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Please cite this paper as: von Dadelszen P, Dwinnell S, Magee LA, Carleton BC, Gruslin A, Lee B, Lim KI, Liston RM, Miller SP, Rurak D, Sherlock RL, Skoll MA, Wareing MM, Baker PN, for the Research into Advanced Fetal Diagnosis and Therapy (RAFT) Group. Sildenafil citrate therapy for severe early‐onset intrauterine growth restriction. BJOG 2011;118:624–628. Currently, there is no effective therapy for severe early‐onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR‐complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early‐onset IUGR [abdominal circumference (AC) < 5th percentile] and either the gestational age was <25+0 weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil‐naive early‐onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early‐onset IUGR‐complicated pregnancies.

AimsTo compare the disposition of fluoxetine and norfluoxetine enanantiomers in the mother, foetus and infant. MethodsBlood from pregnant women taking fluoxetine ( n = 9), during pregnancy was sampled in the third trimester and at delivery (maternal and cord venous blood), and from the infants 48 h after delivery. The subset of these women who were breastfeeding, plus additional subjects recruited in the postpartum period, were studied further, and maternal and infant blood, and breast milk was sampled between 6 days and 11 months ( n = 23). Drug and metabolite concentrations were measured using gas chromatography/mass spectrometry or liquid chromatography, tandem mass spectrometry. ResultsThere was a high correlation between maternal and foetal (cord blood) fluoxetine and norfluoxetine enantiomers ( r 2 − 0.9), the mean foetal/maternal ratios (95% confidence intervals) being 0.91 (0.61, 1.02) and 1.04 (0.93, 1.05), for fluoxetine and norfluoxetine, respectively. In 2 day old infants exposed to the drug in utero , the fluoxetine and norfluoxetine plasma concentrations were the same as in cord blood at delivery. Over the next 2 months, the plasma concentrations in the infants fell progressively. Stereoselective disposition of both the drug and metabolite in the mother, foetus, infant and breast milk was observed. The S : R ratios in the foetus and newborn ( ∼ 3) were significantly higher than in the serum ( ∼ 2) or breast milk ( ∼ 1.9) of the mothers, resulting in greater exposure of the foetus and infants to the biologically active enantiomers, particularly S-norfluoxetine. ConclusionsFoetal and infant exposure to fluoxetine and norfluoxetine is enhanced by their stereoselective disposition in the mother, foetus, breast milk and infant. Increased exposure may also result from decreased metabolism of the drug in the foetus and neonate.

Selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines are frequently used to treat maternal depression during pregnancy, however the effect of increased serotonin (5HT) and ␥-amino-butyric acid (GABA) agonists in the fetal human brain remains unknown. 5HT and GABA are active during fetal neurologic growth and play early roles in pain modulation, therefore, if prolonged prenatal exposure alters neurodevelopment this may become evident in altered neonatal pain responses. To examine biologic and behavioral effects of prenatal exposure, neonatal responses to acute pain (phenylketonuria heel lance) in infants with prolonged prenatal exposure were examined. Facial action (Neonatal Facial Coding System) and cardiac autonomic reactivity derived from the relationship between respiratory activity and short term variations of heart rate (HRV) were compared between 22 infants with SSRI exposure (SE) [fluoxetine (n ϭ 7), paroxetine (n ϭ 11), sertraline (n ϭ 4)]; 16 infants exposed to SSRIs and clonazepam (SEϩ) [paroxetine (n ϭ 14), fluoxetine (n ϭ 2)]; and 23 nonexposed infants during baseline, lance, and recovery periods of a heel lance. Length of maternal SSRI use did not vary significantly between exposure groups-[mean (range)] SE:SEϩ 183 (31-281):141 (54 -282) d (p Ͼ 0.05). Infants exposed to SE and SEϩ displayed significantly less facial activity to heel lance than control infants. Mean HR increased with lance, but was significantly lower in SE infants during recovery. Using measures of HRV and the transfer relationship between heart rate and respiration, SSRI infants had a greater return of parasympathetic cardiac modulation in the recovery period, whereas a sustained sympathetic response continued in the control group. Prolonged prenatal SSRI exposure appears to be associated with reduced behavioral pain responses and increased parasympathetic cardiac modulation in recovery following an acute neonatal noxious event. Possible 5HT-mediated pain inhibition, pharmacologic factors and the developmental course remain to be studied. (Pediatr Res 51: 443-453, 2002) Abbreviations 5HT, 5 hydroxytryptamine (serotonin) BZ, benzodiazepine C, control (nonexposed) infants DA, dopamine GABA, ␥-amino-butyric acid HFP, high-frequency power HRV, heart rate variability LFP, low-frequency power NE, norepinephrine NFCS, Neonatal Facial Coding System NICU, neonatal intensive care unit PKU, phenylketonuria RP, respiratory power RSA, respiratory sinus arrhythmia SE, SSRI-exposed infants SE؉, SSRI-and BZ-exposed infants SSRI, selective serotonin reuptake inhibitors Maternal anxiety and depression are frequently treated during pregnancy with psychotropic medications such as SSRIs and BZs (1). Given that all psychotropic medications diffuse easily across the placenta, clinicians caring for women with psychiatric illness during their pregnancies are faced with the difficult task of making recommendations regarding psychotropic medication use with unknown effects on the growing fetus. To date, none of these medications have been appr...