Lorentz M. Irgens

The Medical Birth Registry of Norway. Epidemiological research and surveillance throughout 30 years

Established in 1967, the Medical Birth Registry of Norway (MBRN) was organized in the wake of the thalidomide catastrophe that caused more than 10 000 cases of limb reduction deformities throughout the world (1). The particular aim was epidemiological surveillance of birth defects and other perinatal health problems in order to detect, as soon as possible, any future increase in rates. The same year, programs with similar objectives were organized in South America and Atlanta, USA. The subsequent years saw the establishment of such programs in many other countries. During the last 20 years, about thirty of these programs have been collaborating in the International Clearinghouse for Birth Defects Monitoring Systems (2). In Europe, a similar number of programs are organized in the EUsponsored network EUROCAT. Most of the other programs represent birth defects registries, some of them organized as permanent case control studies. MBRN, however, is based on compulsory notification of every birth or late abortion in the country from 16 weeks of gestation onwards. Similar medical birth registries were later established in all the Nordic countries, collaborating in the Nordic Association of Medical Birth Registries.

Fetal and maternal contributions to risk of pre-eclampsia: population based study

Abstract Objective: To use familial patterns of recurrence of pre-eclampsia to investigate whether paternal genes expressed in the fetus contribute to the mothers risk of pre-eclampsia and whether mothers susceptibility to pre-eclampsia is related to maternal inheritance by mitochondrial DNA. Design: Linked data on pregnancies of different women who had children with the same father, and subsequently linked data on pregnancies of half sisters who either had same mother and different fathers or had same father and different mothers. Setting: Population based data from the Medical Birth Registry of Norway covering all births since 1967 (about 1.7 million) and the Norwegian Central Population Register. Main outcome measures: Relative risk of pre-eclampsia after a previous pre-eclamptic pregnancy in the family. Relative risks approximated by odds ratios. Results: If a woman becomes pregnant by a man who has already fathered a pre-eclamptic pregnancy in a different woman her risk of developing pre-eclampsia is 1.8 (95% confidence interval 1.2 to 2.6). If the woman has a half sister who had pre-eclampsia and with whom she shares the same mother but different fathers the risk of pre-eclampsia is 1.6 (0.9 to2.6). If the two sisters have the same father but different mothers the risk is 1.8 (1.01 to 2.9). Conclusions: Both the mother and the fetus contribute to the risk of pre-eclampsia, the contribution of the fetus being affected by paternal genes. Mitochondrial genes, which are transmitted by mothers, do not seem to contribute to the risk. Key messages Paternal genes in the fetus may contribute substantially to a pregnant womans risk of pre-eclampsia The role of the fetus may be as important as that of the mother Purely maternal inheritance (specifically by mitochondrial DNA) is probably not involved in pre-eclampsia Search for specific genes that predispose for pre-eclampsia should include the fetus as well as the mother

Early Death, Morbidity, and Need of Treatment Among Extremely Premature Infants

Objective. To determine outcomes, in terms of perinatal and early death, need for treatment, and morbidity at the time of discharge home, among extremely preterm infants. Design. A prospective observational study of all infants with a gestational age (GA) of 22 to 27 completed weeks or a birth weight of 500 to 999 g who were born in Norway in 1999 and 2000. Results. Of 636 births, 174 infants (27%) were stillborn or died in the delivery room, 86 (14%) died in the NICU, and 376 (59%) were discharged from the hospital. The risk of being registered as stillborn or not being resuscitated increased with decreasing GA below 25 weeks. The survival rates for all births and for infants admitted to a NICU were, respectively, 0% for <23 weeks, 16% and 39% for 23 weeks, 44% and 60% for 24 weeks, 66% and 80% for 25 weeks, 72% and 84% for 26 weeks, 82% and 93% for 27 weeks, and 69% and 90% for >27 weeks. For the survivors, days of mechanical ventilation decreased from a median of 37 days to 3 days and the proportion in need of oxygen at 36 weeks’ postconceptional age decreased from 67% to 26% at 23 and 27 weeks’ GA, respectively. At 40 weeks’ postconceptional age, the respective figures were 11% and 6%. The proportion with retinopathy of prematurity (ROP) requiring treatment decreased from 33% for GA of 23 weeks to 0% for >25 weeks. Periventricular hemorrhage of more than grade 2 occurred for 6% of the survivors and significant periventricular leukomalacia occurred for 5%, with no significant association with GA. The proportion of survivors without severe neurosensory or pulmonary morbidity increased from 44% for 23 weeks’ to 86% for 27 weeks’ GA. Apart from ROP, the morbidity rate was not associated with GA. Conclusions. The survival rate was high and the morbidity rate at discharge home was low in the present study, compared with previous population-based studies. With the exception of ROP, the morbidity rates among the survivors were not higher at the lowest GAs, possibly because withholding treatment was considered more acceptable for the most immature infants. The need for intensive care increased markedly for survivors with the lowest GAs.

Recurrence of pre-eclampsia across generations: exploring fetal and maternal genetic components in a population based cohort

Abstract Objectives To assess the impact on risk of pre-eclampsia of genes that work through the mother, and genes of paternal origin that work through the fetus. Design Population based cohort study. Setting Registry data from Norway. Participants Linked generational data from the medical birth registry of Norway (1967-2003): 438 597 mother-offspring units and 286 945 father-offspring units. Main outcome measures Pre-eclampsia in the second generation. Results The daughters of women who had pre-eclampsia during pregnancy had more than twice the risk of pre-eclampsia themselves (odds ratio 2.2, 95% confidence interval 2.0 to 2.4) compared with other women. Men born after a pregnancy complicated by pre-eclampsia had a moderately increased risk of fathering a pre-eclamptic pregnancy (1.5, 1.3 to 1.7). Sisters of affected men or women, who were themselves born after pregnancies not complicated by pre-eclampsia, also had an increased risk (2.0, 1.7 to 2.3). Women and men born after pre-eclamptic pregnancies were more likely to trigger severe pre-eclampsia in their own (or their partners) pregnancy (3.0, 2.4 to 3.7, for mothers and 1.9, 1.4 to 2.5, for fathers). Conclusions Maternal genes and fetal genes from either the mother or father may trigger pre-eclampsia. The maternal association is stronger than the fetal association. The familial association predicts more severe pre-eclampsia.

International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working?

Abstract Objectives To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects. Design Retrospective cohort study of births monitored by birth defect registries. Setting 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review. Main outcome measures Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable). Results The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects. Conclusions Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.

The spectrum of congenital anomalies of the VATER association: An international study

The spectrum of the VATER association has been debated ever since its description more than two decades ago. To assess the spectrum of congenital anomalies associated with VATER while minimizing the distortions due to small samples and referral patterns typical of clinical series, we studied infants with VATER association reported to the combined registry of infants with multiple congenital anomalies from 17 birth defects registries worldwide that are part of the International Clearinghouse for Birth Defects Monitoring Systems (ICB-DMS). Among approximately 10 million infants born from 1983 through 1991, the ICB-DMS registered 2,295 infants with 3 or more of 25 unrelated major congenital anomalies of unknown cause. Of these infants, 286 had the VATER association, defined as at least three of the five VATER anomalies (vertebral defects, anal atresia, esophageal atresia, renal defects, and radial-ray limb deficiency), when we expected 219 (P<0.001). Of these 286 infants, 51 had at least four VATER anomalies, and 8 had all five anomalies. We found that preaxial but not other limb anomalies were significantly associated with any combination of the four nonlimb VATER anomalies (P<0.001). Of the 286 infants with VATER association, 214 (74.8%) had additional defects. Genital defects, cardiovascular anomalies, and small intestinal atresias were positively associated with VATER association (P<0.001). Infants with VATER association that included both renal anomalies and anorectal atresia were significantly more likely to have genital defects. Finally, a subset of infants with VATER association also had defects described in other associations, including diaphragmatic defects, oral clefts, bladder exstrophy, omphalocele, and neural tube defects. These results offer evidence for the specificity of the VATER association, suggest the existence of distinct subsets within the association, and raise the question of a common pathway for patterns of VATER and other types of defects in at least a subset of infants with multiple congenital anomalies.

Low Birth Weight Increases Risk for End-Stage Renal Disease

Case-control studies have shown an association between low birth weight and risk for renal failure. The Medical Birth Registry of Norway, which comprises data on all births in Norway since 1967, and the Norwegian Renal Registry, which comprises data on all patients who have developed ESRD in Norway since 1980, were used to examine whether birth-related variables were associated with risk for ESRD. Of the 2,183,317 children born between 1967 and 2004, 526 were found in the ESRD registry. Compared with birth weight in the 10th to 90th percentiles, births <10th percentile had a relative risk (RR) for ESRD of 1.7 (95% confidence interval 1.4 to 2.2; P < 0.001). Births with a weight for gestational age <10th percentile had an RR of 1.5 (95% confidence interval 1.2 to 1.9; P = 0.002). These associations were virtually identical after adjustment for birth-related confounders such as congenital malformations, multiple delivery, maternal age at birth, and maternal preeclampsia. Low birth weight was more strongly associated with development of ESRD during the first 14 years of life than after age 15. Low birth weight and low birth weight for gestational age were similarly associated with multiple causes of ESRD. In conclusion, in this cohort study with a maximum follow-up of 38 years, low birth weight and intrauterine growth restriction were associated with increased risk for ESRD.

Late-Onset Septicemia in a Norwegian National Cohort of Extremely Premature Infants Receiving Very Early Full Human Milk Feeding

Objectives. To investigate the occurrence of and risk factors for late-onset septicemia (LOS) in a national cohort of extremely premature infants who received very early full human milk feeding. Methods. A prospective study of all infants born in Norway in 1999 and 2000 with gestational age of <28 weeks or birth weight of <1000 g was performed. Extensive clinical information, including data on feeding practices and episodes of septicemia, was collected on predefined forms. LOS was defined as growth of bacteria or fungi in blood cultures in conjunction with clinical symptoms consistent with systemic infection occurring after day 6 of life. Cox regression models, including models allowing for time-dependent covariates, were applied in the analysis of LOS. Results. Of 464 eligible infants, 462 (99.6%) were enrolled and 405 (87.7%) survived until day 7. LOS was diagnosed for 80 (19.7%). The predominant pathogens were coagulase-negative staphylococci, followed by Candida spp. Case fatality rates associated with septicemia were 10% in general and 43% for Candida spp septicemia. Necrotizing enterocolitis or bowel perforation was diagnosed for 19 infants (4%). Enteral feeding with human milk was initiated within the third day for 98% of patients, and 92% were receiving full enteral feeding (FEF) with human milk within the third week. Both high Clinical Risk Index for Babies scores and an umbilical venous catheter in situ at 7 days of age significantly predicted LOS. However, the overall most influential risk factor for LOS was the number of days without establishment of FEF with human milk, with an adjusted relative risk of 3.7 (2.0–6.9) for LOS if FEF was not established within the second week of life. Conclusions. The incidence and case fatality rate of septicemia for this cohort of extremely preterm infants were lower than values in comparable studies. The main difference, compared with other studies, was the feeding practice, and the data suggest that very early FEF with human milk significantly reduces the risk of LOS among extremely premature infants.

Birth defects among offspring of Norwegian farmers, 1967-1991.

We investigated birth defects (N = 4,565) reported to the Medical Birth Registry of Norway among 192,417 births between 1967 and 1991 to parents identified as farmers in five agricultural and horticultural censuses between 1969 and 1989. The prevalences at birth of all and specific birth defects deviated little from those among 61,351 births to non‐farmers in agricultural municipalities. We classified exposure indicators on the basis of information provided at the agricultural censuses. The main hypotheses were that parental exposure to pesticides was associated with defects of the central nervous system, orofacial clefts, some male genital defects, and limb reduction defects. We found moderate increases in risk for spina bifida and hydrocephaly, the associations being strongest for exposure to pesticides in orchards or greenhouses [spina bifida: 5 exposed cases, odds ratio (OR) = 2.76, 95% confidence interval (CI) = 1.07–7.13; hydrocephaly: 5 exposed cases, OR = 3.49, 95% CI = 1.34–9.09]. Exposure to pesticides, in particular in grain farming, was also associated with limb reduction defects (OR = 2.50; 95% CI = 1.06–5.90). We also saw an association with pesticides for cryptorchism and hypospadias. We found less striking associations for other specific defects and pesticide indicators, animal farming, and fertilizer regimens.

Pregnancy outcome in women before and after cervical conisation : population based cohort study

Objectives To examine the consequences of cervical conisation in terms of adverse outcome in subsequent pregnancies. Design Population based cohort study. Data sources Data on cervical conisation derived from the Cancer Registry of Norway and on pregnancy outcome from the Medical Birth Registry of Norway, 1967-2003. 15 108 births occurred in women who had previously undergone cervical conisation and 57 136 who subsequently underwent cervical conisation. In the same period there were 2 164 006 births to women who had not undergone relevant treatment (control). Results The proportion of preterm delivery was 17.2% in women who gave birth after cervical conisation versus 6.7% in women who gave birth before cervical conisation and 6.2% in women who had not undergone cervical conisation. The relative risk of a late abortion (<24 weeks’ gestation) was 4.0 (95% confidence interval 3.3 to 4.8) in women who gave birth after cervical conisation compared with no cervical conisation. The relative risk of delivery was 4.4 (3.8 to 5.0) at 24-27 weeks, 3.4 (3.1 to 3.7) at 28-32 weeks, and 2.5 (2.4 to 2.6) at 33-36 weeks. The relative risk of preterm delivery declined during the study period and especially of delivery before 28 weeks’ gestation. Conclusion Cervical conisation influences outcome in subsequent pregnancies in terms of an increased risk of preterm delivery, especially in the early gestational age groups in which the clinical significance is highest. A careful clinical approach should be taken in the selection of women for cervical conisation and in the clinical care of pregnancies after a cervical conisation.