil and tacrolimus. The teratology information physical examination, a non-recovering paleness and the ear service of the RIVM (National Institute for Public Health and the malformation were seen (Figure 1). The liver was palpable for Environment, The Netherlands) uses the information of the US 2 cm. Based on clinical signs of dyspnoe, tachypnoe and paleness, National Transplantation Pregnancy Registry. In 2003, worldwide, we performed chest and abdominal X-rays to see if there were signs 16 pregnancies were reported, of which eight ended in spontaneous of fetal hydrops. Besides IRDS grade II, a large heart configuration abortions. Congenital malformations were seen in two of the eight pleural effusion, a large liver and ascites were seen, whichconfirmed our diagnosis. Blood count showed a hemoglobin of Correspondence: Dr IFA Tjeertes, Department of Neonatology, Isala klinieken Zwolle, 3 mmol/l (11.7 mmol/l±1.2 ¼ normal for GA) and a hematocrit of 0.15 l/l (0.60±0.07l/l) and the reticulocyte count was not E-mail: i.f.a.tjeertes@isala.nlReceived 3 June 2006; revised 2 October 2006; accepted 11 October 2006 Neonatal anemia and hydrops fetalisIFA Tjeertes et al Myelosuppression can occur in mycophenolate mofetil use. As aresult of bone marrow suppression, extramedullary blood cellformation will occur in other blood-forming organs, which leads tohepatomegaly, as seen in our patient.
In our case, no further fetal screening like fetal MRI or screening for fetal anemia was considered because both fetalhydrops and the malformation of the ear were not recognizedbefore birth.
Plasma concentration of mycophenolate mofetil in the newborn was 3.1 mg/l (therapeutic level 1–3 mg/l), indicating thatmycophenolate mofetil crosses the placental barrier. Unfortunately,the relationship between maternal and fetal levels could not bedetermined as the maternal levels were not assessed. Ten days afterbirth, the concentration decreased below 0.6 mg/l. The mother wasmildly anemic during the last 2 months of pregnancy, but this isalso a normal feature after renal transplant and in these months ofpregnancy (6 and 7). Other cell lines were not affected.
Prednisolone is not associated with either fetal malformations or hydrops. A meta-analysis showed no significant risk for fetalmalformations owing to corticosteroid use, although a small Figure 1 The patients malformated right ear, the structure in front of increase in risk of oral clefts was suggested in case–control the ear was identified as the anti-helix.
studies.4 Both diazepam and haloperidol are not known for causingfetal or neonatal anemia, and were not used in the first 4 monthsof pregnancy. Research indicates that olanzapine does not have an The patient was admitted to our Neonatal Intensive Care Unit, increased risk of major malformations.2 Erythropoietin injections where he was intubated, and given pulmonary surfactant are not known to cause fetal anemia.
endotracheally as a treatment for IRDS, received three bloodtransfusions via an umbilical venous catheter, and recoveredrapidly.
Infectious etiology was ruled out by a negative bacterial and viral (including toxoplasmosis, rubella, CMV and hepatitis Despite maternal multidrug therapy, after exclusion of viral (TORCHES) and parvo B19 virus) blood cultures and an ear infections, metabolic and all the other agents, we concluded that it swap. We also performed metabolic screening in urine for pH, was most likely the mycophenolate mofetil to be the cause of bone creatinine, nitric acid, sulfite, protein and glucose, organic acids, marrow suppression, causing fetal anemia that led to the non- oligosaccharides, lysosomal enzymes in urine and plasma, and no immune hydrops fetalis. It was also the drug most likely to have abnormalities were found. Postnatal chromosome studies showed caused the malformation of the right ear. Although it can be a serious and also life-threatening complication, fetal anemia is Further diagnostic investigation showed this was a non-immune no contraindication for mycophenolate mofetil use in pregnant hydrops fetalis: the blood types of mother and patient were identical women. Extensive fetal monitoring for signs of anemia using and the direct antiglobulin test was negative, meaning there were for example ultrasound and MCA Dopplers should, however, be no irregular antibodies in maternal blood. The Kleihauer test was strongly recommended. In excessive malformations on fetal negative, thereby excluding feto-maternal transfusion.
ultrasounds to advice carrying out a fetal magnetic resonance Echocardiography on the second day of life showed a normal structure of the heart. In the first week of life, myoclonicmovements of both arms and legs were observed. Cerebral functionmonitoring was normal, and electroencephalography showed noepileptic activity. We therefore concluded it to be withdrawal symptoms from diazepam and haloperidol. A magnetic resonance Pergola PE, Kancharia A, Riley DJ. Kidney transplantation during the first imaging (MRI) scan of the cerebrum was made. It showed a total trimester of pregnancy: immunosuppression with mycophenolate mofetil, absence of the right auditory pathway, without other defects.
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Le Ray C, Coulomb A, Elefant E, Frydman R, Audibert F. Mycophenolate McKenna K, Koren G, Tetelbaum M, Wilton L, Shakir S, Diav-Citrin O, Mofetil in pregnancy after renal transplantation: a case of major fetal Levinson A, Zipursky RB, Einarson A. Pregnancy outcome of women using malformations. Obstet Gynaecol 2004; 103(5 Part 2): 1091–1094.



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