Prematurity and neonatal outcome including congenital malformations after maternal malignancy within six months prior to or during pregnancy.

INTRODUCTION: The proportion of women who postpone childbearing is increasing. As malignancy risk increases with age, pregnancy in connection with malignancy will become more common. MATERIAL AND METHODS: We compared infants born 1994-2011 to women with a malignancy within six months prior to the last menstrual period or during pregnancy with offspring of women without a previous malignancy. Five national registers were used. RESULTS: A total of 790 women with a malignancy diagnosis from six months prior to the last menstrual period up to delivery were identified. Their 802 infants were compared with 1 742 757 infants of women without a malignancy. A high rate of prematurity was found, especially when the malignancy was diagnosed during the second or third trimesters (33%). Most of these premature births were the result of induced delivery before 35 weeks (91%). The most remarkable finding is the observation that these premature infants had a significantly higher risk for neonatal morbidity than premature infants in the control group with an adjusted odds ratio of 2.67 (95% confidence interval; 1.86-3.84). We found a significantly increased risk of mainly relatively mild malformations among infants of women with a malignancy diagnosis within six months prior to the last menstrual period or during the first trimester with a risk ratio of 1.81 (95% confidence interval; 1.20-2.61). CONCLUSIONS: A high incidence of prematurity, mostly due to induced delivery, was found, including an increased risk for neonatal morbidity among these infants. An increased risk for relatively mild malformations was also found.

Characteristics of the Offspring of Women with a History of Malignancy, Excluding Congenital Malformations.

OBJECTIVE: To study the characteristics (except congenital malformations) of offspring born to women with a history of malignancy. METHODS: Data were obtained by linkage between four different Swedish national health registers. We compared the offspring born between 1994 and 2011 of women with a history of malignancy with all other infants. Survival of the infants was followed up through 2013. Adjusting for confounders was performed using Mantel-Haenszel methodology. We identified 7315 infants born to women with a history of a malignancy diagnosed at least 1 year before delivery. The total number of deliveries in Sweden in these years was 1 746 870, with 1 780 112 infants being born. We assessed rates of intrauterine death, preterm birth, low birth weight, and the nature of intrauterine growth. We also examined neonatal diagnoses (asphyxia, chronic respiratory condition, intracranial hemorrhage, jaundice, hypoglycemia, CNS symptoms) and infant death. RESULTS: In women with a history of malignancy, we found no significantly increased risk for stillbirth or infant death. There were elevated rates of preterm birth (OR 1.50, 95% CI 1.37 to 1.64), very preterm birth (OR 1.89, 95% CI 1.54 to 2.32), and low birth weight (OR 1.50, 95% CI 1.34 to 1.68). There was a significantly increased risk of birth asphyxia, jaundice, hypoglycemia, and low Apgar score among infants born to women with a history of malignancy (OR 1.24, 95% CI 1.15 to 1.33), and this risk was maintained after excluding infants born after IVF. CONCLUSION: We found an increased risk of preterm birth and low birth weight among infants of women with a history of malignancy, and as a result, found an increased risk of neonatal morbidity. No significant increase in risk of intrauterine or postnatal death was noted.

Maternal use of 5-aminosalicylates in early pregnancy and congenital malformation risk in the offspring.

OBJECTIVE: Most previous studies have failed to demonstrate any effect of maternal use of 5-aminosalicylates (5-ASA) on malformation risk, but the number of infants studied have, in most cases, been low. The objective of the study was to get data from a large study with prospectively ascertained exposure information. MATERIAL AND METHODS: The study was based on data in the Swedish Medical Birth Register (1996-2011) where identification of maternal drug use is made from midwife interviews in early pregnancy. The presence of congenital malformations was ascertained from three national registers. Adjusted odds ratios were calculated by the Mantel-Haenszel methodology. RESULTS: Among 1,552,109 women, 3651 with 3721 infants had reported the use of 5-ASAs in early pregnancy. The risk of a major malformation was increased (1.37, 95% confidence interval = 1.17-1.62) and still more for a cardiovascular defect (1.74, 1.37-2.22). This effect seemed to be influenced by concomitant use of systemic glucocorticosteroids or immunosuppressants but some confounding by indication may also exist. There was no marked difference between the four 5-ASA drugs studied. CONCLUSIONS: Infants born of women who use 5-ASA drugs in early pregnancy have an increased risk of a congenital malformation, notably a cardiovascular defect. This could be a drug effect or an effect of an active inflammatory bowel disease.

Fetal safety of erythromycin. An update of Swedish data.

PURPOSE: In previous studies from the Swedish Medical Birth Register, a possible association between erythromycin therapy and an increased risk for cardiovascular defects was found. Other studies using different methodology have not verified this observation. The finding resulted in a warning for the use of erythromycin in early pregnancy, followed by a marked decline in such use. The present study was conducted to follow up on the previous observations and to find methodological explanations for the variation in results in these different published studies. METHODS: Data on Swedish women who gave birth during the period 1996-2011 were studied using the drug information in the Medical Birth Registry, obtained from midwife interviews conducted toward the end of the first trimester. Data on the presence of congenital malformations were ascertained from national health registers. Odds ratios were then determined using the Mantel-Haenszel methodology. RESULTS: A persistent association was seen between erythromycin use and the occurrence of cardiovascular defects, with a risk estimate of 1.70 (95 % confidence interval (CI): 1.26-2.39), of similar strength during the first and last 8 years of observation. We discussed the contradictory findings of the other published studies and pointed out possible methodological problems that may explain the absence of an effect in studies based on prescription registers. CONCLUSIONS: Our study verified an association between early pregnancy erythromycin use and infant cardiovascular defects; most defects were mild. The cause of this association is unclear.

Maternal obesity and risk of Down syndrome in the offspring.

OBJECTIVE: The objective of this article is to determine if maternal obesity is associated with an increased risk of Down syndrome in the offspring and whether the risk estimates for trisomy 21 based on combined screening is affected by maternal body mass index (BMI). METHODS: Study group I consisted of a nationwide cohort of 1 568 604 women giving birth; outcome was infants born with Down syndrome [Correction made here after initial online publication.]. Adjustment was made for maternal age. Study group II consisted of 10 224 women undergoing 1st trimester combined screening. Outcome was risk assessment for Down syndrome. All women were divided into six BMI groups, and outcomes were evaluated over the BMI strata with BMI 18.5 to 24.9 as reference and correcting for maternal age. RESULTS: Obese women had an increased risk for giving birth to an infant with Down syndrome compared with normal-weight women, BMI 30 to 34.9 odds ratio (OR) 1.31 [95% confidence interval (CI) 1.10-1.55], BMI 35 to 39.9 OR 1.12 (95% CI 0.82-1.53), BMI ≥ 40 OR 1.56 (95% CI 1.00-2.43). The observed and the expected numbers of women with a risk of Down syndrome >1/300 based on 1st trimester combined screen and maternal age were similar in each BMI group. CONCLUSION: Maternal obesity seems to increase the risk for Down syndrome births. The risk estimate for Down syndrome with 1st trimester combined screening is unaffected by BMI.

Association between preterm birth and intrauterine growth retardation and child asthma.

An association between preterm birth and an increased risk of childhood asthma has been demonstrated, but the importance of intrauterine growth retardation on asthma risk is unclear. Using data from Swedish health registers, infant characteristics and childhood asthma were studied. Analyses were made using Mantel-Haenszel methodology with adjustment for year of birth, maternal age, parity, smoking in early pregnancy and maternal body mass index. Preterm birth, birth weight and birth weight for gestational week were analysed and childhood asthma was evaluated from prescriptions of anti-asthmatic drugs. Neonatal respiratory problems and treatment for them were studied as mediating factors. Both short gestational duration and intrauterine growth retardation appeared to be risk factors and seemed to act separately. The largest effect was seen from short gestational duration. Use of mechanical ventilation in the newborn period and bronchopulmonary dysplasia were strong risk factors. A moderately increased risk was also seen in infants born large for gestational age. We conclude that preterm birth is a stronger risk factor for childhood asthma than intrauterine growth disturbances; however, the latter also affects the risk, and is also seen in infants born at term.

Maternal drug use during pregnancy and asthma risk among children.

BACKGROUND: Maternal use of some drugs, notably paracetamol and drugs for gastroesophageal reflux, has been associated with an increased risk of childhood asthma in the child. We wanted to analyze these associations with consideration to the confounding of maternal asthma. METHODS: Childhood asthma was identified from the Swedish National Prescription Register and maternal drug use during the latter part of pregnancy from antenatal records, computerized in the Swedish Medical Birth Register. Risks were estimated as odds ratios (OR) with 95% confidence intervals, using Mantel-Haenszel technique with adjustment for year of birth, maternal age, parity, smoking habits, and BMI. RESULTS: A statistical association between maternal use of many different drugs, including paracetamol, and childhood asthma existed but was mainly due to concomitant drug use, related to maternal asthma. The only associations that appeared to be true were with drugs for gastroesophageal reflux (adjusted (OR) = 1.32, 95% CI, 1.18-1.54) and with opiates (adjusted OR = 1.56 (96% CI, 1.05-2.34). CONCLUSIONS: Maternal use of paracetamol did not seem to increase the risk of childhood asthma, but the previously described association with drugs for gastroesophageal reflux was supported. The analysis is complicated by the confounding from maternal asthma.

Neonatal complications after maternal concomitant use of SSRI and other central nervous system active drugs during the second or third trimester of pregnancy.

Drugs acting on the central nervous system (CNS) and given to a pregnant woman during the latter part of pregnancy may affect neonatal morbidity of the infant. Little is known on the combined effects of different categories of such drugs. The redeeming of prescriptions for CNS-active drugs during the second or third trimester of pregnancy was studied by linkage between a register of prescribed drugs and the Swedish Medical Birth Register for the deliveries during 2006-2008 (n = 15,045 live-born infants). Neonatal morbidity was defined as the presence of neonatal diagnoses of respiratory problems, hypoglycemia, convulsions, or other CNS pathologic abnormalities including intraventricular hemorrhage, or low 5-minute Apgar score. The risk of such neonatal morbidity after maternal use of selective serotonin reuptake inhibitors (SSRIs) with or without other CNS-active drugs were evaluated as odds ratios or risk ratios, comparing with unexposed infants or infants only exposed to SSRI drugs. An increased risk for neonatal morbidity was seen for most studied groups of CNS-active drugs when used alone. Benzodiazepines seemed to have a stronger effect than other sedatives/hypnotics. The combination of SSRIs with 1 or more other CNS-active drug groups increased the risk for neonatal morbidity. This was seen for all types of sedatives/hypnotics, which may suggest a confounding by indication. Polypharmacy with CNS-active drugs during the later part of the pregnancy seems to increase the occurrence of neonatal morbidity but difference in nature or strength of underlying psychiatric pathology may confound the findings.

Are hypnotic benzodiazepine receptor agonists teratogenic in humans?

BACKGROUND: Hypnotic benzodiazepine receptor agonists (HBRAs; zolpidem, zopiclone, and zaleplon) are used in the treatment of insomnia. Little is known about the safety of HBRAs during pregnancy. METHODS: Data from the Swedish Medical Birth Registry from July 1, 1995, up to 2007 were used to identify 1318 women who reported the use of HBRAs in early pregnancy. They gave birth to 1341 infants. Maternal characteristics and the presence of congenital malformations were compared with all other women who gave birth (n = 1,106,001) and all other infants (n = 1,125,734) born during the study period. RESULTS: Use and/or reporting of HBRAs increased with maternal age and were higher at first than higher parity. Maternal smoking was strongly associated with reported use of HBRAs. The probability of using HBRAs increased in women who had had 3 or more earlier miscarriages or 5 or more years of involuntary childlessness. An excess use of other drugs and above all psychoactive drugs were seen in women reporting use of HBRAs.Hypnotic benzodiazepine receptor agonists were not associated with an increased risk for congenital malformations. A statistically significant high risk for other intestinal malformations than atresias/stenosis was based on only 4 infants. CONCLUSIONS: Maternal use of HBRAs does not seem to increase malformation risk. The tentative association with some intestinal malformations may be due to chance because of multiple testing and needs confirmation.

School performance at age 16 in children exposed to antiepileptic drugs in utero--a population-based study.

PURPOSE: In order to evaluate long-term effects on neurodevelopment in children born to women with epilepsy during pregnancy we studied the children's school grades at age 16. METHODS: We used the Patient Register, the Medical Birth Register, and a local study at South Hospital, Stockholm, to identify women with epilepsy in Sweden who had given birth between 1973 and 1986. The Swedish School Mark Registry was used to obtain information about school grades from the last year of compulsory school, at age 16. Exposed children were compared to all other children born in Sweden between 1973 and 1986. KEY FINDINGS: Medical records were analyzed for 1,235 children. Six hundred forty-one children had been exposed in utero to antiepileptic drugs (AEDs) in monotherapy, 429 in polytherapy, and 165 to no known AED. Children exposed to polytherapy had an increased risk of not receiving a final grade--odds ratio (OR) 2.99 [95% confidence interval (CI) 2.14-4.17]. Children exposed to monotherapy, mainly carbamazepine or phenytoin, did not have a significantly increased risk of not receiving a final grade-OR 1.19 (95% CI 0.79-1.80). Children born to women with epilepsy had a decreased chance of getting a "pass with excellence." SIGNIFICANCE: Exposure to several AEDs in utero may have negative effects on neurodevelopment, and polytherapy should, if possible, be avoided in pregnant women.

Antidepressant use during pregnancy: comparison of data obtained from a prescription register and from antenatal care records.

PURPOSE: To compare interview data on drug use during pregnancy with data identified from a register of prescriptions. MATERIALS: We compared information from the Swedish Prescribed Drug Register with the Swedish Medical Birth Register on antidepressant use. In order to evaluate the clinical significance of the difference in ascertainment with the two methods, the rate of preterm births among singletons and of neonatal symptoms were studied. RESULTS: During the year before the last menstrual period, 1.5% of the women filled prescriptions for antidepressants each month. Already before the pregnancy was known, the rate of filled prescriptions decreased and reached 0.5% towards the end of the pregnancy. Twenty-two percent of first-trimester use of antidepressants was unidentified using interview data and prescriptions during the 2nd and 3rd pregnancy months covered only 55% of actual use. When women who filled prescriptions 1 or 3 months before the last menstrual period were included, 17 and 43% respectively of women were included who probably did not use the drugs in the first trimester. Prescriptions gave a more complete ascertainment of drug use after the first trimester than data from antenatal care, which seemed to overestimate drug use. CONCLUSIONS: Interview data seem to give the most valid results on early use. When interview data are not available, prescription data could be used, but should not include prescriptions given earlier than 1 month before the last menstrual period. Studies of drug use later in pregnancy are best based on prescription data in the absence of interview data.

Maternal and child outcome after in vitro fertilization--a review of 25 years of population-based data from Sweden.

OBJECTIVE: To summarize data on deliveries after in vitro fertilization (IVF) performed in Sweden up to 2006. DESIGN: Cohort study of women and children, conceived after IVF, with comparisons of deliveries after IVF before and after 1 April 2001. SETTING: Study based on Swedish health registers. POPULATION: Births registered in the Swedish Medical Birth Register with information on IVF from all IVF clinics in Sweden. METHODS: Results from the second study period are summarized, and outcomes between the two periods are compared. Long-term follow-up is based on data from both periods. MAIN OUTCOME MEASURES: Maternal and perinatal outcomes, long-term sequels. RESULTS: Some maternal pregnancy complications decreased in rate, notably pre-eclampsia and premature rupture of membranes. The rate of multiple births and preterm births decreased dramatically, with a better neonatal outcome, including reduced neonatal mortality. No difference in outcome existed between IVF and intracytoplasmic sperm injection or between the use of fresh and cryopreserved embryos, but children born after blastocyst transfer had a slightly higher risk for preterm birth and congenital malformations than children born after cleavage stage transfer. An increased risk for cerebral palsy, possibly for attention deficit and hyperactivity disorder, for impaired visual acuity and for childhood cancer was noted, but these outcomes were rare also after IVF. An increased risk for asthma was demonstrated. No effect on maternal cancer risk was seen. CONCLUSION: A marked decrease in multiple births was the main reason for better pregnancy and neonatal outcome and may also have a beneficial effect on long-term results, notably cerebral palsy.

Confirmed association between neonatal phototherapy or neonatal icterus and risk of childhood asthma.

We have previously demonstrated an association between neonatal phototherapy and/or neonatal icterus and risk of hospitalization for childhood asthma. This study included children who were prescribed anti-asthmatic medication on a population basis to study exposures during the foetal and neonatal period and risk of childhood asthma. The Swedish Medical Birth Register was linked to the Swedish Prescribed Drug Register. Perinatal data for singleton children who were prescribed anti-asthmatic medication (n = 61,256) were compared with corresponding data for all singleton children born in Sweden from 1 January 1990 to 30 June 2003 and surviving to 1 July 2005 (n = 1,338,319). Mantel-Haenszel's odds ratios were calculated after adjustment for various known confounders. Being the first-born child, maternal age above 44 yr, involuntary childlessness for more than 1 yr, maternal smoking during pregnancy, maternal diabetes mellitus of any kind, pre-eclampsia, caesarean section, and instrumental vaginal delivery were all associated with an increased prescription of anti-asthmatic medication during childhood. Preterm birth, low birth weight, being small for gestational age, respiratory problems, mechanical ventilation, and sepsis and/or pneumonia were also associated with increased drug prescriptions. Neonatal phototherapy and/or icterus were risk determinants for children who developed asthma before the age of 12. After controlling for confounders, the odds ratio for phototherapy and/or icterus remained at 1.30 (95% confidence interval 1.16-1.47). In conclusion, this large population-based study confirms an association between some maternal and perinatal factors and childhood asthma, including neonatal phototherapy and/or icterus.

Maternal obesity and morbid obesity: the risk for birth defects in the offspring.

BACKGROUND: The objective of this study was to assess, in a large data set from Swedish Medical Health Registries, whether maternal obesity and maternal morbid obesity were associated with an increased risk for various structural birth defects. METHODS: The study population consisted of 1,049,582 infants born in Sweden from January 1, 1995, through December 31, 2007, with known maternal weight and height data. Women were grouped in six categories of body mass index (BMI) according to World Health Organization classification. Infants with congenital birth defects were identified from three sources: the Swedish Medical Birth Registry, the Register of Birth Defects, and the National Patient Register. Maternal age, parity, smoking, and year of birth were thought to be potential confounders and were included as covariates in the adjusted odds ratio analyses. RESULTS: Ten percent of the study population was obese. Morbid obesity (BMI > or = 40) occurred in 0.7%. The prevalence of congenital malformations was 4.7%, and the prevalence of relatively severe malformations was 3.2%. Maternal prepregnancy morbid obesity was associated with neural tube defects OR 4.08 (95% CI 1.87-7.75), cardiac defects OR 1.49 (95% CI 1.24-1.80), and orofacial clefts OR 1.90 (95% CI 1.27-2.86). Maternal obesity (BMI > or = 30) significantly increased the risk of hydrocephaly, anal atresia, hypospadias, cystic kidney, pes equinovarus, omphalocele, and diaphragmatic hernia. CONCLUSION: The risk for a morbidly obese pregnant woman to have an infant with a congenital birth defect is small, but for society the association is important in the light of the ongoing obesity epidemic.

Congenital malformations in infants born after in vitro fertilization in Sweden.

BACKGROUND: The risk for congenital malformations is increased in infants born after in vitro fertilization (IVF). Some specific malformations appear to be more affected than others. METHODS: The presence of congenital malformations in 15,570 infants born after IVF with an embryo transfer between April 1, 2001, and the end of 2006 were compared with all infants born in Sweden during 2001 to 2007 (n = 689,157). Risk estimates were made after adjusting for year of birth, maternal age, parity, smoking, and body mass index. The risks of specific malformations were compared with data from a previous study (1982 to March 31, 2001) of 16,280 infants born after IVF. Different IVF methods were compared to respect to malformation risk. RESULTS: Increased risks of a similar magnitude were found for most cardiovascular malformations and limb reduction defects for both study periods. For neural tube defects, cardiac septal defects, and esophageal atresia, there was still an increased risk, but it was lower during the second than during the first period. For small bowel atresia, anal atresia, and hypospadias, the risk increase observed during the first study period had disappeared during the second period. An increased risk was seen for some syndromes that have been associated with imprinting errors. No difference in malformation risk according to IVF method was apparent. CONCLUSIONS: A slightly increased risk for congenital malformations after IVF persists. A decreasing risk is seen for some specific malformations, either true or the result of multiple testing.

Early pregnancy azathioprine use and pregnancy outcomes.

BACKGROUND: Azathioprine (AZA) is used during pregnancy by women with inflammatory bowel disease (IBD), other autoimmune disorders, malignancy, and organ transplantation. Previous studies have demonstrated potential risks. METHODS: The Swedish Medical Birth Register was used to identify 476 women who reported the use of AZA in early pregnancy. The effect of AZA exposure on pregnancy outcomes was studied after adjustment for maternal characteristics that could act as confounders. RESULTS: The most common indication for AZA use was IBD. The rate of congenital malformations was 6.2% in the AZA group and 4.7% among all infants born (adjusted OR: 1.41, 95% CI: 0.98-2.04). An association between early pregnancy AZA exposure and ventricular/atrial septal defects was found (adjusted OR: 3.18, 95% CI: 1.45-6.04). Exposed infants were also more likely to be preterm, to weigh <2500 gm, and to be small for gestational age compared to all infants born. This effect remained for preterm birth and low birth weight when infants of women with IBD but without AZA exposure were used as a comparison group. A trend toward an increased risk of congenital malformations was found among infants of women with IBD using AZA compared to women with IBD not using AZA (adjusted OR: 1.42, 95% CI: 0.93-2.18). CONCLUSIONS: Infants exposed to AZA in early pregnancy may be at a moderately increased risk of congenital malformations, specifically ventricular/atrial septal defects. There is also an increased risk of growth restriction and preterm delivery. These associations may be confounded by the severity of maternal illness.

Maternal use of antihypertensive drugs in early pregnancy and delivery outcome, notably the presence of congenital heart defects in the infants.

PURPOSE: To investigate the association between maternal use of antihypertensives in early pregnancy and delivery outcome, notably infant congenital malformations. METHODS: A cohort study of 1,418 women who had used antihypertensive drugs in early pregnancy but had no diabetes diagnosis were identified from the Swedish Medical Birth Register. RESULTS: There was an excess risk for placental abruption, caesarean section, delivery induction, and post-delivery hemorrhage in women taking hypertensives. Infants were more often than expected born preterm, were small for gestational age, and had an excess of various neonatal symptoms. Cardiovascular defects occurred with an adjusted odds ratio of 2.59 (95% CI 1.92-3.51). The results were similar when the woman had used ACE inhibitors or other antihypertensives, notably beta blockers. Stillbirth rate was increased (risk ratio 1.87, 95% CI 1.02-3.02), again without any clear drug specificity. CONCLUSIONS: There seems to be little drug specificity in the association between maternal use of antihypertensives and an increased risk for infant cardiovascular defects.

Maternal morbidity and mortality in in-vitro fertilization.

Pregnancies following in-vitro fertilization (IVF) are known to be at increased risk of a number of pregnancy- and delivery-related complications when compared with non-IVF pregnancies. Most of these complications seem to be due to underlying fertility problems. Ovarian stimulation carries a marked risk for two serious conditions - ovarian torsion and ovarian hyperstimulation syndrome - both of which are relatively rare. Although some common pregnancy complications show an up to five times increased risk over non-IVF pregnancies, the absolute frequencies are still low for most of these conditions. However, an increased risk of placenta praevia might be to some extent due to the IVF procedure. No long-terms effects on cancer risk or mortality can be linked to the IVF procedure, although follow-up time is still relatively short.