Reproductive Safety Research Articles

Experimental Assessment of the Effect of Kagocel on Reproductive Function in Pubertal Male Rats.

We studied possible toxic effects of antiviral drug Kagocel on reproductive function in pubertal male rats. The drug was administered in therapeutic and 10-fold higher doses throughout the spermatogenesis cycle (48 days). Kagocel did not reduce mating and fertilizing capacities, did not suppress spermatogenesis, and had no toxic effects on the offspring. The results characterize Kagocel as a drug with a broad reproductive safety profile and demonstrate that the age limits for using Kagocel in pediatric practice can be extended.

Erratum to: Pregnancy Outcomes Following In Utero Exposure to Lamotrigine: A Systematic Review and Meta-Analysis.

Lamotrigine is used in pregnancy to control epilepsy and mood disorders. The reproductive safety of this widely used drug remains undefined and may represent a significant public health concern. We aimed to perform a systematic review and meta-analysis of existing knowledge related to malformation rates and maternal–neonatal outcomes after in utero exposure to monotherapy with lamotrigine. Relevant studies were identified through systematic searches conducted in MEDLINE (Ovid), Embase (Ovid), CENTRAL (Ovid), and Web of Science (Thomson Reuters) from database inception to July 2016; no language or date restrictions were applied. All publications of clinically relevant outcomes of pregnancies following in utero exposure to lamotrigine were included in this systematic review and meta-analysis. A total of 21 studies describing immediate pregnancy outcomes and rates of congenital malformations fulfilled the inclusion criteria. Compared with disease-matched controls (n = 1412, total number of patients) and healthy controls (n = 774,571, total number of patients), in utero exposure to lamotrigine monotherapy was found to be associated with significantly decreased rates of inborn defects (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.62–2.16 and OR 1.25; 95% CI 0.89–1.74, respectively). Rates of miscarriages, stillbirths, preterm deliveries, and small for gestational age (SGA) neonates were not found to have been increased after in-utero exposure to LTG compared to the general population. Similarly, in utero exposure to lamotrigine monotherapy was not found to be associated with increased rates of inborn defects compared with in utero exposure to carbamazepine, and lamotrigine was found to be statistically significantly less teratogenic than valproic acid (n = 12,958 and 10,748; OR 0.84; 95% CI 0.68–1.03 and OR 0.32; 95% CI 0.26–0.39, respectively). No association was found between prenatal lamotrigine monotherapy and increased rates of birth defects and other explored variables related to adverse pregnancy outcomes.

Effects of prenatal exposure to antipsychotic risperidone on developmental neurotoxicity, apoptotic neurodegeneration and neurobehavioral sequelae in rat offspring

A tremendous increase has been documented in the recent past in prescribing second generation atypical antipsychotic drugs (AAPDs) to the pregnant women with psychosis, considering their reproductive and teratogenic safety. Among AAPDs, risperidone (RIS) ranked third after olanzapine (OLZ) and quetiapine (QUE) used during pregnancy, as OLZ is associated to substantial weight gain in adults and offspring. Although teratogenic safety of RIS has been established, its potential role in developmental neurotoxicity and related neurobehavioral impairments in adolescents has not been documented so far. Therefore, present study has been undertaken to elucidate the effect of prenatal exposure to risperidone (RIS) on developmental neurotoxicity and apoptotic neurodegeneration in neocortical region of fetal brain; and related functional sequelae in young rat offspring. The pregnant Wistar rats were exposed to RIS at 0.8, 1.0 and 2.0mg/kg, at equivalent therapeutic doses, orally from GD 6 to 21. Half of the pregnant rats were sacrificed and their brains were collected, weighed, and processed for neurohistopathological and apoptotic neurodegenerative evaluation. The remaining dams were allowed to deliver naturally, and their offspring were reared up to 10 weeks for neurobehavioral study. Prenatal exposure to RIS induced significant stunting of fetal body and brain weight, substantial reduction in the thickness of neocortical layers and apoptotic neurodegeneration in fetal brains, and delayed postnatal development and growth of the offspring; as well as long- lasting impact on anxiety like impaired behavioral responses on explorative mazes. Therefore, health care providers should be careful in prescribing atypical antipsychotics in general and RIS in particular, to the pregnant psychotic population.

Revision of the ICH guideline on detection of toxicity to reproduction for medicinal products: SWOT analysis.

SWOT analysis was used to gain insights and perspectives into the revision of the ICH S5(R2) guideline on detection of toxicity to reproduction for medicinal products. The current ICH guideline was rapidly adopted worldwide and has an excellent safety record for more than 20 years. The revised guideline should aim to further improve reproductive and developmental (DART) safety testing for new drugs. Alternative methods to animal experiments should be used whenever possible. Modern technology should be used to obtain high quality data from fewer animals. Additions to the guideline should include considerations on the following: limit dose setting, maternal toxicity, biopharmaceuticals, vaccines, testing strategies by indication, developmental immunotoxicity, and male-mediated developmental toxicity. Emerging issues, such as epigenetics and the microbiome, will most likely pose challenges to DART testing in the future. It is hoped that the new guideline will be adopted even outside the ICH regions.

Effects of the Oral Oxytocin Receptor Antagonist Tocolytic OBE001 on Reproduction in Rats.

OBE001 is a novel, orally active nonpeptide oxytocin receptor antagonist under development for the treatment of preterm labor and improvement in embryo implantation and pregnancy rate in assisted reproductive technology (ART). The reproductive safety of OBE001 was evaluated in customized fertility embryonic development (FER)/early embryonic development (EED) and fetal development (FD) and pre/postnatal development (PPN) studies mimicking clinical exposure scenarios. Oral OBE001 was evaluated at doses of 37.5, 75, and 125 mg/kg/d in female rats during a FER/EED study (from premating to implantation) and throughout FD during a FD/PPN study. No OBE001 effects were observed during the FER/EED study. The FD/PPN study did not result in adverse OBE001 effects in females allowed to litter, their offspring, and second-generation fetuses. Females at 125 mg/kg/d who underwent cesarean section before term had slight reductions in body weights and food consumption, and associated fetuses had slightly delayed ossification of skull bones, which was not adverse in the absence of effects on live offspring. OBE001 at up to 125 mg/kg/d had no effects on EED and no adverse effects on FD and postnatal development of rats. These results constitute an important step toward the development of OBE001 in preterm labor and ART indications.

Managing Your Own Mood Lability: Use of Mood Stabilizers and Antipsychotics in Pregnancy.

The management of psychiatric disorders during the perinatal period can be difficult; psychiatric decompensation during pregnancy can affect not only the mother but also the fetus and neonate. It is imperative that psychiatric providers proactively discuss pregnancy planning, and be able to thoughtfully weigh the risks of untreated psychiatric illness and psychotropic medications in pregnancy and breast-feeding. With the exception of valproate and carbamazepine, several mood stabilizers and antipsychotics can be utilized during pregnancy with minimal risk to the fetus and neonate in terms of major malformations; there is a growing body of evidence regarding the risk profile of use of these medications in pregnancy. Key Points Preconception planning is very helpful when it can be done; consider discussion and documentation of risks at time of administration of psychotropic medications for any reproductive-aged women, regardless of plans for conception. Continued psychiatric stability through the perinatal period is imperative; the risks of an untreated psychiatric disorder are just as important, if not more so important, than the risks of psychotropic medication exposure. Exposure to one psychotropic medication is safer than exposure to multiple medications. Utilize lowest effective dose of medication; most risks are not dose dependent, therefore would typically prefer higher dose of medication, rather than emergence of psychiatric symptoms, in order to avoid exposure of the fetus to both psychotropic medications and psychiatric symptoms. General recommendations are to avoid valproate and carbamazepine in reproductive-aged women. With close monitoring, lithium can be safely utilized in pregnancy. Preliminary data regarding use of atypical antipsychotics is reassuring in regards to major malformations; however, larger numbers of participants are needed to provide more complete reproductive safety data with this class. Clearly document risks of an untreated psychiatric illness as well as risks of psychotropic medication management to the mother and developing fetus/neonate.

Supplement use by women during pregnancy: data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

Women of reproductive age commonly use integrative treatments. However, the reproductive safety for most complementary products lacks systematic study. We aimed to study the use of supplements by women in a prospective pregnancy registry. The Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics was established to evaluate the reproductive safety of atypical antipsychotics. Exposed and control participants were systematically queried about the use of vitamins and supplements. Slightly greater than half (53.2%) of the participants eligible for analysis (N = 534) were using at least one vitamin or supplement at the time of enrollment, not including prenatal vitamins or folic acid. The most common supplements used were omega-3 fatty acids (38.0%), vitamin D (11.0%), calcium (8.2%), and iron (4.7%). Probiotics and melatonin were used by 2.6 and 0.9%, respectively. In this prospective pregnancy registry, we found that over half of the participants were taking supplements or vitamins other than prenatal vitamins and folic acid. These findings underscore the need for active query on the part of health care providers about the use of supplements during pregnancy, and the need to obtain rigorous reproductive safety and efficacy data for supplements used by pregnant women and reproductive aged women.

Integrating family planning and primary care at publicly funded organizations in Texas to repair the reproductive health safety net

Objectives: Following dramatic funding cuts in 2011 that closed 25% of clinics, the Texas state legislature aimed to rebuild family planning services by allocating US$100 million in 2013 to establish the Expanded Primary Health Care (EPHC) program, which covers primary care and contraceptive services for low-income adult women. We examine organizations' experiences providing family planning services during the EPHC program's first year.

Neurodevelopment of children prenatally exposed to selective reuptake inhibitor antidepressants: Toronto sibling study.

The reproductive safety of selective reuptake inhibitor (SRI) antidepressants needs to be established to provide optimal control of maternal depression while protecting the fetus. To define a child's neurodevelopment following prenatal exposure to SRIs and to account for genetic and environmental confounders in a sibling design using the Toronto Motherisk prospective database. Intelligence and behavior of siblings prenatally exposed and unexposed to SRIs were assessed by using the Wechsler Preschool and Primary Scale of Intelligence-Third Edition, Child Behavior Checklist, and Conners Parent Rating Scale-Revised and subsequently compared. Mothers, diagnosed with depression using DSM-IV, were assessed for intelligence quotient (IQ) and for severity of depressive symptoms with the Center for Epidemiologic Studies Depression scale. Prenatal drug doses and durations of exposure, child's age, child's sex, birth order, severity of maternal depression symptoms, and Full Scale IQ, the primary outcome measure, of both the mother and the child were considered in the analyses. Forty-five sibling pairs (ages 3 years to 6 years 11 months, prenatally exposed and unexposed to SRIs) did not differ in their mean ± SD Full Scale IQs (103 ± 13 vs 106 ± 12; P = .30; 95% CI, -7.06 to 2.21) or rates of problematic behaviors. Significant predictor of children's intelligence was maternal IQ (P = .043, β = 0.306). Severity of maternal depression was a significant predictor of Child Behavior Checklist Internalizing (P = .019, β = 0.366), Externalizing (P = .003, β = 0.457), and Total scores (P = .001, β = 0.494). Drug doses and durations of exposure during pregnancy did not predict any outcomes of interest in the exposed siblings. SRI antidepressants were not found to be neurotoxic. Maternal depression may risk the child's future psychopathology. The sibling design in behavioral teratology aids in separating the effects of maternal depression from those of SRIs, providing stronger evidence in clinical decision-making.

Exposure to aripiprazole during embryogenesis: a prospective multicenter cohort study.

The main purpose of this study was to evaluate the risk of major malformations after aripiprazole exposure during the embryonic period. The secondary purposes were to assess the risk of miscarriage, prematurity, fetal growth retardation and maternal complications and to describe possible neonatal adverse effects. We conducted a cohort study using data prospectively collected by the French Pharmacovigilance Centres participating to the Terappel program and the Centre de Référence sur les Agents Tératogènes between 2004 and 2011. The exposed group consisted of pregnant women exposed to aripiprazole during embryogenesis, and the unexposed group consisted of pregnant women without exposure or exposed to non-teratogenic agents. Two unexposed patients, matched for age and gestational age at call, were randomly selected for each exposed patient. Eighty-six patients were included in the exposed group and 172 in the unexposed group. Exposure to aripiprazole was not significantly associated with an increased rate of major malformations (OR 2.30, 95%CI 0.32-16.7) or miscarriage (1.66, 0.63-4.38) or gestational diabetes (1.15, 0.33-4.04) compared to non-exposure. The study revealed significantly increased rates of prematurity (OR 2.57, 95%CI 1.06-6.27) and fetal growth retardation (2.97, 1.23-7.16) in exposed newborns, difficult to interpret because of the short duration of maternal exposure. Two cases of neonatal complications were reported among the 19 newborns exposed to aripiprazole near delivery. This study failed to demonstrate a significant association between aripiprazole exposure during the embryonic period and major malformations. More powerful prospective studies are required to clarify the reproductive safety profile of aripiprazole.

Pregnancy outcome following prenatal exposure to triptan medications: a meta-analysis.

Migraine is a common disorder among women of childbearing age. Triptan medications are effective and commonly used to treat migraines in pregnancy. However, the reproductive safety of this group of drugs has not yet been confirmed. The aim of this study was to determine the reproductive safety of triptan medications by performing a literature review and a meta-analysis. Available publications regarding pregnancy outcomes following prenatal exposure to triptans from 1991 to 2013 were identified and reviewed according to the inclusion criteria. A random-effects meta-analysis model was implemented to combine the available pregnancy outcome data for the exposed and comparison groups. One case-control study and 5 cohort studies met the inclusion criteria. The included studies provided information on duration of gestation, major congenital malformations, and spontaneous abortions of infants following prenatal triptan exposure. The 6 studies included 4208 infants of women who used sumatriptan or other triptan medications, and 1,466,994 children of women who did not use triptans during pregnancy. No significant increases in rates for major congenital malformations (MCMs), prematurity, or spontaneous abortions were found when comparing the triptan-exposed group to the migraine - no triptans control group (odds ratio [OR] = 0.84 [0.61-1.16]; OR = 0.90 [0.35-2.30]; OR = 1.27 [0.58-2.79], respectively). There were no increased rate of MCMs (OR = 1.18 [0.97-1.44]) or prematurity (OR = 1.16 (0.67-1.99) when the triptan-exposed group was compared with the healthy controls; however, there was a significant increase in the rates of spontaneous abortions (OR = 3.54 [2.24-5.59]). When the migraine no-triptan group was compared with healthy controls, a significant increase in the rates of MCMs was found (OR = 1.41 [1.11-1.80]). The use of triptans during pregnancy does not appear to increase the rates for MCMs or prematurity. The increased rates of spontaneous abortions in the triptan-exposed group and the increased rates of MCM in the migraine no-triptan group require further research.

Women's experiences seeking publicly funded family planning services in Texas.

Little is known about low-income women's and teenagers' experiences accessing publicly funded family planning services, particularly after policy changes are made that affect the cost of and access to such services. Eleven focus groups were conducted with 92 adult women and 15 teenagers in nine Texas metropolitan areas in July-October 2012, a year after legislation that reduced access to subsidized family planning was enacted. Participants were recruited through organizations that serve low-income populations. At least two researchers independently coded the transcripts of the discussions and identified main themes. Although most women were not aware of the legislative changes, they reported that in the past year, they had had to pay more for previously free or low-cost services, use less effective contraceptive methods or forgo care. They also indicated that accessing affordable family planning services had long been difficult, that applying and qualifying for programs was a challenge and that obtaining family planning care was harder than obtaining pregnancy-related care. As a result of an inadequate reproductive health safety net, women experienced unplanned pregnancies and were unable to access screening services and follow-up care. Teenagers experienced an additional barrier, the need to obtain parental consent. Some women preferred to receive family planning services from specialized providers, while others preferred more comprehensive care. Women in Texas have long faced challenges in obtaining subsidized family planning services. Legislation that reduced access to family planning services for low-income women and teenagers appears to have added to those challenges.

Administration of standard-dose BEP regimen (bleomycin + etoposide + cisplatin) is essential for treatment of ovarian yolk sac tumour

AimThe aim of this study was to investigate prognostic factors, including postoperative chemotherapy regimen, for the treatment of ovarian yolk sac tumour (YST), and resulting fertility outcome. MethodsA multi-institutional retrospective investigation was undertaken to identify patients with ovarian pure or mixed YST who were treated between 1980 and 2007. Postoperative chemotherapy regimen and other variables were assessed in univariate and multivariate analyses. Additionally, the reproductive safety of the BEP (bleomycin, etoposide and cisplatin) regimen was evaluated. ResultsThere were 211 patients enrolled from 43 institutions. The BEP regimen and a non-BEP regimen were administered to 112 and 99 patients as postoperative chemotherapy, respectively. In univariate and multivariate analyses, age⩾22, alpha-fetoprotein⩾33,000ng/ml, residual tumours after surgery and non-BEP regimen were independently and significantly associated with poor overall survival (OS). BEP was significantly superior to non-BEP in 5-year OS (93.6% versus 74.6%, P=0.0004). Reduced-dose BEP (<75% standard-dose bleomycin and<50% etoposide dose) was significantly associated with poorer 5-year OS compared with standard-dose BEP (89.4% versus 100%, P=0.02 and 62.5% versus 96.9%, P=0.0002). All patients who underwent fertility-sparing surgery recovered their menstrual cycles. Sixteen of 23 patients receiving BEP (70.0%) and 13 of 17 patients receiving non-BEP (76.5%) who were nulliparous at fertility-sparing surgery and married at the time of investigation gave birth to 21 and 19 healthy children, respectively. ConclusionsThe results of the present study suggest that standard-dose BEP should be administered for ovarian YST. BEP is as safe as non-BEP for preserving reproductive function.

Биотехнологические методы повышения эффективности ведения скотоводства

There was studied the distribution of postpartum pathology of cows and disease of calves in early postnatal period in conditions of Nizhny Novgorod region. It was established, that the new tissue drug &amp;#34;bio-tec&amp;#34; has positive influence on reproductive function, safety and live weight gain of calves. The postpartum pathology of cows gained wide spread among nizhnynovgorod farms up to 80%, e.g. Endometritis and subinvolution of uterus 37,4 and 23,9 respectively. By clinical examination of newborn calves it was established, that in the first month of life 50,3% fall ill with gastrointestinal diseases of various etiologies. The die-off of calves reached 29%. Using &amp;#34;bio-tec&amp;#34; drug to dry cows decreased the percentage of postpartum pathology by 35% and reduced the time of involution of uterus for 11,2 days; the service period reduced by 21,2 days and the diseases of newborn calves was twice less, that increased the energy of growth and in 16 month age heifers went over animals of the control group by 10%, that allowed their earlier use for reproduction. So, the results of conducted research showed, that twice a day injection of tissue drug &amp;#34;bio-tec&amp;#34; to dry cows in 10ml dose 60-55 and 40-35 days to calving contributes reducing of obstetric pathology. Subsequent use to calves in 4ml dose in 5-8 days age increases the safety of calves and positively influences the live weight gain, that in fact gives abilities of more effective cattle breeding.&#x0D;

Nonclinical reproductive and developmental safety evaluation of the MAGE-A3 Cancer Immunotherapeutic, a therapeutic vaccine for cancer treatment.

We assessed potential toxic effects of the MAGE-A3 Cancer Immunotherapeutic on female fertility and embryo-fetal, pre- and post-natal development in rats and on male fertility in rats and monkeys. Three groups of 48 female (Study 1) or 22 male (Study 2) CD rats received 5 or 3 injections of 100μL of saline, AS15 immunostimulant, or MAGE-A3 Cancer Immunotherapeutic (MAGE-A3 recombinant protein combined with AS15) at various timepoints pre- or post-mating. Male Cynomolgus monkeys (Study 3) received 8 injections of 500μL of saline (n=2) or the MAGE-A3 Cancer Immunotherapeutic (n=6) every 2 weeks. Rats were sacrificed on gestation day 20 or lactation day 25 (Study 1) or 9 weeks after first injection (Study 2) and monkeys, 3 days or 8 weeks after last injection. Injections were well tolerated. Female rat mating performance or fertility, pre- and post-natal survival, offspring development up to 25 days of age, and male mating performance (rats) or fertility parameters (rats and monkeys) were unaffected.

Treatment of bipolar disorders during pregnancy: maternal and fetal safety and challenges.

Treating pregnant women with bipolar disorder is among the most challenging clinical endeavors. Patients and clinicians are faced with difficult choices at every turn, and no approach is without risk. Stopping effective pharmacotherapy during pregnancy exposes the patient and her baby to potential harms related to bipolar relapses and residual mood symptom-related dysfunction. Continuing effective pharmacotherapy during pregnancy may prevent these occurrences for many; however, some of the most effective pharmacotherapies (such as valproate) have been associated with the occurrence of congenital malformations or other adverse neonatal effects in offspring. Very little is known about the reproductive safety profile and clinical effectiveness of atypical antipsychotic drugs when used to treat bipolar disorder during pregnancy. In this paper, we provide a clinically focused review of the available information on potential maternal and fetal risks of untreated or undertreated maternal bipolar disorder during pregnancy, the effectiveness of interventions for bipolar disorder management during pregnancy, and potential obstetric, fetal, and neonatal risks associated with core foundational pharmacotherapies for bipolar disorder.

Reproductive safety and fetal risk of drugs

An article about the safe use of drugs during pregnancy. Describes the most signifi cant steps of development of ideas about the impact of drugs on the fetus, the brief history of their classifi cation and the list of drugs of diff erent pharmacological groups, depending on the degree of risk and the level of adverse eff ects on the fetus. Presents current data on the results of a study of some mechanisms of medication teratogenesis.

Maternal obesity and adverse reproductive outcomes: reducing the risk.

Obesity is associated with multiple adverse reproductive outcomes such as infertility, ovulation dysfunction, miscarriage, preeclampsia, gestational diabetes mellitus, preterm delivery, operative delivery, and fetal growth disorders. Although the prevalence of maternal obesity is increasing, it is unclear which method of weight loss is most effective before conception to improve reproductive outcomes. This article reviews the amount of weight loss needed to improve ovulation and fertility, behavioral methods for optimal weight loss, as well as medical and surgical interventions to promote weight loss with the intention of providing a tool to promote weight loss in the preconception period. Behavioral modification that includes motivational interviewing, energy intake restriction, and increased energy expenditure is first-line therapy. Behavioral therapy has been shown to improve menstrual cyclicity, ovulation, conception rates, hormone profile, and amount of weight loss. Bariatric surgery and drug therapy may be used in overweight or obese patients who fail behavioral modification. However, women who undergo bariatric surgery or drug therapy must be cautioned about safety profiles, nutritional requirements, and some adverse pregnancy outcomes such as intrauterine growth restriction. There are several areas for further investigation including amount of weight loss needed to resume ovulation by obesity class and improve reproductive outcomes, safety and efficacy of very low energy diets in the preconception period, as well as safety of obesity medications in the preconception period.

Treatment of nonpsychotic major depression during pregnancy: patient safety and challenges.

In pregnant women with major depression, the overarching goal of treatment is to achieve or maintain maternal euthymia, thus limiting both maternal and fetal exposure to the harmful effects of untreated or incompletely treated depression. However, the absence of uniformly effective therapies with guaranteed obstetric and fetal safety makes the treatment of major depression during pregnancy among the most formidable of clinical challenges. Clinicians and patients are still faced with conflicting data and expert opinion regarding the reproductive safety of antidepressants in pregnancy, as well as large gaps in our understanding of the effectiveness of most antidepressants and nonpharmacological alternatives for treating antenatal depression. In this paper, we provide a clinically focused review of the available information on potential maternal and fetal risks of untreated maternal depression during pregnancy, the effectiveness of interventions for maternal depression during pregnancy, and potential obstetric, fetal, and neonatal risks associated with antenatal antidepressant use.

A safety evaluation of aripiprazole for treating schizophrenia during pregnancy and puerperium

Introduction: Aripiprazole (ARI) is a second-generation antipsychotic acting as a dopamine-serotonin system stabilizer and partial agonist at D2 receptors. The drug is indicated in several and severe psychiatric disorders which are particularly frequent in women during the childbearing age.Area covered: A systematic review of studies investigating the reproductive safety of ARI.Expert opinion: For first trimester use, reviewed data provide no clear evidence about the safety of the drug for the developing fetus. However, a decline of plasma levels (PLs) throughout the pregnancy compared with PLs before pregnancy was observed. This finding suggests the need to increase the dosage during pregnancy in order to maintain stable PLs. If used during late pregnancy, some signals exist suggesting that ARI may worse neonatal outcomes. Hence, clinicians should consider withdrawing the drug before the last month of pregnancy to reduce the risks of neonatal complications. However, such risks must be weighed against the risks of woman’s symptom deterioration. In any case, parturition should happen in hospitals equipped with well-organized neonatal intensive care units. No information is available on the impact of antenatal exposure to ARI on the main neurodevelopmental milestones. Infant exposure to the drug through maternal milk may increase the risk of insufficient milk production and neonatal somnolence.