Major limb malformations following intrauterine exposure to ethanol: two additional cases and literature review

Two children are reported in whom major limb malformations were identified and whose mothers had consumed large quantities of alcohol in the first trimester of pregnancy. In one there was complete amelia of the upper limbs, while the other had preaxial polydactyly of both hands. These cases, taken together with previously reported instances of major limb anomalies following intrauterine ethanol exposure, as well as animal investigations that have demonstrated virtually identical limb malformations following ethanol administration, suggest that maternal ethanol abuse may be casually related to these limb malformations. We suggest that interruption of blood supply to the developing limb may be caused by ethanol exposure and may result in all of the various limb malformations described.     

Maternal birthplace and major congenital malformations among New York Hispanics

BACKGROUND: Little is known about the association between maternal nativity and congenital malformations among Hispanics living in the United States. METHODS: We conducted a cross-sectional study to investigate the association between maternal nativity and various congenital malformations among singleton live-births born to Hispanic women in New York from 1993 to 2001. Birth certificates, used to identify maternal birthplace, were linked with congenital malformation registry files to obtain birth defects outcome. We examined how the risk of birth defects varied by maternal birthplace by estimating the adjusted odds ratios (aORs) using logistic regression. RESULTS: A foreign maternal birth showed statistically negative associations with overall congenital malformations (aOR, 0.70; 95% CI, 0.68-0.73), cardiovascular defects (aOR, 0.85; 95% CI, 0.77-0.93), central nervous system defects (aOR, 0.76; 95% CI, 0.63-0.91), and multiple defects (aOR, 0.80; 95% CI, 0.74-0.86). Specifically, foreign-born Hispanic women were statistically at reduced risk to deliver live babies with cleft palate (aOR, 0.56; 95% CI, 0.40-0.80), atresia and stenosis of rectum or anus (aOR, 0.58; 95% CI, 0.35-0.97), and craniosynostosis (aOR, 0.71; 95% CI, 0.51-0.99). Hispanic mothers born in Puerto Rico had a similar risk of delivering children with birth defects compared to U.S.-born Hispanic mothers. In contrast, Hispanic mothers born in Mexico, or Cuba and Central and South America were at reduced risk of delivering infants with overall congenital malformations (aOR, 0.64; 95% CI, 0.60-0.67) and (aOR, 0.65; 95% CI, 0.63-0.68), respectively. CONCLUSIONS: Foreign-born Hispanic mothers had a slightly lower risk to deliver live-born singleton infants with major congenital malformations than did U.S. born Hispanic mothers.     

Children's health and their mothers’ risk of divorce or separation

Abstract

The purpose of this study is to determine how children's health conditions are related to their mothers’ risk of divorce or separation. The study is based on data from over 7,000 children born to once‐married mothers identified in the 1988 Child Health Supplement to the National Health Interview Survey. The effects of 15 childhood health conditions on the mothers’ risk of divorce are estimated with Cox's proportional hazard models. Controlling for demographic, marital, and reproductive measures, we find that mothers’ prospects for divorce are affected both positively or negatively by their children's health status, depending on the type of childhood condition and, in the case of low birth weight children, timing within the marriage. Women whose children have congenital heart disease, cerebral palsy, are blind, or had low birth weight appear to have higher risks of marital disruption than mothers of healthy children. In contrast, mothers whose children have migraines, learning disabilities, respiratory allergies, missing/deformed digits or limbs, or asthma have somewhat lower rates of divorce.     

Congenital Malformations among Babies Born Following Letrozole or Clomiphene for Infertility Treatment

Context

Clomiphene citrate (CC) is the first line drug for ovulation induction but because of its peripheral antiestrogenic effect, letrozole was introduced as the 2^nd line drug. It lacks the peripheral antiestrogenic effect and is associated with similar or even higher pregnancy rates. Since letrozole is a drug for breast cancer, its use for the purpose of ovulation induction became controversial in the light of studies indicating an increased incidence of congenital malformations.

Aims

To evaluate and compare the incidence of congenital malformations among offsprings of infertile couples who conceived naturally or with clomiphene citrate or letrozole treatment.

Settings and Design

A retrospective cohort study done at a tertiary infertility centre.

Methods and Material

A total of 623 children born to infertile women who conceived naturally or following clomiphene citrate or letrozole treatment were included in this study. Subjects were sorted out from medical files of both mother and newborn and follow up study was done based on the information provided by parents through telephonic conversations. Babies with suspected anomaly were called and examined by specialists for the presence of major and minor congenital malformations. Other outcomes like multiple pregnancy rate and birth weight were also studied.

Results

Overall, congenital malformations, chromosomal abnormalities were found in 5 out of 171 (2.9%) babies in natural conception group and 5 out of 201 babies in the letrozole group (2.5%) and in 10 of 251 babies in the CC group (3.9%).

Conclusions

There was no significant difference in the overall rate of congenital malformations among children born to mothers who conceived naturally or after letrozole or CC treatment.

Key Messages

Congenital malformations have been found to be comparable following natural conception, letrozole and clomiphene citrate. Thus, the undue fear against letrozole may be uncalled for.     

Offspring of male and female parents with thalidomide embryopathy: birth defects and functional anomalies

BACKGROUND: The aim of the study was to evaluate congenital malformations and functional anomalies in the offspring of Swedish parents with thalidomide embryopathy (TE). METHODS: Sixty-four children (29 girls, 35 boys) with ages ranging from 0-18 years, born to 34 Swedish parents (14 women, 20 men) with TE, were studied. Data on malformations and dysfunction were collected from medical records at maternity and child healthcare units, delivery units, hospitals, outpatient clinics and schools. RESULTS: Five children had both a mother and father with TE, 23 had a mother suffering from TE, and in 36 children the father had TE. One girl had a major malformation consisting of pulmonary stenosis, and single cases of minor physical features and positional deformities were observed. One boy had autism. Four children were born preterm, all to a TE mother. One child died within 24 hr after birth. Seven spontaneous abortions were registered, five of them in TE mothers. The cesarian section rate was 39% among the TE mothers, compared to 14% among the non-TE mothers. CONCLUSIONS: Malformations or functional anomalies similar to those typical for TE were not found in this group of children born to Swedish parents with TE. Cesarian sections were more frequently performed in TE mothers, partly because of pelvic and uterine malformations.     

Orofacial clefts and infections during pregnancy

Orofacial clefts (OFCs) are common congenital malformations of the lip, palate, or both caused by complex genetic and environmental factors. Specific antibodies against viruses influenza, rubella, cytomegalovirus, Epstein-Barr, parotitis and hepatitis B were investigated serologically in children with orofacial clefts and in their mothers. The results were compared with those obtained in control children and their mothers. Evaluation of the results and their statistical processing supports the assumption that infection during pregnancy may have occurred in the series studied induced by viruses of influenza, rubella, cytomegalovirus and possibly also by the Epstein-Barr virus. No association with the viruses of hepatitis B and parotitis was established.     

Birth rate and mortality rate of infants with congenital malformations of the limbs in the Awajishima free-ranging group of Japanese monkeys (Macaca fuscata)

The birth rate and mortality rate of infants with congenital malformations of the limbs were examined in the Awajishima free-ranging group of Japanese macaques (Macaca fuscata). Of the 606 infants born between 1978 and 1995, 86 (14.2%) were malformed. The male-female ratio did not differ between malformed and normal infants. Most kin-groups included females who gave birth to malformed infants at least once. The mortality rate within the first year after birth for malformed infants (28.2%) was significantly higher than that for normal infants (10.0%). However, this indicates that more than 70% of malformed infants were able to survive for the first year of life, even though they were unable to cling to their mothers ventrum due to their limb deformities. This finding indicates that maternal care-taking is sufficient to enable malformed infants to survive during the early stages of development and that clinging by the infant is not necessary for the display of maternal care. Am. J. Primatol. 42:225–234, 1997. © 1997 Wiley-Liss, Inc.     

Cancer Risks in Parents Who had a Child with a Congenital Malformation

Cancer risk in parents may be related to congenital malformations (CMs) in their children if they share genetic susceptibility or environmental exposure that may be teratogenic and carcinogenic. We conducted a population‐based cohort study based on Danish register data. We identified 795,607 mothers and 781,424 fathers who had all their children between 1977 and 2007 in Denmark. Information on CM was obtained from the Danish Hospital Registry and information on cancer was obtained from the Danish Cancer Registry. Parents were followed from the birth of their first child until the diagnosis of cancer, death, emigration, or December 31, 2007. We used Cox regression models to estimate hazard ratios (HRs) for cancer including cancer in specific organs in mothers and fathers. Overall, 75,701 (9.5%) mothers and 72,724 (9.3%) fathers had at least one child diagnosed with CMs within the first year of life. Neither mothers (HR = 1.04; 95% CI: 0.99–1.04) nor fathers (HR = 1.03; 95% CI: 0.98–1.09) who had a child with a CM had a higher overall risk of cancer. Mothers (HR = 0.76, 95% CI: 0.58–1.00) or fathers (HR = 0.89, 95% CI: 0.66–1.19) who had a child with a chromosomal malformation had a lower overall cancer risk. The findings also showed a higher risk for some specific types of cancer in parents who had children with a CM in the specific system. Some, or perhaps all, of these findings may be due to chance caused by multiple comparisons. We present all results on paper or online to provide clues for further research and to avoid publication bias.     

Parental consanguinity as a cause for increased incidence of births defects in a study of 238,942 consecutive births.

The risk for birth defects in the offspring of first-cousin matings has been estimated to increase sharply compared to non consanguineous marriages. As a general decline in the frequency of consanguineous marriages was observed in this century, one wonders whether consanguinity is still a factor in the appearance of birth defects in developed countries. Based on our registry of congenital anomalies we tried to answer to this question. In the population studied in North-Eastern France a consanguineous mating was known in 1.21% of the cases with congenital anomalies, vs. 0.27% in controls, (p < 0.001). The frequency of the malformations recorded paralleled the degree of consanguinity: out of 89 malformed children, 51 were seen in first-cousins mating (10.3 times more frequent than in offspring of non consanguineous couples), 17 in second-cousins marriages and 18 in more distant relatives mating. Three were uncle-niece marriage. Excluding known mendelian conditions these numbers were 73, 36, 17 and 17 respectively and the corresponding relative risk were 3.68, 3.01, 3.41 and 4.89 respectively. Therefore there is a negative dose-response effect between level of inbreeding and risk of congenital malformations. Consanguineous mothers were more often pregnant than non consanguineous mothers (p < 0.01) and they had more stillbirths than non consanguineous mothers. These results show that consanguinity is still a factor of birth defects and they must be taken into account for genetic counseling of inbred marriages, in developed countries.     

Clinical-genealogic analysis of diaphragmatic hernias]

The results of clinical-genetic examination of 174 probands with congenital diaphragmatic hernias and their families are presented. Genetic heterogeneity of diaphragmatic hernias, the spectrum of inherited syndromes obtained in the present study and shown in literature the spectrum and frequency of congenital malformations accompanying diaphragmatic hernias were shown. No increase in the average age of the probands' parents and in the marriage distances changes was observed both for isolated diaphragmatic hernias and those accompanied by other malformations was observed. Because of the high risk of neural tube defects occurrence in the sibs of children with diaphragmatic hernias, the probands' mothers should be recommended to undergo prenatal diagnosis of their further pregnancies for this character. The evidence of multifactorial inheritance for the most of diaphragmatic hernia cases was obtained. Empirical recurrent risk for probands' sibs was 1.54 + 1.5%.     

Maternal panic disorder and congenital abnormalities: a population-based case-control study

BACKGROUND: Maternal panic disorder in pregnancy is the most common manifestation of anxiety disorders in Hungary. The association between panic disorder during pregnancy and structural birth defects, i.e., congenital abnormalities, was studied. METHODS: The prevalence of maternal panic disorder in cases with different congenital abnormalities was compared to that of matched controls in the population-based Hungarian Case-Control Surveillance System of Congenital Abnormalities. RESULTS: Of 22,843 cases with congenital abnormalities, 210 (0.9%) had mothers with panic disorder during pregnancy compared to 187 (0.5%) of 38,151 controls (adjusted prevalence odds ratio [POR] 1.6; 95% CI, 1.3-2.0). Specific groups of congenital abnormalities were also assessed versus controls. Cases with isolated cleft lip with or without cleft palate (CL/P) (adjusted POR, 3.4; 95% CI, 1.3-9.0) and multiple congenital abnormalities (adjusted POR, 3.0; 95% CI, 1.2-7.2) were more likely to have had mothers with panic disorder during the study pregnancy. Notably, among mothers with panic disorders, the associations were found only in offspring of untreated mothers. CONCLUSIONS: A higher rate of isolated CL/P and multiple congenital abnormalities may be caused by the direct biological effect of panic disorder or by the interaction of maternal panic disorder and lifestyle factors. Antipanic drug treatment seems to have a protective effect for isolated CL/P and multiple congenital abnormalities. Birth Defects Research (Part A), 2006.     

Limb reduction defects in the first generation and deafness in the second generation of intrauterine exposed fetuses to diethylstilbestrol

Maternal treatment with diethylstilbestrol (DES) during pregnancy can produce vaginal adenocarcinoma and other abnormalities of the vagina in her daughters when they reach adolescence or adulthood, miscarriages and absence of full term infants. Concerning malformations in newborns whose mothers were treated with DES, clitoromegaly and malformations of the uterus were reported in females and genital lesions in males. However, the frequencies of major congenital anomalies were not greater than expected. We report three cases of limb reduction defects (LRD) in the first generation of children whose mothers were treated with DES during pregnancy, and two children (one male, one female) with deafness in the second generation after intrauterine exposure to DES. The LRD were not associated with other congenital anomalies. The malformed children with LRD were born between 1965 and 1973. The deafness was also isolated. The two mothers who have no hearing problems and who are healthy were exposed in utero to DES in 1963 and 1965, respectively. Their children were born in 1989 and 1994, respectively. In conclusion, the association of LRD and hearing loss with intrauterine exposure to DES could be coincidental. However, some hypothesis may explain these associations. Congenital hearing loss in the second generation may suggest a transgenerational effect.     

Associated malformations in cases with congenital diaphragmatic hernia

The etiology of congenital diaphragmatic hernia (CDH) is unclear and its pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with CDH, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 115 patients with the most common type of CDH, the posterolateral, or Bochdalek-type hernia, 70 (60.8%) had associated malformations. These included: chromosomal abnormalities (n = 21, 30.0%); non-chromosomal syndromes (Fryns syndrome, fetal alcohol syndrome, De Lange syndrome, CHARGE syndrome, Fraser syndrome, Goldenhar syndrome, Smith-Lemli-Opitz syndrome, multiple pterygium syndrome, Noonan syndrome, and spondylocostal dysostosis); malformation sequences (laterality sequence, ectopia cordis); malformation complexes (limb body wall complex) and non syndromic multiple congenital anomalies (MCA) (n = 30, 42.9%). Malformations of the cardiovascular system (n = 42, 27.5%), urogenital system (n = 27, 17.7%), musculoskeletal system (n = 24, 15.7%), and central nervous system (n = 15, 9.8%) were the most common other congenital malformations. We observed specific patterns of malformations associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. Geneticists and pediatricians should be aware that the malformations associated with CDH can often be classified into a recognizable malformation syndrome or pattern (57.1%).     

Pregnancy after cytotoxic chemotherapy for gestational trophoblastic tumours.

To examine the possibility that cytotoxic drugs may cause sterility or congenital malformations in the offspring of women of childbearing age who are cured of cancer a study was conducted of the obstetric histories of 445 long term survivors treated in this unit with chemotherapy for gestational trophoblastic tumours between 1958 and 1978. After completing treatment 97% of those who wished for a pregnancy (49% of all women studied) conceived and 86% had at least one live birth. All these women had received methotrexate. Of the 47 women who wished to conceive and whose combination therapy included cyclophosphamide, 37 (79%) had a live birth. Women who received three or more drugs were less likely to have a live birth than those who received methotrexate alone or with only one other drug (p less than 0.001). There was no statistically significant excess of congenital malformations. These results are strong evidence that the cytotoxic drug regimens used in this unit for treating gestational trophoblastic tumours are compatible with the preservation of fertility in most women and not associated with any increase in congenital abnormalities.     

Amelia: incidence and associated defects in a large population

Amelia, or complete absence of a limb, is a very rare congenital anomaly. The incidence of amelia in a population of 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 was studied using the records of a population-based registry with multiple sources of ascertainment. There were 18 cases of amelia, giving a minimal incidence rate of 0.15 per 10,000 livebirths for this birth defect. Amelia occurred equally frequently in upper and lower limbs, and 11 of 18 (61%) liveborn cases also had malformations of other organ systems. In the group with lower limb amelia a specific pattern of associated malformations, which included omphalocele and diaphragmatic defects, was identified. There was no evidence for familial recurrence of amelia. Conditions to be considered in differential diagnosis are discussed.     

Congenital heart disease and prenatal exposure to exogenous sex hormones.

One-hundred and four infants with congenital heart disease were identified from their birth certificates and matched with normal controls. Their gestational histories were examined to see whether they had been exposed to exogenous sex hormones. Exposure was 8-5 times more common among the infants with malformations than among controls. A history of hormone exposure was more common among those patients with multiple malformations, and the exposed infants were also more likely to have died (and to have died earlier) than those who had not been exposed, which suggests that hormone exposure causes severe types of malformations. The commonest type of exposure was to hormone pregnancy tests, which was needless exposure. Only two of the mothers of malformed infants had inadvertently used oral contraceptives in the first trimester.     

Congenital malformations at birth in Central India: A rural medical college hospital based data

OBJECTIVE:

To study the incidence of congenital anomalies and the associated risk factors in Department of Pediatrics at Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, a rural medical college hospital in central Maharashtra.

MATERIALS AND METHODS:

All the intramural deliveries between 1 January 2005 and 31 July 2007 comprised 9386 births and their 9324 mothers (62 mothers gave birth to twin babies). The newborns were examined and assessed systematically for the presence of congenital anomalies, system wise distribution of anomalies and risk factors attributable.

RESULTS:

Out of the total 9386 deliveries, 9194 were live births and 192 were stillbirths. The total number of babies with congenital malformations was 179 (1.91%). Out of the 9262 singleton births, 177 (1.05%) were malformed, whereas 2 of the 62 pairs of twins had birth defects. Nine of the 179 malformed babies (5.02%) were still born. Prematurity, increased maternal age, increasing birth order and low birth weight were found to have a higher risk of congenital anomalies. Cardiovascular malformations were most common in live births, followed by musculoskeletal and genitourinary anomalies.

CONCLUSION:

Congenital anomalies are a major cause of stillbirths and infant mortality. Evaluation of cardiovascular system to rule out congenital heart disease in high-risk mothers’ babies is the important factor to be considered.     

Early growth retardation in diabetic pregnancy.

Thirty-five insulin-dependent diabetic women with reliable menstrual histories were examined by ultrasonic scanning in the 7th-14th weeks of pregnancy. Judged from crown-to-rump length the fetuses were on average 5.4 days smaller than those in a local normal series. Ten of the fetuses were nine days or more smaller than normal and had a lower mean birth weight than the others, though the mean gestational age was similar. Maternal diabetes was not more severe in this group, but only two of the mothers had attended a special hospital for control of their disease as compared with 19 of the remainder. Although babies of diabetic mothers are often overweight, there appears to be a subgroup of cases in which fetal growth is retarded early in pregnancy, leading to low birth weight and possibly a higher incidence of congenital malformations.     

In vitro fertilization (IVF) in Sweden: risk for congenital malformations after different IVF methods

BACKGROUND: The possible excess of congenital malformations in infants born after in vitro fertilization (IVF) has been much discussed in the literature, with controversial conclusions. This population based study is aimed at analyzing the presence of congenital malformations in a large group of infants born after IVF and to compare malformation risk both with that of all infants born and according to IVF method used. METHODS: Infants born after IVF during the period 1982-2001 were ascertained from all IVF clinics in Sweden. The presence of congenital malformations was identified from three national health registers: the Swedish Medical Birth Register, the Swedish Registry of Congenital Malformations, and the Swedish Hospital Discharge Register. The IVF children were compared with all children born in Sweden during the same period and recorded in the Swedish Medical Birth Register. RESULTS: Among 16,280 IVF children (30% conceived after intracytoplasmatic sperm injection [ICSI]) a 42% excess of any congenital malformation was found, explainable by parental characteristics and in some cases by the high rate of multiple births. Among these children, 8% had a congenital malformation, and 5% had a relatively severe condition. For neural tube defects, choanal atresia, and alimentary tract atresia, an additional risk increase was seen. There was no difference in malformation rate according to IVF method except for an excess of hypospadias after ICSI. CONCLUSIONS: An increased risk for congenital malformations occurs after IVF, similar for the different IVF techniques used, and mainly a consequence of parental characteristics. A few specific conditions show an extra increase in risk.     

Exogenous sex hormone exposure and the risk for VACTERL association

In several studies investigators have suggested that maternal use of exogenous sex hormones during early pregnancy may be associated with various congenital malformations. A group of malformations, the VACTERL (vertebral, anal, cardiac, trachea, esophageal, renal, limb-acronym) association, has been statistically associated with maternal exposure to exogenous sex hormones during the first trimester of pregnancy. The VACTERL association is a nonrandom group of major malformations that occur together more often than would be expected on the basis of chance. To assess this association, we conducted a case-control study of first-trimester exposure to sex hormones among mothers of 34 infants with the VACTERL association and of 1,024 comparison infants with one or more of ten major malformations or Down syndrome. The study subjects were malformed infants born between July 1970 and June 1979 and registered in a population-based birth defects registry. Information concerning the use of exogenous sex hormones during pregnancy was obtained by systematically interviewing the mothers of the malformed infants. Most of the mothers were interviewed within 6 months of their children's births. Each mother was interviewed within a year of her child's birth. We found an odds ratio of 0.98 (90% confidence limits 0.40, 2.38) for the relationship between VACTERL association and use of any sex hormone in the first trimester of pregnancy. Our study had adequate statistical power to detect a true relative risk of 2.8 or greater.