Incidence Of Major Malformations Research Articles

Assessment of the Safety of Exposure to Cefcapene Pivoxil during the First Trimester of Pregnancy: A Prospective Cohort Study in Japan.

Cefcapene pivoxil hydrochloride is an antibiotic often used by women who are or may be pregnant. However, the safety of exposure to it during the first trimester of pregnancy has not been assessed. In this study, we aimed to clarify the effects of exposure during the first trimester of pregnancy on maternal and fetal outcomes. Data were obtained from pregnant women who were counseled on drug use during pregnancy at two Japanese facilities from April 1988 to December 2017. The incidence of major malformations in singleton pregnancy was compared between neonates born to women who took cefcapene pivoxil hydrochloride (n = 270) and control drugs (n = 1594) during their first trimester. The adjusted odds ratio of the incidence of major malformations was calculated using multivariate logistic regression analysis adjusted for smoking during pregnancy and maternal age. The incidence of major malformations was 2.6% in the cefcapene pivoxil hydrochloride group and 1.8% in the control group. There were no significant differences in the incidence between the cefcapene pivoxil hydrochloride and control groups (adjusted odds ratio: 1.48 [95% confidence interval: 0.64-3.42], p = 0.36). This prospective cohort study showed that exposure to cefcapene pivoxil hydrochloride during the first trimester of pregnancy was not associated with increased risk of major malformations in infants. Our findings will help healthcare providers in choosing appropriate medicines.

Large prospective, pregnancy and infant follow-up trial assures the health of 1000 fetuses conceived after treatment with the GnRH antagonist ganirelix during controlled ovarian stimulation

A concern for new compounds in fertility treatment is the possible risk of perinatal complications or birth defects. To demonstrate long-term safety of ganirelix (GnRH antagonist) treatment in controlled ovarian stimulation (COS), follow-up data on pregnancy and neonatal outcome were analysed for 1000 fetuses (>or=16 gestational weeks). Obstetrical and neonatal data on 839 pregnancies, resulting in 969 live born infants after ganirelix treatment were compared with a historical cohort of 753 pregnancies after long GnRH agonist (buserelin) treatment, resulting in 963 live born infants. All treatment cycles were performed in a single fertility centre. The infants were examined at the Universitair Ziekenhuis Brussel using an identical follow-up protocol. Incidence of major malformations (i.e. causing functional impairment or requiring surgical correction) was the primary end-point and was analysed by logistic regression including treatment, age of mother, IVF method and pregnancy type (singleton/multiple) as independent variables. There were no relevant differences in maternal characteristics, fertilization method and pregnancy and delivery complications between the ganirelix and historical GnRH agonist groups. There were relatively more multiple pregnancies in the historical GnRH agonist group (31.9%) than the ganirelix group (18.7%; P < 0.0001). The groups were comparable with respect to pregnancy loss after 16 weeks gestation. The incidence of major congenital malformations in fetuses with gestational age >or=26 weeks was 5.0% in the ganirelix cohort versus 5.4% in the historical GnRH agonist group (odds ratio 0.94, 95% confidence interval, 0.62-1.42). In terms of neonatal outcome and risk of major malformations, treatment with the GnRH antagonist ganirelix during COS is as safe as traditional GnRH agonists.

Congenital malformations among newborns in Kenya

Available literature suggests that congenital malformations are a major cause of prenatal infant deaths and postnatal physical defects [1, 2]. Therefore, a study was conducted to determine the patterns and incidence of congenital malformations at birth in newborns in Kenya and thereby analyze associated predisposing factors in their mothers. This single cross-sectional survey adopted the quasi-experimental study design to investigate a total of 7,355 consecutive births at the maternity unit ofKenyatta National Referral Hospital over a period of uninterrupted 12 months beginning 8th September to 7th September of the following year. Data collection involved clinical examination of the malformed newborns for final diagnosis using a standard proforma. The study included a control group of new born babies selected systematically among babies who were born during the same study period but had no recognizable defects at birth (n=210). These included normal babies delivered immediately after the malformed newborns. The experimental group comprised the malformed babies (n=207). Mothers were also interviewed for demographicinformation and data on life style and behavioral risk factors. In this paper only the results of the experimental group are described. A total of 207 malformations were documented. Results showed overall incidence of externally discernible malformations of 28.1 per 1000 total births (28.1/1000). The incidence of major malformations was 15/1000 births. Malformations of musculoskeletal system were the most frequently observed, accounting for 33.9% of all the major malformations,followed by malformations of the central nervous system (28.6%). Polydactyl was the most common single malformation with an incidence of 10/1000 total births. Neural tube defects (with an overall incidence of 4.6/1000 births) and chromosomal disorders were also common. On the overall, congenital malformations occurred in proportions that were comparable to other findings in Africa and other parts of the world. Thesefindings highlight the need for stepping up nutritional prevention efforts, for instance, folic acid supplements; strengthening surveillance to monitor trends; and the establishment of a genetic centre in Kenya in order to strengthen local capacity for chromosomal studies, prenatal diagnosis, and genetic counseling on these complex issues.

Incidence of Major Malformations in Infants following Antidepressant Exposure in Pregnancy: Results of a Large Prospective Cohort Study

To ascertain if antidepressants, as a group, increase the risk for major malformations, as well as assessing each individual antidepressant. At The Motherisk Program, we analyzed pregnancy outcomes of women (n = 1243) from prospectively collected cases in our database, who were exposed to antidepressants during their pregnancy. We then compared them with a matched comparison group of women (n = 1243) who were not exposed (nonteratogen group). Women (n = 928) who fit the criteria for inclusion, were exposed in the first trimester of pregnancy, and gave birth to a live-born infant were matched to women (n = 928) in the comparison group. There were 30 (3.2%) major malformations in the antidepressant group and 31 (3.3%) in the comparison group (OR 0.9; 95% CI 0.5 to 1.61). The antidepressants included in the analysis were: bupropion (113), citalopram (184), escitalopram (21), fluvoxamine (52), nefazodone (49), paroxetine (148), mirtazepine (68), fluoxetine (61), trazodone (17), venlafaxine (154), and sertraline (61). As a group, antidepressant use in the first trimester of pregnancy is not associated with an increased risk for major malformation above the baseline. In addition, no individual antidepressant was associated with an increased risk of a specific malformation.

Incidence of Major Malformations in Infants Following Antidepressant Exposure in Pregnancy: Results of a Large Prospective Cohort Study

Incidence of Major Malformations in Infants Following Antidepressant Exposure in Pregnancy: Results of a Large Prospective Cohort Study

Incidence of major malformations in infants following antidepressant exposure in pregnancy: Results of a large cohort study

Incidence of major malformations in infants following antidepressant exposure in pregnancy: Results of a large cohort study

Lithium use in special populations

Byline: E. Mohandas, V. Rajmohan Lithium, a monovalent cation, was first used for the treatment of mania in the 1940s. Half a century into its use, the drug continues to be the preeminent choice for bipolar disorder with antimanic, antidepressant (modest) and antisuicidal property. Lithium is the "gold standard" mood stabilizer against which potential mood stabilizer agents are judged. The therapeutic uses of lithium also include use as an augmenting agent in depression, schizoaffective disorder, aggression, impulse control disorder, eating disorders, attention deficit disorder and in certain subsets of alcoholism. Lithium has been used in many medical disorders, especially cluster headache and dermatological disorders (seborrheic dermatitis, eczematoid dermatitis, genital herpes).[sup] [1] The drug is however associated with neurologic, endocrine, cardiovascular, renal, dermatologic and gastrointestinal adverse effects and possible teratogenicity. History Lithium was first discovered and defined by Johan August Arfvedson in 1817 when he did an analysis of the mineral petalite [LiAl(Si2O5)2]. Petalite was first found by Brazilian scientist Jose Bonifacio Andrade e Silva in 1800. Lepidolite, spodumene, petalite and amblygonite are the more important minerals containing lithium. It was Arfwedson's laboratory chief John Jacob Berzelius who named this alkali metal "lithion." Arfvedson was never able to fully isolate lithium, and it wasn't until 1855 that it was isolated by William Thomas Brande. Brande and Sir Humphrey Davy earlier had done electrolysis on lithium oxide in 1818. Lithium was first produced commercially in 1923 by Metallgesellschaft AG.[sup] [2] The use of lithium for medicinal purposes can be traced back 1,800 years to the Greek physician Galen, who treated patients with mania by having them bathe in alkaline springs and drink the water, which probably contained lithium. In 1843 Alexander Ure introduced lithium into modern medicine, and he showed the in vitro reduction of weight of a uric acid bladder stone in a lithium carbonate solution. Sir Alfred Garrod later discovered that gouty uric acid deposits also were soluble in lithium solution. The view in that time was that uric acid imbalances caused a wide range of diseases, and Armand Trousseau and Alexander Haig proposed that mania and depression also may result from this imbalance and lithium may be effective in these conditions. In the 1840s, lithium was mixed with carbonate or citrate to form a salt and was used to treat gout, epilepsy, diabetes, cancer and insomnia. In the 1870s, the then American Surgeon General William Hammond had provided anecdotal evidence for the use of lithium bromide in the treatment of acute mania. In the 1880s and 1890s the Lange brothers Carl and Fritz used lithium in depression, and Carl Lange was the first to systematically use lithium in the acute and prophylactic treatment of depression.[sup] [2] The introduction of lithium preparations and tablets in the 1900s brought to the fore the toxic effects of the drug; and there were reports of weakness, tremor, diarrhea, vomiting and deaths. The drug disappeared from the British Pharmacopoeia by 1932, but later in the 1940s it was used as a sodium substitute in low sodium diets; but the reports of severe intoxication led to its removal from American markets in 1949. [sup] [1] The appearance in 1949 in the Medical Journal of Australia of a paper entitled "Lithium salts in the treatment of psychotic excitement" by John F. J. Cade was an unspectacular entry into a new era of psychiatry. Manic patients showed improvement, with the patient becoming calmer after four to five days. There was no improvement in the excited schizophrenic patients, though there was a calming effect. There was no improvement or deepening of depression. The paper also gave details of initial dosage, maintenance doses, appearance of toxic symptoms and warning about lithium over-dosage. …

Pregnancy outcome after exposure to ranitidine and other H2-blockers: A collaborative study of the European Network of Teratology Information Services

Background: Published data on pregnancy outcome after exposure to H2-blockers is scarce. The aim of the present study was to evaluate the data collected by the memberships of the European Network of Teratology Information Services (ENTIS). Methods: The patients were pregnant women who or whose doctor or midwife did contact a Teratology Information Service for risk assessment after the use of a H2-blocker in pregnancy. The data were prospectively collected, i.e. before the outcome of pregnancy was known. Standardized procedures for data collection were used by each centre. The data of the exposed women were compared to those of a control group exposed to non-teratogenic substances. Results: Data on the outcome of 553 pregnancies with exposure to an H2-blocker were evaluated (ranitidine n = 335; cimetidine n = 113, famotidine n = 75; nizatidine n = 15, roxatidine n = 15). Most of them had been exposed at least in the first trimester. The incidence of premature deliveries was higher in the exposed group compared to the control group. There was no increase in the incidence of major malformations. Two pregnancies with maternal use of famotidine in early pregnancy were terminated after the prenatal diagnosis of a neural tube defect. Conclusion: There is no indication for an increased risk of major malformations after the use of H2-blockers during pregnancy.

Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies

Objective: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate.Design Meta-analysis.Setting: Studies from 1966 to present.Subjects: Studies...

The safety of omeprazole during pregnancy: A multicenter prospective controlled study

OBJECTIVES: Our purpose was to determine whether omeprazole use during pregnancy is associated with an increased risk of malformations, spontaneous abortions, decreased birth weight, or perinatal complications. STUDY DESIGN: In a multicenter, prospective controlled study, pregnant women exposed to omeprazole during gestation were matched with controls exposed to nonteratogens and with disease-paired controls who used histamine blockers for similar indications. The primary end point was the incidence of major malformations. RESULTS: One hundred thirteen pregnant women were exposed to omeprazole during pregnancy. Rates of major malformations in the omeprazole group (4%) did not differ from controls exposed to nonteratogens (2%) ( P = .68, relative risk = 1.94, 95% confidence interval 0.36 to 10.36) and disease-paired controls (2.8%). Birth weight, gestational age at delivery, preterm deliveries, and neonatal complications were comparable among the three groups. CONCLUSIONS: No association was found between exposure to omeprazole during the period of organogenesis and increased risk for major malformations. Exposure throughout pregnancy is not associated with increased risk of spontaneous abortions, decreased birth weight, or perinatal complications. (Am J Obstet Gynecol 1998;179:727-30.)

Clinical application of new micromanipulative technologies to treat the male.

Traditional treatments of the male have produced no improvement in sperm parameters. Since the rate of normal fertilization rate is significantly lower in these cases after classic in-vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) has become the preferred method of treatment. It has been successfully applied in cases of extreme oligoasthenoteratozoospermia, and obstructive and non-obstructive azoospermia. Cryopreservation of testicular tissue will replace the repeated use of fresh testicular tissue. Full information has to be provided to patients about the frequency (approximately 3%) of sex chromosome and autosomal aberrations in men with extreme oligoasthenoteratospermia. The need for screening for Yq deletions is still under study, and any therapeutic consequences for the newborn child will have to be analysed. The incidence of major malformations in newborn children is approximately 2.5%, i.e. comparable with that of the general population. Screening for de-novo sex chromosome aberrations may be particularly useful for men with sperm counts of < 5 x 10(6) and those with non-obstructive azoospermia.

High incidence of central nervous system malformations associated with marked parental consanguinity in an Israeli Arab community

It is common among Israeli Arabs who live in villages to prefer consanguineous marriages, particularly among first cousins. In addition, such villages are populated by a few (< 20) original families, and inter-family/inter-village marriages are infrequent. The purpose of this study was to examine the incidence of congenital malformation of the central nervous system associated with such “consanguinity” in Taibe, a large Arab village, 30 km from Tel Aviv. Six hundred and ten families were prospectively ascertained through infants who were routinely seen in the local “Well Baby Clinics”. A significant increase in the incidence of major malformations was noted in relation to the closeness of the parental relationship. For the index cases group, the prevalence of individuals with major malformations was 5.8% in the product of inter-village marriages, 8.3% in the intea-village non-related matings, 15.1% in the distant consanguineous group, and up to 15.8% in the progeny of first-cousin marriages ( P < 0.001). Malformations of the central nervous system consisted of 1 3 to 1 2 of the total malformations in the consanguineous groups versus less than 1 5 in the non-consanguineous groups. The study demonstrates a marked high rate of consanguineous marriages, the effect of which leads to a marked increase in major malformations and especially those of the central nervous system. This requires a unique genetic counseling approach.

Marked parental consanguinity as a cause for increased major malformations in an Israeli Arab community

It is common among Israeli Arabs who live in the villages to prefer consanguineous marriages, particularly among first cousins. In addition, such villages are populated by a few (less than 20) original families, and inter-family/inter-village marriages are infrequent. The purpose of this study was to examine the consequences of such "consanguinity" in Taibe, a large Arab village, 30 km from Tel Aviv. Six hundred ten families were prospectively ascertained through infants who were routinely seen in the local "Well Baby Clinics." A significant increase in the incidence of major malformations was noted in relation to the closeness of the parental relationship. For the index cases group the prevalence of individuals with major malformations were 5.8% in the product of inter-village marriages, 8.3% in the intra-village non-related matings, 15.1% in the distant consanguineous group, and up to 15.8% in the progeny of first-cousin marriages (P less than 0.001). In the siblings of these index cases, the frequency of major malformations was 4.3%, 4.5%, 10.5%, and 10.3%, respectively. Analysis of the major malformations by each body system showed the same trend. The study demonstrates a marked high rate of consanguineous marriages, whose effect leads to a marked increase in major malformations and thus a prominent public health problem in such villages. This requires a unique genetic counseling approach.

Pregnancy Complications and Short‐Term Follow‐Up of Infants Born After in Vitro Fertilization and Embryo Transfer (IVF/ET)

Two hundred and six pregnancies occurring after in vitro fertilization (IVF) and embryo transfer (ET) during a 7-year period in Göteborg were analysed with respect to pregnancy outcome. The clinical abortion rate was 26%, the rate of ectopic pregnancy was 10%, the rate of ongoing pregnancies beyond 24 weeks was 15%, and the rate of deliveries was 49% (n = 100). The hospital records of 98 women with the 100 deliveries resulting in 131 infants were studied. Multiple pregnancy occurred in 27%, including one quadruplet and two triplet pregnancies. Preterm birth occurred in 30% of all pregnancies and in 20% of singleton pregnancies. Thirty-four percent of the infants had a birth weight of less than 2500 g. The perinatal mortality was 46/1000, as estimated from the 24th week of pregnancy. The incidence of major malformation, 2.3%, was similar to that reported from studies in the general population. The first 100 infants born were followed up for 18 months to 8 years. Long-term sequelae were associated with immaturity and low birth weight. No problems during follow-up were disclosed in children who had had an uneventful neonatal period. It is concluded that IVF pregnancies are an obstetric risk group requiring special attention.

The wider perinatal significance of the Australian in vitro fertilization data collection program.

The most recent report (1986) from the Australian Register of In Vitro Fertilization pregnancies comprises 2242 in vitro fertilization (IVF) pregnancies and 261 gamete intrafallopian transfer (GIFT) pregnancies. A review of this data base indicated that this population had a relatively high incidence of both obstetric and perinatal morbidity and perinatal mortality. About 58% of the IVF pregnancies resulted in live births and 36.4% of the infants weighted less than 2500 gm at birth. These high rates could be partially accounted for by maternal prepregnancy risk factors, such as age, and by risk factors associated with the infertility management, such as multiple pregnancy (22% of all pregnancies more than 20 weeks), which accounted for approximately 50% of the preterm births (less than 37 weeks). Singleton pregnancies also had a higher incidence of preterm birth (17.8% at gestational age 24 to 36 weeks), low-birthweight babies (15.9% less than 2500 g) and perinatal mortality rates (35.4% per 1000 live births) than the Australian population at large. This warrants these patients being regarded as high risk. It is reassuring that the incidence of major malformations in IVF births (2.2%) is similar to that in the general population (1.4%).

Anticonvulsant drugs in monotherapy. Effect on the fetus.

We describe a material of 577 infants born of epileptic women treated with anticonvulsants in monotherapy during early pregnancy and collected from France, Italy, and Sweden. The incidence of major malformations is increased compared with the general population but no definite difference in risk can be demonstrated between the various anticonvulsants, but valproic acid was associated with a doubling of the average risk. The increased risk for facial clefts and for cardiac malformations, described from most studies on epilepsy during pregnancy, cannot be seen in this material. Unusually many cases of penis abnormalities (micropenis, hypospadias) were noted. An effect on fetal growth can be demonstrated and is apparently more pronounced for carbamazepine than for the other drugs. It results in a reduced birth weight in spite of normal gestational length, reduced body length and head circumference. The possible biological significance of this finding is discussed.

Effects of streptozotocin-induced diabetes on fetal development of the rat.

The purpose of this study was to determine whether or not in rats with experimentally induced diabetes there is an increased frequency of congenital malformations; data in the literature are not consistent on this point. Virgin CD females rats were injected with 40-50 mg/kg streptozotocin (Stz) before mating (SIBM group) or on the first day of pregnancy (SI1). Both SIBM and SI1 females were divided into two groups according to their blood glucose levels: severely diabetic (SD, greater than 300 mg%) and mildly diabetic (MD, 120-250 mg%). Food and water consumption by the control and MD groups were the same, but the SD females developed polyphagia, polyuria, and polydypsia, which continued to increase throughout pregnancy, as did the blood glucose levels. All the MD females mated and carried to term. In SD females both frequency of mating and fertility were only slightly lower than in the controls. All the females were killed on the 21st day of pregnancy. Pre- and postimplantation losses were the same for diabetic and control rats, but SIBM-SD females ovulated less than other groups. Weights of fetuses of SD dams were lower and blood sugar levels higher than those of the other groups. The placentas of SD rats were significantly heavier and there was cystic degeneration of spongiosa. The incidence of major malformations was minimal (approximately 2%) in fetuses of SD females and there were none at all in controls or MD females. In conclusion, our data are in agreement with those of other investigators who have found that rats with experimentally induced diabetes have smaller fetuses and increased placental weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Teratogenic evaluation of mancozeb in the rat following inhalation exposure

Crl:CD rats were exposed (whole body) to mancozeb by inhalation at 0, 1, 17, 55, 110, 890, or 1890 500 mg/m 3 for 6 hr/day from Day 6 through 15 of gestation (sperm-positive vaginal smear considered Day 1). Dams were killed 1 day prior to natural delivery and fetuses were examined externally, viscerally, and skeletally for any alterations. Maternal toxicity, as evidenced by significantly decreased body weight gain, hindlimb paralysis, general debilitation, and death or termination in extremis, was noted among rats exposed to mancozeb at concentrations of 500 to 1890 mg/m 3. Dams from the 55 and 110 mg/m 3 groups exhibited decreased body weight gain and hindlimb weakness. There was no maternal toxicity for dams exposed at a concentration of 17 mg/m 3. Embryofetal toxicity, as evidenced by a significantly increased incidence of totally resorbed litters, external hemorrhage, and wavy ribs, was noted at concentrations of 55 mg/m 3 and above. The embryofetal toxicity occurred only at concentrations toxic to the dam. Among the groups exposed to mancozeb, the incidence of major malformations was not dose related. Hence, under the test conditions of this study, mancozeb was not found to be teratogenic and produced no toxicity unique to the conceptus.

1295 FETAL PRIMIDONE EFFECTS

The incidence of major malformations in the offspring of epileptic women is approximately 2-3 times that of the general population. The delineation of recognizable patterns of malformation associated with specific drug exposures in utero implicates drug therapy as a major causative factor. Review of the literature and recent evaluation of 3 children with intrauterine primidone exposure reveal a distinctive pattern of malformation secondary to primidone, i.e., fetal primidone effects. The 3 affected children include an 18-month-old Hispanic boy and 2 white half siblings, a 13-year-old girl and an 8-year-old boy. In each case the mother took primidone daily throughout gestation. There was no family history of mental retardation or birth defects. The pattern of malformation was remarkably similar among the 3 children reported here and previous cases from the literature. Features include: developmental delay, ptosis, midfacial hypoplasia, flat nasal bridge, epi-canthus, telecanthus, short nose with anteverted nares, and 5th finger clinodactyly. Variable features include: seizures, hearing loss, upslanting palpebral fissures, unusual hair patterns, and short 5th metacarpals and/or metatarsals. Data from these patients indicate that maternal primidone intake during gestation may be associated with a recognizable pattern of malformation in exposed offspring.

Cardiovascular birth defects and antenatal exposure to female sex hormones: a reevaluation of some base data.

A re-evaluation of the base data as reported by Heinonen et al. from the Drug Epidemiology Unit of the Boston Collaborative Perinatal Project (CPP) was undertaken in order to examine particularly three matters which were not fully considered in the publication. These were, first, the timing of administration of sex hormones during the index pregnancy, which is relevant to determining whether any statistical association reported between sex hormone exposure and malformations could be causal; second, the incidence of serious maternal vaginal bleeding in early pregnancy, which could be an indication of threatened abortion, which in turn is associated with an increased malformation rate, and in addition is an indication for sex hormone administration; and third, the incidence of malformations or other adverse outcome in previous pregnancies, which, if present, might play a material role in the risk of malformation in the index pregnancy. Examination of the records of the 19 cases described by Heinonen et al. as hormone-exposed/cardiac-malformed revealed that no preparation containing hormone was administered in two patients, that five cases were given hormones too late in the index pregnancy to have any effect on cardiac organogenesis (which by general consensus begins on day 19 and ends at the latest on day 50 of gestation), that two cases were given hormones too early and two cases had Down's Syndrome. Thus eight children were exposed to hormones during the critical period of cardiac organogenesis, out of 17 actual hormone takers (47%). The description of vaginal bleeding did not allow any conclusions regarding differential rates of threatened abortion. It was found that the incidence of major malformations was 17% in the index group and 4% in the non-malformed group. This suggests that the hormone-exposed patients who gave rise to children with cardiac malformations were a highly selected group. The re-evaluation therefore reveals that the incidence of exposure to sex hormones during the critical period of cardiac organogenesis was not significantly different statistically in those women whose children had cardiac lesions as compared to those without such lesions. It is suggested that the result of this re-evaluation should direct the attention of epidemiologists to the quality of their base data. Re-examination of the base data of the Boston CPP does not support their reported association between the exposure to female sex hormones during pregnancy and the occurrence of cardiac malformations.