Laura Yates

TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins

We previously showed that mutations in LIS1 and DCX account for ∼85% of patients with the classic form of lissencephaly (LIS). Some rare forms of LIS are associated with a disproportionately small cerebellum, referred to as lissencephaly with cerebellar hypoplasia (LCH). Tubulin alpha1A (TUBA1A), encoding a critical structural subunit of microtubules, has recently been implicated in LIS. Here, we screen the largest cohort of unexplained LIS patients examined to date to determine: (i) the frequency of TUBA1A mutations in patients with lissencephaly, (ii) the spectrum of phenotypes associated with TUBA1A mutations and (iii) the functional consequences of different TUBA1A mutations on microtubule function. We identified novel and recurrent TUBA1A mutations in ∼1% of children with classic LIS and in ∼30% of children with LCH, making this the first major gene associated with the rare LCH phenotype. We also unexpectedly found a TUBA1A mutation in one child with agenesis of the corpus callosum and cerebellar hypoplasia without LIS. Thus, our data demonstrate a wider spectrum of phenotypes than previously reported and allow us to propose new recommendations for clinical testing. We also provide cellular and structural data suggesting that LIS-associated mutations of TUBA1A operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins (MAPs).

Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant

BACKGROUND In April 2009 a novel influenza A virus (AH1N1v) of swine origin (swine flu) emerged, spreading rapidly and achieving pandemic status in June 2009. Pregnant women were identified as being at high risk of severe influenza-related complications and as a priority group for vaccination against AH1N1v. Limited information was available about the maternal and fetal risks of AH1N1v infection or of antiviral drug or AH1N1v vaccine use in pregnancy. OBJECTIVES To assess rates of and risk factors for adverse outcomes following AH1N1v infection in pregnancy and to assess the adverse effects of the antiviral drugs and vaccines used in prevention and management. METHODS Prospective national cohort studies were conducted to identify pregnant women who were (1) suspected to be infected with AH1N1v or being treated with antiviral medication in primary care; (2) vaccinated against AH1N1v; and (3) admitted to hospital with confirmed AH1N1v. Characteristics of women with influenza-like illness (ILI) in primary care were compared with those of women without symptoms accepting or declining immunisation. Characteristics of women admitted to hospital with confirmed AH1N1v infection in pregnancy were compared with a historical cohort of over 1200 women giving birth in the UK who were uninfected with AH1N1v. Outcomes examined in hospitalised women included maternal death, admission to an intensive care unit, perinatal mortality and preterm birth. Risk factors for hospital and intensive care unit admission were examined in a full regression model. RESULTS The weekly incidence of ILI among pregnant women averaged 51/100,000 over the study period. Antiviral drugs were offered to 4.8% [95% confidence interval (CI) 4.0% to 5.9%] and vaccination to 64.8% (95% CI 64.7% to 68.9%) of registered pregnant women. Ninety pregnant women with ILI presenting in primary care were reported to the research team, 55 of whom were prescribed antiviral drugs and in 42 (76%) cases this was within 2 days of symptom onset. After comparison with 1329 uninfected pregnant women offered vaccination, pre-existing asthma was the only maternal factor identified as increasing risk of ILI presentation [adjusted odds ratio (OR) 2.0, 95% CI 1.0 to 3.9]. Maternal obesity and smoking during pregnancy were also associated with hospital admission with AH1N1v infection. Overall, 241 pregnant women were admitted to hospital with laboratory-confirmed AH1N1v infection. Eighty-three per cent of these women were treated with antiviral agents, but only 6% received antiviral treatment before hospital admission. Treatment within 2 days of symptom onset was associated with an 84% reduction in the odds of admission to an intensive therapy unit (OR 0.16, 95% CI 0.08 to 0.34). Women admitted to hospital with AH1N1v infection were more likely to deliver preterm; a three times increased risk was suggested compared with an uninfected population cohort (OR 3.1, 95% CI 2.1 to 4.5). CONCLUSIONS Earlier treatment with antiviral agents is associated with improved outcomes for pregnant women and further actions are needed in future pandemics to ensure that antiviral agents and vaccines are provided promptly to pregnant women, particularly in the primary care setting. Further research is needed on longer-term outcomes for infants exposed to AH1N1v influenza, antiviral drugs or vaccines during pregnancy.

Pregnancy outcomes following gabapentin use: Results of a prospective comparative cohort study

Objectives: Our objectives were to 1) determine whether first-trimester use of gabapentin is associated with an increased risk for major malformations; 2) examine rates of spontaneous abortions, therapeutic abortions, stillbirths, mean birth weight and gestational age at delivery; and 3) examine rates of poor neonatal adaptation syndrome following late pregnancy exposure. Methods: The study design was prospective. Women were included who initially contacted the services between 5 and 8 weeks with a comparison group of women exposed to nonteratogens, collected in a similar manner. Results: We have data on 223 pregnancy outcomes exposed to gabapentin and 223 unexposed pregnancies. The rates of major malformations were similar in both groups (p = 0.845). There was a higher rate of preterm births (p = 0.019) and low birth weight <2,500 g (p = 0.033) in the gabapentin group. Among infants who were exposed to gabapentin up until delivery, 23 of 61 (38%) were admitted to either the neonatal intensive care unit or special care nursery for observation and/or treatment, vs 6 of 201 (2.9%) live births in the comparison group (p < 0.001). There were 2 cases of possible poor neonatal adaptation syndrome in neonates exposed to gabapentin close to delivery, compared with none in the comparison group, although it must be noted that these infants were concomitantly exposed to other psychotropic drugs. Among the women who took gabapentin, the major indications were pain (n = 90; 43%) and epilepsy (n = 71; 34%); the remainder were for other indications, mostly psychiatric. Conclusion: Our results suggest that although this sample size is not large enough to make any definitive conclusions, and there was no comparator group treated with other antiepileptic drugs, gabapentin use in pregnancy does not appear to increase the risk for major malformations. This finding and the increased risk for low birth weight and preterm birth require further investigation.

A perspective on inversin

Over the past 5 years, there has been increasing evidence for the role of primary (9+0) cilia in renal physiology and in establishing the left—right axis. The cilia in the renal tract are immotile and thought to have a sensory function. Cilia at the murine embryonic node have a vortical movement that sets up a leftward flow. Inversin, the protein defective in the inv mouse and in patients with type‐2 nephronophthisis, localizes to both renal and node primary cilia. However, we present evidence that it is also expressed before the node forms and that its subcellular localization in renal tubular cells is not confined to the cilia. Its role in both the pathway determining left—right axis and renal function remains to be elucidated.

Prescribing without evidence – pregnancy

Prescribing of medicines during pregnancy is common, and for some groups of women is essential for maintaining maternal and therefore fetal health. Pregnant women and prescribers are rightly concerned, however, about the potential adverse fetal effects of medicines. These may include fetal death or stillbirth, congenital malformations, developmental impairment, neonatal effects or late carcinogenesis. It is therefore essential that the risks and benefits for mother and fetus are considered carefully before prescribing in pregnancy. This is often challenging because of the paucity of information available. To complicate the issue further, drug pharmacokinetics are commonly altered in pregnancy, potentially affecting optimal dosing as well as interpretation of plasma concentration measurements, with specific information on individual drugs seldom available. Most drugs cross the placenta, especially lipophilic drugs and those with low plasma protein binding. Active membrane transporters also have an important role in enhancing or preventing drug transfer, although this is not yet clearly understood. Animal studies have limited applicability to humans because of species‐specific effects, and clinical trials in pregnancy are only undertaken in special circumstances. Prescribers therefore need to rely on observational studies of fetal outcomes following drug exposure in human pregnancy. These often involve limited numbers, and data are also subject to confounding and bias, making interpretation difficult. It therefore remains essential that appropriate mechanisms for systematic data collection, including congenital malformation registries, teratology information services, pregnancy registers and linked population registries, are maintained and enhanced to increase the amount and quality of information available.

Pregnancy outcome following maternal exposure to pregabalin may call for concern

Objective: To investigate pregnancy outcomes following maternal use of pregabalin. Methods: This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to pregabalin with those of matched controls (not exposed to any medications known to be teratogenic or to any antiepileptic drugs). Teratology Information Services systematically collected data between 2004 and 2013. Results: Data were collected from 164 exposed pregnancies and 656 controls. A significantly higher major birth defect rate in the pregabalin group was observed after exclusion of chromosomal aberration syndromes, and when cases with exposure during first trimester of pregnancy were analyzed separately (7/116 [6.0%] vs 12/580 [2.1%]; odds ratio 3.0, 95% confidence interval 1.2–7.9, p = 0.03). The rate of live births was lower in the pregabalin group (71.9% vs 85.2%, p < 0.001), primarily due to a higher rate of both elective (9.8% vs 5.0%, p = 0.02) and medically indicated (5.5% vs 1.8%, p = 0.008) pregnancy terminations. In the Cox proportional cause specific hazards model, pregabalin exposure was not associated with a significantly higher risk of spontaneous abortion. Conclusions: This study demonstrated a signal for increased risk of major birth defects after first trimester exposure to pregabalin. However, several limitations such as the small sample size, differences across groups in maternal conditions, and concomitant medication exposure exclude definitive conclusions, so these results call for confirmation through independent studies.

Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review

Importance Nausea and vomiting affects approximately 85% of pregnant women. The most severe form, hyperemesis gravidarum, affects up to 3% of women and can have significant adverse physical and psychological sequelae. Objective To summarize current evidence on effective treatments for nausea and vomiting in pregnancy and hyperemesis gravidarum. Evidence Review Databases were searched to June 8, 2016. Relevant websites and bibliographies were also searched. Titles and abstracts were assessed independently by 2 reviewers. Results were narratively synthesized; planned meta-analysis was not possible because of heterogeneity and incomplete reporting of findings. Findings Seventy-eight studies (n  = 8930 participants) were included: 67 randomized clinical trials (RCTs) and 11 nonrandomized studies. Evidence from 35 RCTs at low risk of bias indicated that ginger, vitamin B6, antihistamines, metoclopramide (for mild symptoms), pyridoxine-doxylamine, and ondansetron (for moderate symptoms) were associated with improved symptoms compared with placebo. One RCT (n = 86) reported greater improvements in moderate symptoms following psychotherapy (change in Rhodes score [range, 0 {no symptoms} to 40 {worst possible symptoms}], 18.76 [SD, 5.48] to 7.06 [SD, 5.79] for intervention vs 19.18 [SD, 5.63] to 12.81 [SD, 6.88] for comparator [P < .001]). For moderate-severe symptoms, 1 RCT (n = 60) suggested that pyridoxine-doxylamine combination taken preemptively reduced risk of recurrence of moderate-severe symptoms compared with treatment once symptoms begin (15.4% vs 39.1% [P < .04]). One RCT (n = 83) found that ondansetron was associated with lower nausea scores on day 4 than metoclopramide (mean visual analog scale [VAS] score, 4.1 [SD, 2.9] for ondansetron vs 5.7 [SD, 2.3] for metoclopramide [P = .023]) but not episodes of emesis (5.0 [SD, 3.1] vs 3.3 [SD, 3], respectively [P = .013]). Although there was no difference in trend in nausea scores over the 14-day study period, trend in vomiting scores was better in the ondansetron group (P = .042). One RCT (n = 159) found no difference between metoclopramide and promethazine after 24 hours (episodes of vomiting, 1 [IQR, 0-5] for metoclopramide vs 2 [IQR, 0-3] for promethazine [P = .81], VAS [0-10 scale] for nausea, 2 [IQR, 1-5] vs 2 [IQR, 1-4], respectively [P = .99]). Three RCTs compared corticosteroids with placebo or promethazine or metoclopramide in women with severe symptoms. Improvements were seen in all corticosteroid groups, but only a significant difference between corticosteroids vs metoclopramide was reported (emesis reduction, 40.9% vs 16.5% at day 2; 71.6% vs 51.2% at day 3; 95.8% vs 76.6% at day 7 [n = 40, P < .001]). For other interventions, evidence was limited. Conclusions and Relevance For mild symptoms of nausea and emesis of pregnancy, ginger, pyridoxine, antihistamines, and metoclopramide were associated with greater benefit than placebo. For moderate symptoms, pyridoxine-doxylamine, promethazine, and metoclopramide were associated with greater benefit than placebo. Ondansetron was associated with improvement for a range of symptom severity. Corticosteroids may be associated with benefit in severe cases. Overall the quality of evidence was low.

Rates of Major Malformations in Infants Following Exposure to Duloxetine During Pregnancy: A Preliminary Report

Method. In this observational multicenter cohort study, data on duloxetine exposure were collected prospectively from either women or their health care providers who had requested information regarding the use of duloxetine during pregnancy. These data came mainly from national teratogen information services that provide evidence-based information regarding the safety of and risks associated with drugs and other exposures during pregnancy. The data were collected from March 2010 to April 2012 and were from Canada, France, Israel, England, Italy, Australia, Switzerland, and Finland. French data were collected from several pharmacovigilance centers, which use procedures similar to those of teratogen information services, although requests are received mostly from physicians. The United Kingdom Teratology Information Service does not currently routinely collect data from women, as it is their health provider who makes the initial inquiry. During the initial contact, demographics, medical and obstetric histories, and details of drug exposure, as well as concurrent exposures to other substances, were recorded by teratogen information service staff on a standardized questionnaire. Then, shortly after birth to approximately 2 to 3 months after delivery, research assistants at the teratogen information services contacted women who had taken duloxetine during pregnancy and obtained their oral and/or written consent to complete the pregnancy outcome questionnaire. The study design included 2 comparison groups of equal numbers of women unexposed to duloxetine, who were chosen randomly: (1) women who were inquiring about exposure to other antidepressants and (2) women inquiring about an exposure not considered teratogenic, such as acetaminophen, antibiotics, or hair color. These women were matched to the duloxetine group for age and alcohol and tobacco use. The main outcome of interest was the presence or absence of major malformations (genetic and cytogenetic anomalies were excluded). This study was approved by the Research Ethics Board at The Hospital for Sick Children in Toronto, Ontario, Canada, and, for centers in the other countries, by local research ethics boards. In the United Kingdom, data collection is covered by Section 251 of the NHS Act 2006. 3 Results. We completed 624 pregnancy outcomes, with 208 in each group, and rates of major malformations were similar between the 3 groups (P = .992). There were 165 live births and 3

British Association for Psychopharmacology consensus guidance on the use of psychotropic medication preconception, in pregnancy and postpartum 2017:

Decisions about the use of psychotropic medication in pregnancy are an ongoing challenge for clinicians and women with mental health problems, owing to the uncertainties around risks of the illness itself to mother and fetus/infant, effectiveness of medications in pregnancy and risks to the fetus/infant from in utero exposure or via breast milk. These consensus guidelines aim to provide pragmatic advice regarding these issues. They are divided into sections on risks of untreated illness in pregnancy; general principles of using drugs in the perinatal period; benefits and harms associated with individual drugs; and recommendations for the management of specific disorders.

Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study

To conduct enhanced surveillance for signals of teratogenesis following use of the neuraminidase inhibitors zanamivir and oseltamivir in the treatment or post‐exposure prophylaxis of 2009 A/H1N1 influenza during pregnancy.