Trastuzumab administration during pregnancy: an update.

BACKGROUND: Over than one third (28-58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome. METHODS: Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words "breast", "cancer", "trastuzumab" and "pregnancy". This study was performed in accordance with the PRISMA guidelines. RESULTS: A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1-32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher's exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy. CONCLUSIONS: Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored.

Use of pertuzumab and trastuzumab during pregnancy.

Trastuzumab and pertuzumab are monoclonal antibodies used for the treatment of breast cancer. Until now, there have been no reports on the use of pertuzumab during pregnancy and on its potential effects on the fetus. Herein, we present a breast cancer patient who received trastuzumab and pertuzumab treatment during the first 20 weeks of pregnancy. This 22-year-old patient initially diagnosed with invasive ductal carcinoma of the breast was found to be negative for estrogen receptor and progesterone receptor and positive for human epidermal growth factor receptor in the immunohistochemical examination. At the time of diagnosis, she had metastatic lesions and a protocol of docetaxel, trastuzumab, pertuzumab, q21, and zolendronic acid 4 mg every month was started. Following six courses of therapy, she had near-complete response, and, after administration of the same course of treatment for two additional cycles, treatment with pertuzumab plus trastuzumab was continued. While she was being followed-up with remission, a 20-week pregnancy was detected. A fetal ultrasound examination showed oligohydramnios and right renal agenesis. Treatment was stopped, and the fetus was monitored. After 7 weeks of follow-up, fetal growth retardation and anhydramnios were detected. The pregnancy was terminated. Fetal autopsy showed no urinary system pathology, but macroscopic and microscopic hyperplasia of the right adrenal gland was identified. Concomitant use of pertuzumab and trastuzumab during pregnancy may be associated with an unresolved oligohydramnios and/or anhydramnios risk. Extreme caution should be used when these monoclonal antibodies are administered during pregnancy.

[Case Report on Treatment of Metastatic Breast Cancer with Trastuzumab during Pregnancy]. / Fallbericht einer Trastuzumab-Therapie während der Schwangerschaft bei metastasiertem Mammakarzinom.

The increasing number of pregnant breast cancer patients calls for a therapy that is as efficient as possible. After 10 years of collecting data on pregnant breast cancer patients in the German Breast Group (GBG), proposals for diagnostic measures and therapy regarding this special situation have been developed on the basis of 500 observed cases. Chemotherapy is regarded as safe from the 14(th) week of gestation on, but it is strongly advised not to use trastuzumab. Adverse outcomes for the newborn were predominantly observed in cases of early preterms. In our department, a 29-year-old second gravida with metastatic breast cancer first diagnosed 7 years ago continued to receive trastuzumab treatment at her express request after detailed information and advice. Trastuzumab treatment had been started 1.5 years before the pregnancy after surgical removal of a lymph node metastasis. After 7 intravenous administrations at intervals of 3 weeks, an oligohydramnios occurred in the 24(th) week of pregnancy. For this reason, trastuzumab treatment was interrupted for 7 weeks, during which time the quantity of amniotic fluid returned to a normal level. As the 8(th) administration of trastuzumab led to a renewed oligohydramnios, the trastuzumab treatment was suspended until birth. The quantity of amniotic fluid having recovered to normal, labour was induced after 36 weeks of pregnancy, followed by a Caesarian section because of prolonged labour. The newborn boy showed no sign of respiratory or renal dysfunction and has developed normally, having at present reached the age of 3 years. From the few reported cases of pregnancies with trastuzumab therapy, it seems that an occurring oligohydramnios is the typical complication with the problem of life-threatening RDS after birth. Probably the reduction of amniotic fluid can be reversed by interrupting the trastuzumab therapy, as we observed in our case.

Decrease of the incidence of renin-angiotensin-system inhibitor induced oligohydramnios-sequence in Germany in 2011.

AIM: to assess whether the incidence of angiotensin II-receptor type 1 antagonist (AT1-antagonist)­ or ACE-inhibitor induced cases of oligohydramnios sequence (OHS) in 2011 was reduced after intensive alerts as to the causal association between AT1-antagonist /ACE-inhibitor and OHS in the German medical literature. METHOD: 3 sources of information were used: A nationwide active surveillance of OHS in German paediatric hospitals (ESPED); Embryotox, (Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy) and screening of pubmed (AT1-antagonist/ACE-inhibitor induced OHS). RESULTS: 45 cases of OHS were identified, no case due to maternal AT1-antagonist/ACE-inhibitor treatment. Causes for OHS were: premature rupture of membranes (PPROM) (n = 28), congenital anomalies of fetal kidneys and urinary tract(CAKUT (n = 15), placental insufficiency (n = 1),unknown cause (n = 1). Mortality until discharge was 37.8 % (32.1 % PPROM, 57.1 % CAKUT). Embryotox identified 3 exposures to AT1-antagonists in pregnancy, no case was associated with OHS. The pubmed search did not identify any case of OHS related to AT1-antagonist/ACE-inhibitor in pregnancy in Germany in 2011. CONCLUSION: Treatment of pregnant women with ACE inhibitors or AT1-antagonists still occurs but no cases of AT1-antagonist- or ACE-inhibitor induced OHS were reported in 2011 in Germany most likely due to repeated published alerts underlining the importance of consequent education. OHS remains a serious condition with high mortality despite modern intensive care.

Angiotensin-II receptor 1 antagonist fetopathy--risk assessment, critical time period and vena cava thrombosis as a possible new feature.

AIMS: Angiotensin-II receptor 1 antagonists (AT1-antagonists) may cause severe and even lethal fetopathy in late pregnancy. However, exposure still occurs in spite of warnings in package leaflets. This study aimed to assess the risk of fetopathy, the sensitive time window, and possible new symptoms in prospective as well as retrospective cases with AT1-antagonist treatment during the second or third trimester of pregnancy. METHODS: Patients were enrolled by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy between 1999 and 2011 through risk consultation. Symptoms defined as indicative of AT1-antagonist fetopathy were: oligo-/anhydramnios, renal insufficiency, lung hypoplasia, joint contractures, skull hypoplasia and fetal/neonatal death. RESULTS: In 5/29 (17%) prospectively enrolled cases with AT1-antagonist exposure beyond the first trimester oligo-/anhydramnios was diagnosed. Two infants showed additional symptoms of fetopathy. The risk is more than 30% if treatment continues beyond the 20th week of pregnancy. Oligo-/anhydramnios was reversible after AT1-antagonist withdrawal. Among 16 retrospective case reports, three infants presented with a thrombosis of the inferior vena cava in the vicinity of the renal veins. Four out of 13 live births did not survive. CONCLUSIONS: Our survey suggests that the risk increases with duration of AT1-antagonist treatment into late pregnancy and oligo-/anhydramnios may be reversible after AT1-antagonist discontinuation. Thrombosis of inferior vena cava may be a new feature of AT1-antagonist fetopathy. AT1-antagonist medication during pregnancy constitutes a considerable risk and must be discontinued immediately. In case of indicative diagnostic findings in either the fetus or newborn, previous maternal AT1-antagonist exposure should be considered.

Use of non-steroidal anti-inflammatory drugs in pregnancy and oligohydramnios: a review.

OBJECTIVE: The aim of this review is to evaluate the relationship between the use of non-steroidal anti-inflammatory drugs (NSAIDs) during last trimesters of the pregnancy and the reduction of amniotic fluid. METHODS: Electronic databases were searched (PubMed, Medline, and Scopus). Selection criteria included studies reporting the relationship between oligohydramnios and use of NSAID during pregnancy. We analyzed the median age of women, weeks of pregnancy at the beginning of the drug administration, kind of medication, period of exposure and dosage, deepest vertical pocket (DVP), and amniotic fluid index (AFI). RESULTS: Of the 68 records identified, we analyzed 29 studies investigating the administration of NSAIDs, including 11 studies examined the administration of the Indomethacin, four articles have focused on the use of Nimesulide, and only two manuscripts considered the use of Diclofenac. We found a strict correlation between the development of oligohydramnios and the use of NSAIDs. The oligohydramnios is reversible, and the normal amount of amniotic fluid is restored after the interruption of the treatment. CONCLUSIONS: The use of NSAIDs should be considered when maternal benefits outweigh the potential fetal risk, at the lowest effective dose for shortest duration. Beyond 48 h of NSAIDs treatment, we consider ultrasound monitoring of amniotic fluid, and we suggest stopping therapy if a decline AFI is present.

Prognosis and outcome of pregnancies exposed to renin-angiotensin system blockers.

OBJECTIVE: To study pregnancy outcomes and fetal renal prognosis markers in cases of exposure to renin-angiotensin system blockers. METHODS: We conducted a retrospective study of a series of 21 patients exposed to blockers of the renin-angiotensin system during pregnancy. Two markers were prenatally studied, fetal serum ß2-microglobulin and amniotic fluid volume. Poor renal prognosis evaluation was based on postnatal glomerular filtration rate or on the presence of renal histologic lesions. RESULTS: Of the 21 fetuses, only one had a normal postnatal renal function at birth (oligohydramnios regression and normal ß2-microglobulin). All fetuses with persistent oligohydramnios or ß2-microglobulin ≥ 5 mg/L presented an adverse renal outcome. CONCLUSION: Exposure to renin-angiotensin system blockers complicated by oligohydramnios is associated with a very poor outcome. We propose a prenatal management based on amniotic fluid volume monitoring and fetal serum ß2-microglobulin. However, our preliminary results have to be confirmed by a larger study.

Indomethacin in pregnancy: applications and safety.

Preterm labor (PTL) is a major cause of neonatal morbidity and mortality worldwide. Among the available tocolytics, indomethacin, a prostaglandin synthetase inhibitor, has been in use since the 1970s. Recent studies have suggested that prostaglandin synthetase inhibitors are superior to other tocolytics in delaying delivery for 48 hours and 7 days. However, increased neonatal complications including oligohydramnios, renal failure, necrotizing enterocolitis, intraventricular hemorrhage, and closure of the patent ductus arteriosus have been reported with the use of indomethacin. Indomethacin has been also used in women with short cervices as well as in those with idiopathic polyhydramnios. This article describes the mechanism of action of indomethacin and its clinical applications as a tocolytic agent in women with PTL and cerclage and its use in the context of polyhydramnios. The fetal and neonatal side effects of this drug are also summarized and guidelines for its use are proposed.

Angiotensin II receptor blocker induced fetopathy: 7 cases.

BACKGROUND: During a period of 12 months 7 newborns with a partially severe fetopathy caused most probably by maternal sartan-intake in pregnancy were treated in 5 German teaching hospitals. Sartans antagonize the effect of angiotensin II at the AT1-receptor and are used to treat arterial hypertension. METHOD: We presented 2 cases at the yearly GNPI meeting 2010 and we were informed about similar cases in other German teaching hospitals which we brought together in this publication. RESULTS: In the presented cases, maternal sartan intake was noticed at different times in pregnancy and was in part discontinued some weeks before delivery. In all pregnancies oligohydramnios was present and fetal kidneys displayed a hyperechogenic structure on ultrasound. The newborns' postnatal course varied: oligohydramnios sequence with lung hypoplasia, arterial hypotension and renal insufficiency were the predominant problems of the first days of life. The majority (4/7) of infants did not survive this period, in other cases there was a complete (1/7) recovery of renal function whereas others survived with renal impairment (2/7), in part requiring chronic dialysis. Further distinctive features seen frequently were disturbances of cranial ossification and flaccid paralysis of hands and feet with deviations as well as sensorineural hearing loss. CONCLUSION: These case reports again underline the hazardousness of maternal sartan intake with potential fatal outcome for the newborn. Though the use of sartans in pregnancy is contraindicated and several case reports of sartan induced fetopathies exist, the risk of sartan treatment generally seems to be underestimated.

Valsartan exposure in pregnancy with resultant anhydramnios and chronic kidney disease in a late preterm infant.

In utero exposure to angiotensin II receptor blockers (ARBs) has fetotoxic effects including renal failure, oligohydramnios and lung hypoplasia. We present the case of a 24-year-old woman who presented to the maternity services in the 34th week of her first pregnancy. She was taking valsartan for hypertension. Ultrasound showed a structurally normal fetus with anhydramnios. The patient was admitted and valsartan was discontinued. She had spontaneous preterm delivery at 35 weeks' gestation of a baby girl. The baby's urine output was minimal in the first week of life and she was transferred to a paediatric hospital for specialist nephrology input. At 6 months of age, she requires ongoing nephrology follow-up and she remains on treatment for hypertension and anaemia. This case demonstrates the serious adverse effects resulting from ARB exposure in utero, and highlights the importance of avoiding fetotoxic medications in women of childbearing age.

Formalin: nephrotoxic teratogen?

Formaldehyde is an extensively used chemical; its ill effects have been of concern. Its nephrotoxic effects in laboratory animals and carcinogenic effects on humans are well established. We report of a pregnant woman with a normal ongoing pregnancy with a morphologically normal fetus. She was exposed to high doses of formaldehyde through inhalational route in the second trimester. Six weeks later she was found to have severe oligohydramnios with dysplastic fetal kidneys and fetal ascites. The various known causes for this problem reported in the literature are discussed. Based on the discussion the author has drawn a conclusion that the fate of the fetus reported can be attributed to transplacental nephrotoxic effect of formaldehyde. Previously two cases of malformations have been reported but this appears to be the first case of transplacental nephrotoxicty of formaldehyde.

Emerging therapeutic options for breast cancer chemotherapy during pregnancy.

BACKGROUND: Breast cancer is the commonest solid tumor observed during pregnancy. Anthracycline-based chemotherapy is feasible during the 2nd and 3rd trimesters of pregnancy, but few data are available on recent and highly active drugs taxanes, vinorelbine and anti-HER-2 agents in this setting. PATIENTS AND METHODS: We carried out a comprehensive review of reports documenting the use of taxanes, vinorelbine, trastuzumab and lapatinib during pregnancy in the English literature, in order to evaluate their safety profile in pregnant patients. RESULTS: Twenty-four pregnancies are described, in which no grade 3-4 maternal toxicity nor malformation in the offspring was reported. Whereas only one report studied the pharmacokinetics of paclitaxel (Taxol) during pregnancy, several preclinical reports indicate that the placental P-glycoprotein could prevent the transplacental transfer of taxanes and vinorelbine. The use of trastuzumab was associated with the occurrence of anhydramnios in three of six cases. CONCLUSION: The administration of recent drugs taxanes and vinorelbine seems feasible during the 2nd and 3rd trimesters of pregnancy, with a favorable toxicity profile. In contrast, anti-HER-2 agents may obscure the normal development of the fetal kidney, and should be avoided during pregnancy.

Trastuzumab use for metastatic breast cancer in pregnancy.

BACKGROUND: Trastuzumab is approved for first-line treatment for breast cancer in combination with docetaxel for stage 2 tumors positive for human epidermal growth factor receptor 2. The effects of trastuzumab on the fetus are mostly unknown. CASE: Our case report focuses on a woman who was treated for invasive ductal carcinoma 1 year before pregnancy. She presented at 20 weeks of gestation with metastases and was treated with docetaxel and trastuzumab. She underwent two cycles of chemotherapy, and an ultrasound scan at 30 weeks showed anhydramnios. There was no history of ruptured membranes. Reappearance of amniotic fluid was noted at 33 weeks of gestation, 7 weeks after cessation of treatment. CONCLUSION: Treatment with trastuzumab during midgestation may be associated with anhydramnios.

The first case of mitoxantrone exposure in early pregnancy.

Mitoxantrone is an antineoplastic agent considered a potential human teratogen because of its mechanism of action and is classified by the US Food and Drug Administration in pregnancy category risk D. In the literature there are only four cases of women exposed to the drug in late pregnancy. We report the first case of mitoxantrone therapy in the first trimester and during the pregnancy. A 41-year-old woman affected with multiple sclerosis, conceived during therapy and continued mitoxantrone until 29 weeks and 3 days of her pregnancy. She delivered by cesarean section at 39 weeks a growth restricted female baby weighing 1950g without evidence of congenital malformations.

Maternal olmesartan exposure causing neonatal failure.

Although angiotensin II receptor blockers (ARBs) are contraindicated during pregnancy, new cases are currently being reported.A 32-week preterm neonate was admitted after C-section due to maternal oligohydramnios. He presented with Potter phenotype, pulmonary hypoplasia with pneumothorax, systemic hypotension and anuria. He required chest drain insertion and continuous positive airway pressure (CPAP), volume expansion plus inotropic support with persistent renal failure. Mother confirmed olmesartan intake during entire pregnancy. Peritoneal dialysis was started with improvement in renal markers and progressive recovery of renal function. He has been followed up until the age of 2 years, observing improved renal function with a glomerular filtration rate (GFR) of 58 mL/min/1.72 m2Both angiogenesis-converting enzyme inhibitor and ARBs affect nephrogenesis; ARBs being more harmful due to its higher activity. Although some patients may recover normal renal function, its teratogen effect may have fatal consequences. Thus, it is important to emphasise its harmful effects in neonates to avoid new cases.

In utero losartan withdrawal and subsequent development of fetal inferior vena cava thrombosis.

BACKGROUND: Angiotensin receptor blockers are antihypertensive medications prescribed by a wide variety of physicians, especially for patients with coexistent diabetes mellitus. Angiotensin receptor blockers, as well as angiotensin-converting enzyme inhibitors, are contraindicated in pregnancy. CASE: We describe the reversal of losartan-induced oligohydramnios at 27 weeks of gestation with subsequent development of fetal thrombosis and possible mechanism of action for this extremely rare in utero complication. CONCLUSION: This theory may help explain the fetal stillbirths in women taking this class of medications during the second and third trimester of pregnancy.

[Fetal toxicity of angiotensin-II receptor antagonists]. / Toxicité foetale du candesartan.

We report a case of a newborn with an oligohydramnios, acute renal failure and ossification abnormalities. The role of maternal treatment of essential hypertension by angiotensin-II receptor antagonists is discussed in regard to the literature and pathophysiological data.