Featured articles 2016

Fish oil supplementation during pregnancy and allergic respiratory disease in the adult offspring.

Maternal supplementation with long chain n-3 polyunsaturated fatty acids (PUFAs) may impact the immune system in the developing fetus through several anti-inflammatory pathways. This has been demonstrated in several randomized controlled trials (RCTs) that have shown reduced TH2 immune responses in infants whose mothers received fish oil in pregnancy. Whether this effect on early immune responses has long-lasting programming effects is however less clear. The aim of the study was to examine the long-term programming effect of maternal supplementation with 2.7 g long-chain n-3 PUFAs in pregnancy on the risk of asthma and allergic respiratory disease in the offspring.
We used data from a randomized controlled trial established in 1990 that enrolled 533 pregnant women in Denmark who were randomly assigned to receive fish oil during the third trimester of pregnancy, olive oil, or no oil in the ratio 2:1:1. The 266 women who were randomized to the fish oil group received four 1-g gelatin capsules with fish oil (32% EPA, 23% DHA, and 2 mg of tocopherol/mL) daily from gestational week 30 until delivery. The 136 women who were randomized to the placebo group were given 4 similar-looking 1-g capsules with olive oil (72% oleic acid [18:1n-9] and 12% linoleic acid [18:2n-6]) per day. Women allocated to the 2 oil capsule groups and the study coordinators were blinded to treatment allocation. A third group of 131 women were randomized to receive no oil capsules but were informed about the purpose of the trial and the potential beneficial effects of supplementation with long-chain n-3 PUFAs, thus acting as a passive-intervention positive control group.
The offspring were followed in a mandatory national prescription register, with complete follow-up for prescriptions related to the treatment of asthma and allergic rhinitis as primary outcomes. Furthermore, in 2008-2009, the offspring were invited to complete a questionnaire (74% participated) and attend a clinical examination (47% participated) at age 18 to 19 years.
We decided a priori to base the evaluation of the effects of fish oil on the comparison between the fish oil group and the olive oil group because these groups consisted of a double-blind administration of oil capsules. Therefore our main analyses included 396 mother-offspring pairs, 262 from the fish oil group and 134 from the olive oil group.
In the main analyses, intention-to-treat analyses revealed that the probability of having had asthma medication prescribed was significantly reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.54, 95% CI, 0.32-0.90; P=0.02). The probability of having had allergic rhinitis medication prescribed was also reduced in the fish oil group compared with the olive oil group (hazard ratio, 0.70, 95% CI, 0.47-1.05; P=0.09), but the difference was not statistically significant. Self-reported information collected at age 18 to 19 years supported these findings. No associations were detected with respect to lung function outcomes or allergic sensitization at 18 to 19 years of age.
When we analyzed data from the no oil group we found that offspring of mothers were remarkably similar to offspring in the fish oil group in terms of the occurrence of asthma and allergic rhinitis. We believe this intriguing finding might be the result of contamination bias and argue that a passive intervention informing women about the potential beneficial effects of fish oil might be as effective as actual fish oil supplementation, at least in a group of motivated pregnant women.
In conclusion, results from this RCT showed that offspring whose mothers had taken fish oil in the third trimester of pregnancy had a reduced probability of having had asthma medication prescribed and of receiving an asthma discharge diagnosis during childhood and early adulthood compared with children whose mothers had received olive oil. These results are compatible with the hypothesis that supplementation with long chain n-3 PUFAs late in pregnancy has prophylactic potential in preventing asthma in the offspring. More generally, our results support the hypothesis that the intrauterine environment is critical for the development of asthma not only in childhood but also in a long-term perspective.

Key words: Randomized controlled trial, allergies, asthma, fetal programming, long-chain n-3 polyunsaturated fatty acids

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Prenatal exposure to persistent organochlorine pollutants and female reproductive function in young adulthood

The biopersistent organochlorine pollutants dichlorodiphenyldichloroethylene (p,p´-DDE), hexachlorobenzene (HCB) and polychlorinated biphenyls (PCBs) can be detected in humans worldwide. The chemicals can cross the placenta and may interfere with endogenous hormonal homeostasis.  In this study, we investigated the possible effects on female reproduction following intrauterine exposure to selected biopersistent organochlorines.

We used data from a Danish pregnancy cohort with follow-up on 436 daughters at approximately 20 years of age. Information on age of menarche (n=335), menstrual cycle length (n=230) and serum concentrations of reproductive hormones (n=243) was obtained. Furthermore, number of ovarian antral follicles was counted by vaginal ultrasound (n=147). Of 244 daughters who attended a clinical examination, 170 used hormonal contraceptives and 74 were non-users. Concentrations of p,p´-DDE, HCB and six PCB congeners were analysed in maternal serum samples obtained in pregnancy week 30.

We found that age of menarche and menstrual cycle length were not statistically significant associated with prenatal organochlorine exposure. Among 43 non-users of hormonal contraceptives with information on antral follicle number, daughters exposed to the highest tertile of p,p´-DDE had 28% (95% confidence interval (95% CI): 5; 46%) lower follicle number compared to the low-level exposed reference group. Those exposed to medium and higher levels of HCB had 30% (95% CI: 5; 48%) and 28% (95% CI: 7; 44%) lower follicle number compared to the reference group. Furthermore, maternal serum HCB concentrations were inversely associated with free androgen index among non-users of hormonal contraceptives (n=73). These associations were not found in women who used hormonal contraceptives.

The results indicate adverse long-term effects on female reproduction following prenatal exposure to biopersistent organochlorines. These findings may have wide implications for public health as intrauterine exposure occurs worldwide.

Kristensen SL, Ramlau-Hansen CH, Ernst E, Olsen SF, Bonde JP, Vested A, Halldorsson TI, Rantakokko P, Kiviranta H, Toft G. Prenatal exposure to persistent organochlorine pollutants and female reproductive function in young adulthood.
Environ Int 2016, 92-93: 366-372. doi: 10.1016/j.envint.2016.04.024. PMID 27132162

Key words: Persistent organochlorines, female reproduction, ovary, fetal development, epidemiology.

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Last revised 25 August 2016