Anti-inflammatory and immunosuppressive drugs and reproduction

Rheumatic diseases in women of childbearing years may necessitate drug treatment during a pregnancy, to control maternal disease activity and to ensure a successful pregnancy outcome. This survey is based on a consensus workshop of international experts discussing effects of anti-inflammatory, immunosuppressive and biological drugs during pregnancy and lactation. In addition, effects of these drugs on male and female fertility and possible long-term effects on infants exposed to drugs antenatally are discussed where data were available. Recommendations for drug treatment during pregnancy and lactation are given.     

Evaluation of drug intake during pregnancy in the Hungarian Case-Control Surveillance of Congenital Anomalies

The data of the Hungarian Case-Control Surveillance of Congenital Anomalies, 1980-1987, were evaluated concerning drug intake during pregnancy in 10,698 index patients, 21,546 negative controls, and 828 positive controls (Down syndrome). Excluding pregnancy supplements, the proportion of no drug use was about 30% and the mean number of drugs used was 2.0 in the negative control group. These figures did not differ significantly from data of study and positive control groups. The analysis of most commonly used drugs indicated an extremely high proportion of hormonal support therapy. The teratogenic effect of several human teratogenic drugs was confirmed. However, their use is relatively rare and their attributable risk within the etiology of congenital anomalies is low, at about 0.3-1.0%. At present the teratogenic risk of drugs in humans is exaggerated and it has several unfortunate consequences: negligence in necessary drug use, unnecessary anxiety in pregnant women, and termination of planned pregnancies without any reasonable cause.     

DRUGS IN PREGNANCY—Their Effects on the Fetus and Newborn

In considering drug therapy for pregnant women, it must be borne in mind that almost all chemical compounds in use as therapeutic agents pass from the maternal to the fetal circulation through the placenta. These drugs can produce a wide range of harmful effects on the fetus and neonatal infant. The effects of some substances for which we have data reflecting a deleterious effect are listed.It is suggested that in the future more caution be exercised in using drugs during pregnancy and that in histories, both obstetrical and pediatric, any therapy given to the mother during gestation be recorded in detail.     

A Modified Murine Embryonic Stem Cell Test for Evaluating the Teratogenic Effects of Drugs on Early Embryogenesis

Mammalian fetal development is easily disrupted by exogenous agents, making it essential to test new drug candidates for embryotoxicity and teratogenicity. To standardize the testing of drugs that might be used to treat pregnant women, the U.S. Food and Drug Administration (FDA) formulated special grade categories, labeled A, B, C, D and X, that define the level of risk associated with the use of a specific drug during pregnancy. Drugs in categories (Cat.) D and X are those with embryotoxic and/or teratogenic effects on humans and animals. However, which stages of pregnancy are affected by these agents and their molecular mechanisms are unknown. We describe here an embryonic stem cell test (EST) that classifies FDA pregnancy Cat.D and Cat.X drugs into 4 classes based on their differing effects on primitive streak formation. We show that ~84% of Cat.D and Cat.X drugs target this period of embryogenesis. Our results demonstrate that our modified EST can identify how a drug affects early embryogenesis, when it acts, and its molecular mechanism. Our test may thus be a useful addition to the drug safety testing armamentarium.     

Fetal thermal dose considerations during the obstetrician's watch: Implications for the pediatrician's observations

There are a number of seemingly "usual" thermal episodes during pregnancy for which it is relatively easy to determine a rudimentary aspect of thermal dose; these episodes include fever, labor, labor plus epidural, and the normally-occurring 0.5 degrees C temperature elevation above maternal core temperature of the fetus during the entirety of the third trimester. Complications can involve, for instance, fever during the third trimester. We consider the thermal doses of five different but "usual" or "normal" hyperthermic episodes during human pregnancy and compare those doses with the thermal doses involved with both single and cohort exposures of pregnant guinea pigs throughout their gestational period. The end-point studied in the guinea pigs was microencephaly. In nine of the 10 comparisons (human fetal thermal dose vs. guinea pig fetal thermal dose) the human dose is substantially larger than that of the guinea pig thermal dose, which was substantially teratogenic. This situation is essentially the inverse of the type of information contained in the Physician's Desk Reference (PDR) on drugs, in which it is not unusual to discern that at high drug levels there may be teratogenic effects in laboratory animals, but such effects were not observed at "clinical" drug levels in animals or subsequent clinical trials. With hyperthermic events, however, it appears that the teratogenically-effective thermal dose levels associated with animal testing are quite low relative to those thermal doses associated with relatively "normal" obstetric observations during a pregnancy.     

LINE-1 DNA methylation is inversely correlated with cord plasma homocysteine in man: A preliminary study

Folic acid supplementation during pregnancy has known beneficial effects. It reduces risk of neural tube defects and low birth weight. Folate and other one-carbon intermediates might secure these clinical effects via DNA methylation. However, most data on the effects of folate on the epigenome is derived from animal or in vitro models. We examined the relationship between cord blood methylation and maternal folic acid intake, cord blood folate and homocysteine using data from 24 pregnant women. Genome-wide methylation was determined by the level of methylation of LINE-1 repeats using Pyrosequencing. We show that cord plasma homocysteine (p = 0.001, r = -0.688), but not serum folate or maternal folic acid intake, is inverse correlated with LINE-1 methylation. This remained significant after correction for potential confounders (p = 0.004). These data indicate that levels of folate-associated intermediates in cord blood during late pregnancy have significant consequences for the fetal epigenome.     

Embryo quality: the missing link between pregnancy sickness and pregnancy outcome

Pregnancy sickness is widespread yet its etiology is poorly understood. It is almost certainly endocrine in origin and most likely a product of placental hormones, with human chorionic gonadotropin being the strongest candidate. It has long been known that greater levels of nausea and vomiting during pregnancy are associated with a lower incidence of spontaneous abortion, yet the causal mechanisms remain unclear. One current popular explanation is that nausea and vomiting during pregnancy is fetoprotective, inducing aversions to foods, especially meat, dairy and seafoods, which may carry toxins, pathogens or mutagens. However, most spontaneous abortions arise from genetic or epigenetic defects that are present at or near conception. Moreover, measurements of human chorionic gonadotropin (hCG) at the time of implantation, particularly its hyperglycosylated isoform, accurately predict subsequent spontaneous abortion. Thus the developmental fate of most embryos is fixed before the onset of the symptoms of pregnancy sickness. An alternative explanation for the link between pregnancy sickness and spontaneous abortion is the embryo quality hypothesis: high quality embryos are both more likely to produce the biochemical antecedents of pregnancy sickness and avoid spontaneous abortion. Recent work has shown that the link between pregnancy sickness and spontaneous abortion grows stronger with maternal age, dramatically so in mothers 35 or older. This reflects the parallel rise in the incidence of autosomal aneuploidies with maternal age. The link between pregnancy sickness and spontaneous abortion exists not because nausea and vomiting during pregnancy is fetoprotective, but because nausea and vomiting is an index of a high quality embryo. Pregnancy sickness is not adaptive per se, but the result of an antagonistic pleiotropy over thyroid function, where embryos use hCG to modulate maternal thyroid hormone production during gestation. Embryos benefit from the thyroid hormone production that is key to neurodevelopment, but produce maternal nausea and vomiting as a by-product. Pregnancy sickness, however, may still serve to protect embryo quality but by a different mechanism that posited under the MEPH. Embryo quality is protected by calibrating the dietary intake of a micronutrient – iodine – critical to neuromotor development. For most humans over most of our evolutionary history, iodine has been in short supply, and iodine deficiency is still the most common source of cognitive impairment across the globe. Thus it is of interest that the food aversions most commonly associated with pregnancy sickness, to meat, dairy and seafoods, are also the chief dietary sources of iodine. There is a further intriguing property about iodine: both too little and too much during early pregnancy are damaging to embryo brain development. Given that pregnancy sickness is closely linked to iodine intake and thyroid function (hypothyroidism is associated with lower levels of nausea and vomiting, hyperthyroidism with more), an obvious interpretation emerges. The previously described link between diet and pregnancy sickness – pregnancy sickness is less likely when plants and particularly corn/maize are the sole food staples – arises not because plant food staples are safe, as previously suggested, but because these foods are iodine poor and may, in addition, be goitrogenic. Pregnancy sickness, which reduces the dietary intake of iodine, is clearly maladaptive under conditions of iodine deficiency and hypothyroidism. Conversely, higher levels of pregnancy sickness induced by hyperthyroidism may protect embryos from the inimical effects of excessive dietary iodine during early gestation by reducing the intake of iodine rich foods.     

Pregnancy in goats does not influence intake of novel or familiar foods with or without toxins

Some hypothesize that mammals decrease intake of foods that contain toxins during pregnancy to protect the fetus. We conducted a longitudinal study of feeding behavior to determine if pregnancy-related changes in food selection and intake occurred in goats. Goats eat modest amounts of toxic plants, some of which contain teratogenic or abortifacient compounds, but it is not known if pregnant and non-pregnant goats differ in food selection. The embryo is susceptible to toxins during all stages of pregnancy, but especially so during organogenesis early in pregnancy. Thus, we hypothesized that food selection and intake by pregnant versus non-pregnant goats may differ during various stages of pregnancy. We examined the following predictions that stem from this hypothesis: relative to non-pregnant goats, pregnant goats may alter selection of familiar foods that contain toxins, and of familiar and unfamiliar foods that do not contain toxins. We fed 14 plants with known or probable teratogenic properties during two pregnancies. We also offered beet pulp containing 0.5% LiCl during one pregnancy to test for increased sensitivity to toxins. In addition, we offered novel foods several times during one pregnancy to test for increased food neophobia or neophyllia. Finally, we measured intake of the basal ration by pregnant and non-pregnant goats daily throughout both pregnancies. Both pregnant and non-pregnant goats ate modest amounts of the plants with toxins and of beet pulp with LiCl. Both groups limited intake of novel foods and beet pulp with LiCl to the same degree. Finally, pregnant and non-pregnant goats did not differ in intake (per kg MBW) of the basal ration—dry matter, energy, or protein—in either pregnancy. Thus, the data do not support the notion that goats experienced pregnancy-related changes in food selection or intake.     

Diethylstilbestrol-induced perinatal lethality in the rat. I. Relationship to reduced maternal weight gain

An analysis was performed to determine the mechanism of depressed maternal weight gain and its effect on perinatal lethality following prenatal exposure to diethylstilbestrol (DES). Pregnant Sprague-Dawley rats were dosed orally by gavage with DES or corn oil (control) during various intervals of gestation. The maternal weight-gain patterns of control and treated dams and the number of live offspring were recorded. The amounts of feed and water intake and feces and urine output in pregnant dams were measured, and metabolic rate and thyroid hormone levels were also determined. DES (at 45 micrograms/kg/day) was embryo- and fetolethal during implantation and parturition, and there was an accompanying decline in maternal weight. Growth of adult males, nonpregnant females, and weanlings of both sexes was also depressed. During pregnancy, the net intake of feed and water was not altered by the drug, but maternal serum thyroxine and metabolic rate were significantly elevated. Reduced metabolic efficiency, then, is the likely mechanism for weight depression. Reduction of maternal weight gain during pregnancy by DES is a diagnostic indicator of fetolethality, but is probably not causally related to it.     

Associations between Drugs Administered during Pregnancy and Congenital Abnormalities of the Fetus

In a retrospective study to compare the drug consumption during pregnancy of mothers of infants with congenital abnormalities and of those without, over 97% of 1,369 mothers took prescribed drugs and 65% self-administered drugs. Significantly more mothers of infants with congenital abnormalities took aspirin, antacids, dextroamphetamine, phenobarbitone, sodium amytal, other barbiturates, cough medicines, iron, sulphonamides, and nicotinamide than mothers in the control group. However, most mothers taking analgesics, antacids, appetite suppressants, barbiturates, cough medicines, iron, sulphonamides, and vitamins produced normal infants. Any teratogenic effect of these drugs is therefore one of low potency. On the other hand, deficiencies such as those of ascorbic acid and folic acid may have a teratogenic effect. There is need for caution in presuming teratogenic effects on the basis of the associations shown here. During pregnancy, however, it would appear wise to avoid the administration of any drug which carries a suspicion of teratogenicity unless that drug is specifically indicated, and self-medication with common household remedies such as aspirin and antacids should be avoided. These recommendations would also apply to any woman of childbearing age in whom conception is likely.     

Congenital heart disease in the offspring and maternal habits and home exposures during pregnancy.

To test the effect of maternal habits and home exposures during early pregnancy on the occurrence of congenital heart disease in the offspring, 406 cases and 756 controls were studied. The cases included all cardiovascular malformations detected in Finland during 1982-1983, while the healthy controls were randomly selected from all babies born during the same period. Case and control mothers were interviewed after delivery using a structured and pre-tested questionnaire. Maternal overall drug consumption during the first trimester was as prevalent among case mothers (13.3%) as controls (14.6%). Neither was the risk of congenital heart disease associated with maternal use of contraceptive pills, salicylates, diazepam, or sweetening agents separately. Maternal exposures to disinfectants, dyes, lacquers, paints, pesticides, or glues at home were equally prevalent in case and control groups. Several earlier miscarriages was a predictor of an infant born with congenital heart disease (OR = 2.7, CI95 = 1.4-5.3). Maternal ultrasound examination was performed during the first 16 weeks of pregnancy more often among the case group (28.3%) than among the control group (22.0%). However, the association between ultrasound examination and the risk of congenital heart disease in the offspring was not statistically significant (OR = 1.2, 95% confidence interval 0.9-1.7) when adjusted for confounding factors such as the threat of miscarriage in logistic regression analysis. It is concluded that maternal ultrasound examination, intake of some common drugs, and exposure to a number of environmental factors at home during early pregnancy are probably not harmful for the developing fetal heart.     

Maternal and Fetal Well-being

Pregnancy outcomes can be improved by following modern recommendations for personal health maintenance. Adequate caloric intake, reflected by a weight gain of about 10 to 12.3 kg (22 to 27 lb) for women of average build, is associated with the lowest rate of perinatal mortality. Maternal dietary protein supplementation should generally be avoided because it may be associated with low-birth-weight pregnancies. Abstinence from social drugs offers the greatest positive opportunity to modify the health of a fetus. Serious perinatal infection can be prevented by preconception immunization (rubella), food hygiene (toxoplasmosis) and attention to the expression of virus in the mother (herpes simplex). Available data do not correlate exercise programs begun before pregnancy and continued during pregnancy with adverse fetal effects. Athletic capacity need not diminish postpartum. Most employment may safely continue until delivery. Routine recommendations for prolonged maternal disability leaves are not medically warranted.     

Effects of immobilization stress in utero on the course of pregnancy in the rat and on various parameters in the newborn animals

The effects of immobilization stress applied during pregnancy on the evolution of pregnant rats and on the fetus and newborn have been studied. Results show alterations in food intake during pregnancy as well as in the weight of some measured structures in 21 day old fetuses. There was similarly found a significant increase in the number of dead newborn. The effect of immobilization stress applied in utero upon the evolution of pregnancy, fetus and newborn, is discussed.     

Normal serum biochemical and hematological parameters in Macaca fascicularis.

The effects of age, sex, pregnancy, were analyzed and data from fasted and fed animals were compared in a population of cynomolgus macaques. No significant sex effects were observed for biochemical values and no changes were found in male hematological parameters in relation to age. Most values of females during pregnancy were within normal ranges. Comparison between fed and fasted animals showed that several biochemical parameters (e.g., ALT, glucose, CPK, LDH) and several hematological parameters (e.g., monocytes, eosinophils, basophils, hemoglobin, MCV, MCHC, and MCH) were affected by food intake.     

Drugs in pregnancy: the effects on mother and her progeny

Drug abuse during pregnancy is a growing problem in all developed countries all over the world. The drugs easily cross the placental barrier into the fetal body and are present also in the maternal milk. Therefore, it may affect the development of the child pre- as well as postnatally. The effects of prenatal drug exposure are long-lasting and persist until adulthood. The present review summarizes the clinical and experimental evidence showing how opioids and psychostimulants can affect maternal behavior of drug-abusing mother and the development of their offspring.     

Associations of Maternal Iron Intake and Hemoglobin in Pregnancy with Offspring Vascular Phenotypes and Adiposity at Age 10: Findings from the Avon Longitudinal Study of Parents and Children

Background

Iron deficiency is common during pregnancy. Experimental animal studies suggest that it increases cardiovascular risk in the offspring.

Objective

To examine the relationship between maternal pregnancy dietary and supplement iron intake and hemoglobin, with offspring’s arterial stiffness (measured by carotid-radial pulse wave velocity), endothelial function (measured by brachial artery flow mediated dilatation), blood pressure, and adiposity (measured by body mass index), test for mediation by cord ferritin, birth weight, gestational age, and child dietary iron intake, and for effect modification by maternal vitamin C intake and offspring sex.

Design

Prospective data from 2958 mothers and children pairs at 10 years of age enrolled in an English birth cohort, the Avon Longitudinal Study for Parents and Children (ALSPAC), was analysed.

Results

2639 (89.2%) mothers reported dietary iron intake in pregnancy below the UK reference nutrient intake of 14.8 mg/day. 1328 (44.9%) reported taking iron supplements, and 129 (4.4%) were anemic by 18 weeks gestation. No associations were observed apart from maternal iron intake from supplements with offspring systolic blood pressure (−0.8 mmHg, 99% CI −1.7 to 0, P = 0.01 in the sample with all relevant data observed, and −0.7 mmHg, 99% CI −1.3 to 0, P = 0.008 in the sample with missing data imputed).

Conclusion

There was no evidence of association between maternal pregnancy dietary iron intake, or maternal hemoglobin concentration (which is less likely to be biased by subjective reporting) with offspring outcomes. There was a modest inverse association between maternal iron supplement intake during pregnancy with offspring systolic blood pressure at 10 years.     

Effects of drugs on nutrition

Drugs can increase nutrient requirements through various mechanisms and if these requirements are not met by dietary modification or provision of nutrient supplements, deficiency disease will result. Commoner nutritional effects of drugs consist in the insidious development of hypovitaminoses; other serious nutritional consequences of drug intake include growth impairment and, in the case of vitamin antagonists, poisoning through interference with metabolic processes dependent on the activity of vitamins or coenzymes. Interactions may exist between pharmacologic agents and nutrients with respect to their absorption, transport, metabolism and excretion. Single drugs can cause nutrient depletion by more than one mechanism and multiple drug regimens can deplete nutrient stores by a synergistic effect. Risks of drug-induced malnutrition with drugs increase with dose and duration of intake, marginal diets and co-existence of disease which increases requirements for the same nutrients that are affected by the drug.     

Prenatal Metformin Exposure in Mice Programs the Metabolic Phenotype of the Offspring during a High Fat Diet at Adulthood

Aims

The antidiabetic drug metformin is currently used prior and during pregnancy for polycystic ovary syndrome, as well as during gestational diabetes mellitus. We investigated the effects of prenatal metformin exposure on the metabolic phenotype of the offspring during adulthood in mice.

Methods

Metformin (300 mg/kg) or vehicle was administered orally to dams on regular diet from the embryonic day E0.5 to E17.5. Gene expression profiles in liver and brain were analysed from 4-day old offspring by microarray. Body weight development and several metabolic parameters of offspring were monitored both during regular diet (RD-phase) and high fat diet (HFD-phase). At the end of the study, two doses of metformin or vehicle were given acutely to mice at the age of 20 weeks, and Insig-1 and GLUT4 mRNA expressions in liver and fat tissue were analysed using qRT-PCR.

Results

Metformin exposed fetuses were lighter at E18.5. There was no effect of metformin on the maternal body weight development or food intake. Metformin exposed offspring gained more body weight and mesenteric fat during the HFD-phase. The male offspring also had impaired glucose tolerance and elevated fasting glucose during the HFD-phase. Moreover, the expression of GLUT4 mRNA was down-regulated in epididymal fat in male offspring prenatally exposed to metformin. Based on the microarray and subsequent qRT-PCR analyses, the expression of Insig-1 was changed in the liver of neonatal mice exposed to metformin prenatally. Furthermore, metformin up-regulated the expression of Insig-1 later in development. Gene set enrichment analysis based on preliminary microarray data identified several differentially enriched pathways both in control and metformin exposed mice.

Conclusions

The present study shows that prenatal metformin exposure causes long-term programming effects on the metabolic phenotype during high fat diet in mice. This should be taken into consideration when using metformin as a therapeutic agent during pregnancy.     

Different physiological roles of serum leptin in the regulation of energy intake and thermogenesis between pregnancy and lactation in primiparous Brandt's voles (Lasiopodomys brandtii)

Reproduction, especially lactation, is associated with major metabolic adaptive changes. In this study, we investigated the metabolic changes and the roles of leptin during different periods of reproduction in primiparous Brandt's voles (Lasiopodomys brandtii). Energy intake, thermogenic capacity and serum leptin levels were examined in non-reproductive, mid pregnant, late pregnant, early lactating and peak lactating voles. Voles increased body mass by nearly 70% during late pregnancy compared to the non-breeding controls. The increase in body mass was mainly due to the increase in body fat mass which increased by 56%, and the growth of the reproductive tissues and digestive organs. Lactating voles decreased body fat by nearly 27% at peak lactation compared to the controls, and 53% compared to late pregnant voles. At the same time they increased food intake significantly. Uncoupling protein 1 (UCP1) content in brown adipose tissue (BAT) decreased significantly at peak lactation. Serum leptin increased significantly in the mid pregnancy, at a time when there was no increase in body fat, and remained at this high level in late pregnancy. Leptin levels decreased after parturition and reached a nadir at peak lactation. Serum leptin was negatively correlated with energy intake during lactation, but not during pregnancy. These data suggest that Brandt's voles adjust energy intake, thermogenic capacity and body reserves to match the high energy demands for reproduction. Hyperleptinemia, without decreased energy intake suggests a state of leptin resistance during pregnancy, and hypoleptinemia during lactation might act as a signal to stimulate energy intake.