Gestational Adverse Outcomes Research Articles

Valproate in Pregnancy: Recent Research and Regulatory Responses.

Valproate and formulations thereof are approved for the management of seizure disorders, bipolar disorder, and migraine. Valproate is also used for many off-label indications. Unfortunately, data from observational studies indicate that valproate is perhaps the most teratogenic drug in the neuropsychiatric pharmacopeia. It is significantly more teratogenic than many other antiepileptic drugs (AEDs). In observational studies, gestational exposure to valproate is also associated with higher risks of cognitive, language, and psychomotor delay during early childhood and possibly with an increased risk of autism, as well. Although untreated epilepsy is itself associated with many adverse gestational and neonatal outcomes, confounding by indication is an unlikely explanation for the adverse outcomes observed with valproate. This is because of the range of the adverse outcomes, the magnitude of the risks, the dose-dependent nature of the risks, the consistency of findings across studies, the specificity of outcomes for valproate exposure, and the greater risks with valproate relative to other AEDs. Despite the existence of a large body of literature that documents these risks, valproate continues to be prescribed to a substantial proportion of women of childbearing potential. As a result, many regulatory bodies across the world have discouraged and even banned the use of valproate during pregnancy and in women of childbearing potential unless no satisfactory alternatives exist or unless a pregnancy prevention program is implemented.

Adverse Gestational Outcomes Associated With Attention-Deficit/Hyperactivity Disorder Medication Exposure During Pregnancy.

The use of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy has increased in recent years. An earlier article in this column examined whether psychostimulant medications, used to treated ADHD and related disorders, increase the risk of major congenital malformations in pregnancies with first trimester exposure to these drugs. This article examines whether amphetamines, methylphenidate, and atomoxetine exposure during early and late pregnancy are associated with other adverse gestational outcomes. One large and 4 small studies provided data relevant to the inquiry. In unadjusted analyses, amphetamines and methylphenidate were associated with an increased risk of most of the adverse outcomes under study. However, in analyses adjusted for potential confounds, amphetamine exposure during early pregnancy was associated only with an increased risk of preeclampsia; otherwise, amphetamine and methylphenidate exposure was not associated with the risk of preeclampsia, placental abruption, small for gestational age, or preterm birth. Late gestational exposure to psychostimulants was associated with an increased risk of preterm birth but not with the other adverse outcomes. In sensitivity analyses, such as one that examined exposure during weeks 8-18 of gestation, amphetamines were associated with an increased risk of preeclampsia, placental abruption, and preterm birth, and methylphenidate, with an increased risk of preeclampsia. For reasons explained in the text, it may be prudent to err on the side of caution, but in the worst case scenario, the number needed to harm is about 63 for amphetamines exposure and preeclampsia and larger (eg, > 500, indicating less risk) for other adverse outcomes. Atomoxetine was not associated with any adverse gestational outcome, but it is not clear whether this is a true finding or a result of underpowered analyses. In conclusion, women need to weigh the benefits of the ADHD medication that they are using against potential gestational risks when deciding whether or not to continue treatment during pregnancy.

Effect of intra-pregnancy nonsurgical periodontal therapy on inflammatory biomarkers and adverse pregnancy outcomes: a systematic review with meta-analysis

BackgroundThe aim of this systematic review with meta-analysis was to analyze the effects of intra-pregnancy nonsurgical periodontal therapy on periodontal inflammatory biomarkers and adverse pregnancy outcomes.MethodsOn June 5, 2017, we searched PubMed, Cochrane, SCOPUS, Web of Science, LILACS, ProQuest, Open Grey, and Google Scholar databases. Randomized clinical trials in which pregnant women with chronic periodontitis underwent nonsurgical periodontal therapy, compared with an untreated group, tested for inflammatory biomarkers, and followed till delivery were included. Primary outcomes were preterm birth, low birth weight, and preeclampsia. Meta-analysis was performed with 5.3.5 version of Review Manager software.ResultsWe found 565 references in the databases, 326 after duplicates removal, 28 met criteria for full text reading, and 4 met eligibility criteria for quantitative and qualitative synthesis. Intra-pregnancy nonsurgical periodontal therapy improved periodontal clinical parameters (periodontal pocket depth, clinical attachment level, and bleeding on probing) and reduced biomarker level from gingival crevicular fluid (GCF), and some from blood serum; however, it did not influence biomarker level from umbilical cord blood. Meta-analysis showed tendency for reduction of the risk of preterm birth before 37 weeks for treated group (risk ratio (RR) = 0.54, 95% CI 0.38–0.77; p = 0.0007; inconsistency indexes (I2) 32%) but did not show any difference for low birth weight occurrence (RR = 0.78, 95%CI 0.50–1.21; p = 0.27; I2 41%). No included study considered preeclampsia as a gestational outcome.ConclusionsThese results demonstrated that the intra-pregnancy nonsurgical periodontal therapy decreased periodontal inflammatory biomarker levels from gingival crevicular fluid and some from serum blood, with no influence on inflammatory biomarker level from cord blood, and it did not consistently reduce adverse gestational adverse outcome occurrence.Systematic review registrationPROSPERO CRD42015027750

“Simulated gastric hydrolysis and developmental toxicity of dioctyltin bis(2-Ethylhexylthioglycolate) [DOTE] in rabbits and mice”

Based on previous studies, dioctyltin dichloride [DOTC] was a putative toxophore for dioctyltin thioesters. Our results, generated with the use of 119Sn-NMR spectroscopy demonstrated that dioctyltin bis(2-ethylhexyl thioglycolate) [DOTE] hydrolyzed to form dioctyltin chloro-(2-ethylhexyl thioglycolate) [DOTCE] under simulated gastric conditions, but no DOTC was formed. DOTE was administered orally at 4, 20, and 80 mg/kg/day [GD6-GD28; rabbits] or at 15, 30, and 60 mg/kg/day [GD5-GD17; mice]. There were no maternal deaths, treatment-related statistically significant reductions in maternal body weight or weight gain, or adverse gestational outcomes in either species. Maternal thymus weight was significantly reduced in mice at 30 and 60 mg/kg. There were no effects on fetal growth, no dose-dependent pattern of external, visceral or skeletal malformations and no increase in anatomical variations in either species. We conclude that DOTE likely forms DOTCE, not DOTC, in the stomach and DOTE was not teratogenic or fetotoxic in rabbits or mice. The rabbit maternal NOAEL was 80 mg/kg/day. The rabbit developmental NOAEL was 80 mg/kg/day. The mouse maternal LOAEL was 30 mg/kg/day based on reduced thymus weight and a dose-dependent effect on maternal weight at 60 mg/kg. The mouse developmental NOAEL was 60 mg/kg bw/day, the high dose.

Use of acetaminophen (paracetamol) during pregnancy and the risk of attention-deficit/hyperactivity disorder in the offspring.

Prenatal exposure to acetaminophen may result in compromised neurodevelopment through inflammatory and immunologic mechanisms, through predisposition to oxidative stress, and through endocrine, endogenous cannabinoid, and other mechanisms. Several small and large prospective studies have found an association between gestational acetaminophen exposure and attention-deficit/hyperactivity disorder (ADHD)-like behaviors, use of ADHD medication, and ADHD diagnoses in offspring during childhood; the only negative study was a small investigation that examined only one aspect of attention as an outcome. Creditably, most of the studies adjusted analyses for many (but not all) confounds associated with ADHD risk. Importantly, one pivotal study also adjusted for pain, infection, inflammation, and fever to reduce confounding by indication; this study found a dose-dependent risk. In the light of the finding of a single study that infection and fever during pregnancy by themselves do not raise the ADHD risk, it appears possible that the use of acetaminophen during pregnancy is itself responsible for the increased risk of ADHD. This suggests that acetaminophen may not be as safe in pregnancy as is widely believed. However, since fever during pregnancy may itself be associated with adverse gestational outcomes, given the present level of uncertainty about the ADHD risk with acetaminophen, it is suggested that, until more data are available, the use of acetaminophen in pregnancy should not be denied in situations in which the need for the drug is clear.

Severe but Not Moderate Vitamin B12 Deficiency Impairs Lipid Profile, Induces Adiposity, and Leads to Adverse Gestational Outcome in Female C57BL/6 Mice.

Vitamin B12 deficiency is widely prevalent in women of childbearing age, especially in developing countries. In the present study, through dietary restriction, we have established mouse models of severe and moderate vitamin B12 deficiencies to elucidate the impact on body composition, biochemical parameters, and reproductive performance. Female weanling C57BL/6 mice were fed for 4 weeks: (a) control AIN-76A diet, (b) vitamin B12-restricted AIN-76A diet with pectin as dietary fiber (severe deficiency group, as pectin inhibits vitamin B12 absorption), or (c) vitamin B12-restricted AIN-76A diet with cellulose as dietary fiber (moderate deficiency group as cellulose does not interfere with vitamin B12 absorption). After confirming deficiency, the mice were mated with male colony mice and maintained on their respective diets throughout pregnancy, lactation, and thereafter till 12 weeks. Severe vitamin B12 deficiency increased body fat% significantly, induced adiposity and altered lipid profile. Pregnant dams of both the deficient groups developed anemia. Severe vitamin B12 deficiency decreased the percentage of conception and litter size, pups were small-for-gestational-age and had significantly lower body weight at birth as well as weaning. Most of the offspring born to severely deficient dams died within 24 h of birth. Stress markers and adipocytokines were elevated in severe deficiency with concomitant decrease in antioxidant defense. The results show that severe but not moderate vitamin B12 restriction had profound impact on the physiology of C57BL/6 mice. Oxidative and corticosteroid stress, inflammation and poor antioxidant defense seem to be the probable underlying mechanisms mediating the deleterious effects.

Controversies in Screening and Diagnosis of Gestational Diabetes: Cuba's Position.

Gestational diabetes is the most common endocrine disorder affecting pregnant women and its prevalence is on the rise. Prevalence in Cuba is about 5.8%, and global prevalence ranges from 2% to 18% depending on the criteria applied. Gestational diabetes can lead to adverse gestational outcomes, such as fetal death, preterm delivery, dystocia, perinatal asphyxia and neonatal complications. Prompt, accurate diagnosis allowing early treatment can benefit both mother and child. The disease is asymptomatic, so clinical laboratory testing plays a key role in its screening and diagnosis. Cuba's approach to diabetes screening and diagnosis differs from some international practices. All pregnant women in Cuba are screened with a fasting plasma glucose test and diagnosed using modified WHO criteria. Some international recommendations are to skip the screening step and instead follow the diagnostic criteria of the Hyperglycemia and Adverse Pregnancy Outcomes study. In Cuba, gestational outcomes for women with diabetes (including gestational diabetes) are satisfactory (preeclampsia 5%; preterm delivery 12%; neonatal macrosomia 7.5%; congenital abnormalities 4.3% and perinatal deaths 4.8%). These data do not indicate a need to change established screening and diagnostic criteria. KEYWORDS Gestational diabetes, screening, diagnosis, early detection, early diagnosis, Cuba.

The safety of duloxetine during pregnancy and lactation.

Depression is common in women, especially during pregnancy and the postpartum period. Untreated depression is associated with many adverse gestational outcomes. It is therefore important to know about the safety of different antidepressant drugs during pregnancy and lactation so that informed decisions can be made regarding treatment. This article summarizes published literature on the subject with regard to duloxetine, an antidepressant with serotonin-norepinephrine reuptake inhibition properties. In general, it appears that the use of duloxetine during pregnancy is associated with an increase in the risk of spontaneous abortion, but no increase in other adverse outcomes, such as major fetal malformations. Late-pregnancy exposure to duloxetine may be associated with poor neonatal adaptation syndrome, but the magnitude of this risk is not known. Infant exposure to duloxetine in breast milk is less than 1% of the maternal weight-adjusted dose, suggesting that duloxetine can be safely administered to a woman who is breastfeeding her infant. In general, the very limited data available on the subject do not uncover a signal that the use of duloxetine during pregnancy or lactation increases the risk of adverse outcomes.

PO-0078 The Relationship Between Maternal And Neonatal 25(oh) Vitamin D Status

Background In this study we aimed to investigate the relationship between maternal and neonatal 25(OH)D levels. Methods The subjects were 58 mothers and their newborns who were born between February 2012 and April 2012. Blood specimens were obtained within 72 h of birth and from mothers. Serum 25(OH)D concentrations were measured. Vitamin D deficiency was defined as serum concentrations ≤20 ng/mL. Results The mean gestational age and birth weight of preterm infants were 33.06 ± 2.2 weeks and 2125.4 ± 546 g and for term infants were 38.84 ± 1 weeks and 3470.3 ± 451 g, respectively. Sociodemographic characteristics of mothers were not significantly different between groups. Twelve percent of infants born before 32 completed weeks, 16% infants born between 32–36 weeks and 28% of term infants had vitamin D deficiency. Vitamin D deficiency was found in 27% mothers of preterm infants and 42% mothers of term infants. Conclusion Vitamin D receptors plays an important role in calcium absorption and bone metabolism. In the literature there are reports that vitamin D deficiency during pregnancy had adverse gestational outcomes including risk of pre-eclampsia, gestational diabetes. The mean vitamin D levels were normal in infants whereas their mothers had low levels of vitamin D. When we consider that all mothers in the study received vitamin D supplements, we should give appropriate vitamin D prophylaxis during pregnancy. Also we should give adequate vitamin D supplementation to the infants without any delay.

Type 2 deiodinase Thr92Ala polymorphism is associated with disrupted placental activity but not with dysglycemia or adverse gestational outcomes: a genetic association study

To study whether the D2 Thr92Ala polymorphism-a genetic marker that is associated with reduced thyroid type 2 deiodinase (D2) activity, increased insulin resistance, and risk for type 2 diabetes-is associated with disrupted placental D2 activity and with glycemic control and gestational outcomes. Cross-sectional study. Tertiary hospital in Brazil. Consecutive singleton-pregnancy patients, 18-45 years old. Clinical examination and genotyping of the D2 Thr92Ala polymorphism, with placental samples collected and assayed for D2 mRNA and activity. Glucose homeostasis and gestational outcomes. A total of 294 patients were included in the study. The clinical and laboratory characteristics were similar among the D2 genotypes. No differences were observed in D2 placental mRNA levels, but D2 activity was decreased in patients with the Ala92Ala genotype (0.35 ± 0.15 vs. 1.96 ± 1.02 fmol/mg/min.). Newborn serum thyroid-stimulating hormone levels (TSHneo) did not differ according to maternal D2 Thr92Ala genotype. Also, maternal glucose control, insulin resistance evaluated by the homeostasis model assessment (HOMA-IR), and gestational outcomes did not differ across D2 genotypes. The D2 Ala92Ala genotype is associated with reduced placental D2 activity but is not associated with dysglycemia, increased insulin resistance, or worse gestational outcomes.

Maternal and neonatal outcomes in pregnancies following colorectal cancer

The risks of adverse obstetric outcomes among young women survivors of colorectal cancer (CRC) are uncertain. This Western Australian, whole-jurisdictional linked-data, retrospective cohort study compared maternal and neonatal outcomes of first postcancer pregnancies among women CRC survivors against randomly selected pregnancies of women with no cancer history. Logistic regression models were used to investigate a range of adverse outcomes independently associated with CRC and its surgical and adjunctive treatments. Among 627,762 deliveries during the study period (1983-2007), 232 were first pregnancies following CRC. Whether following laparoscopic or open cancer surgery, these pregnancies were independently associated with a significantly increased risk of antepartum hemorrhage [odds ratios (ORs): 1.25; 2.13 for the respective procedures], postpartum hemorrhage (ORs: 1.61; 3.31), Cesarean delivery (ORs: 2.42; 4.24), infant low Apgar score (ORs: 1.32; 2.64), need for neonatal resuscitation (ORs: 1.49; 3.20), and special care admission (ORs: 1.42; 2.87). A history of open (but not laparoscopic) cancer surgery was associated with increased risk of gastrointestinal obstruction during pregnancy (OR 1.17) and prolonged postpartum hospitalization (OR 3.11). Neither was significantly associated with perinatal death. Among women with previous CRC, rectal (versus colonic) malignancy was independently associated with a significantly higher risk of overall maternal and neonatal adverse outcomes (ORs: 3.73 and 2.73, respectively), as was radiotherapy (ORs: 4.24 and 2.81, respectively). Chemotherapy was independently associated with a marginally but significantly higher risk of overall maternal but not neonatal outcomes (ORs: 1.11; 0.98). Open versus laparoscopic cancer surgery was associated with a significantly higher risk of antepartum and postpartum hemorrhage, low Apgar score, need for neonatal resuscitation, and neonatal special care admission. Previous CRCs, particularly rectal and radiation-treated tumors, appear to confer an increased likelihood of adverse outcomes in subsequent pregnancies. Laparoscopic technique for CRC surgery may reduce adverse gestational outcomes.

Analysis of Pregnancy Outcomes Using the New IADPSG Recommendation Compared with the Carpenter and Coustan Criteria in an Area with a Low Prevalence of Gestational Diabetes.

Aims. This paper aims to evaluate characteristics and pregnancy outcomes in women prior classified normal by Carpenter and Coustan criteria (old criteria) and now gestational diabetes (GDM) by the IADPSG criteria. Methods. Retrospective analysis of 6727 pregnancies is used. Using the old criteria, 222 had GDM (old GDM). Using the IADPSG criteria, 382 had GDM of which 160 had a normal glucose tolerance with the old criteria (new GDM). We compared the new GDM group with the old GDM group and women with normal glucose tolerance with both criteria (NGT group, 6345). Results. New GDM women were younger (31.6 ± 4.7 versus 33.3 ± 7.2 years, P = 0.010) than old GDM women. Caesarean section was performed in 30.5% of new GDM, in 32.4% of old GDM (P = 0.706), and in 23.3% of NGT women (P = 0.001). Large for gestational age occurred in 10.8% of new GDM, in 13.8% of old GDM (P = 0.473), and in 9.0% of NGT women (P = 0.099). Shoulder dystocia occurred in 3.9% of new GDM, in 3.2% of old GDM (P = 0.736), and in 1.4% of NGT women (P = 0.007). Conclusion. Using the IADPSG criteria, more women are identified as having GDM, and these women carry an increased risk for adverse gestational outcome compared to women without GDM.

Frequency of a Persistent Yolk Sac and Its Relationship With the Gestational Outcome

This study aimed to determine the frequency of a persistent yolk sac in pregnancies at 12 to 13 weeks and to investigate whether a persistent yolk sac is associated with an adverse gestational outcome. This study reviewed a total of 282 women who had normal singleton pregnancies with a gestational age of 12 weeks to 13 weeks 6 days and who were consecutively admitted to the study center for first-trimester screening (for chromosomal abnormalities) between April 2010 and February 2011. A persistent yolk sac has been defined as a yolk sac that has achieved a diameter of 5.6 mm or greater without losing its internal pressure at the 12th week of pregnancy or later. A persistent yolk sac was detected by sonography in 25 pregnancies. The average diameter of the persistent yolk sacs ± SD was 6.3 ± 0.2 mm (range, 5.6-8.0 mm). The frequency of a persistent yolk sac in pregnancies at 12 weeks was significantly higher than that at 13 weeks (P = .017). A persistent yolk sac was not associated with adverse perinatal outcomes, including abnormal sonographic findings, isolated structural defects, poor obstetric outcomes, and perinatal mortality. Although yolk sacs mostly disappear toward the end of the first gestational trimester, they may sometimes persist even to the 13th week of gestation. The persistence of the yolk sac seems to be unrelated to an adverse perinatal outcome.

The prognostic value of a normal oral glucose tolerance test in pregnant women who tested positive at screening: a validation study.

BackgroundControversies surround a diagnosis of gestational diabetes mellitus (GDM). The objective of this study was to evaluate the oral glucose tolerance test (OGTT) for the prediction of adverse gestational and perinatal outcomes in pregnant women with a positive screening test for diabetes mellitus and a negative diagnosis, i.e. a normal 3-hour OGTT.MethodsThis validation study evaluated 409 pregnant women who tested positive for diabetes mellitus at screening. Perinatal and maternal outcomes were considered. Sensitivity and specificity were calculated for each of the values of the OGTT as a diagnostic test, with the gold standard being perinatal outcome.ResultsThe most frequent risk factors were obesity, arterial hypertension and advanced maternal age. The most common neonatal outcomes were large-for-gestational-age infants, Cesarean delivery and preterm birth. A fasting blood glucose level of 87 mg/dL was the most powerful predictor of adverse perinatal outcome.ConclusionsAt the cut-off level adopted by the American Diabetes Association, gestational OGTT was able to successfully identify in which pregnant women outcome would be unfavorable.

Dopplervelocimetria fetoplacentária em gestantes hipertensas e resultados perinatais segundo a idade gestacional

OBJETIVO: Avaliar índices de pulsatilidade das artérias umbilical (IPAU) e cerebral média (IPACM) e relação do índice de pulsatilidade umbilico-cerebral (IPAU/IPACM) em fetos de gestantes hipertensas e presença de resultados perinatais adversos. MATERIAIS E MÉTODOS: Analisamos IPAU, IPACM e IPAU/IPACM de 289 fetos de gestantes hipertensas quanto à previsão dos resultados perinatais adversos. Os resultados foram comparados sem e com ajuste pela idade gestacional. RESULTADOS: O índice de Apgar < 7 no 5º minuto foi associado com resultados alterados após o ajuste por idade gestacional. O risco para recém-nascidos pequenos para a idade gestacional aumentou em três vezes após o ajuste, com significância estatística em todos os parâmetros do Doppler. Na síndrome da hipóxia neonatal o aumento do risco ajustado pela idade gestacional foi estatisticamente significante no IPAU e IPAU/IPACM. Não houve aumento no risco de síndrome do desconforto respiratório na análise ajustada. A mortalidade perinatal e o IPAU alterado apresentaram um risco três vezes maior e foram estatisticamente significantes após o ajuste. CONCLUSÃO: Em gestantes hipertensas, o IPAU apresentou melhor correlação com os resultados perinatais do que o IPACM ou relação IPAU/IPACM. O risco de resultados adversos deve considerar a idade gestacional.

Maternal smoking, social class and outcomes of pregnancy

Exposure to tobacco during pregnancy is an important risk factor for infant health. Recently the prevalence of smoking during pregnancy has declined in our area. The objective of this study was to analyse the association between several social variables and the fetal exposure to smoking, as well as the association between maternal smoking and some adverse gestational outcomes. Data collection was cross-sectional. The study population were women in the city of Barcelona (Catalonia, Spain) delivering a child without birth defects. The sample corresponded to the controls of the Birth Defects Registry of Barcelona, 2% of all pregnancy deliveries in the city from 1994 to 2003 (n = 2297). Information sources were hospital records and a personal interview of mothers. The analysis measured first the association between independent variables (instruction level, social class, occupation, nationality, planned pregnancy, parity, hospital funding and smoking status of the mother's partner) with two dependent variables: smoking at the initiation of pregnancy and quitting during pregnancy. Second, the persistence of smoking over pregnancy and all independent variables were studied with three variables indicating adverse outcomes of pregnancy: low gestation, low birthweight and intrauterine growth restriction (IUGR). Finally, the joint association between the persistence of smoking over pregnancy and social class taken as independent variables was determined with the three variables indicating adverse outcomes of pregnancy. Logistic regression models were fitted, adjusting for maternal age. Results are presented as odds ratios with their 95% confidence intervals. The prevalence of smoking at the onset of gestation was 41%, and 40% of these women quit during pregnancy, so that 25% delivered as active smokers. Fewer women with higher educational levels and from families with non-manual jobs smoked, as did immigrants, those planning pregnancy and women whose partner did not smoke. Smoking immigrants quit more frequently than nationals, as did those planning pregnancy, primiparae, and women whose partner did not smoke. Low gestation, low birthweight and IUGR were more frequent among smokers and women with a manual occupation, but manual occupation lost its significance when adjusting for smoking. The association between smoking and adverse results was higher for IUGR. In conclusion, the prevalence of smoking and quitting during pregnancy varied according to social factors. The influence of social factors on the outcome of pregnancy was mediated strongly by smoking in a country that provides access to health care free of cost. A priority in reducing inequalities in health is to help women from manual work backgrounds quit smoking.

Nutrient partitioning during pregnancy: adverse gestational outcome in overnourished adolescent dams.

Appropriate nutrient partitioning between the maternal body and gravid uterus is essential for optimum fetal growth and neonatal survival, and in adult sheep nutrient partitioning during pregnancy generally favours the conceptus at the expense of the dam. However, recent studies using an overnourished adolescent sheep model demonstrate that the hierarchy of nutrient partitioning during pregnancy can be dramatically altered in young growing females. Overnourishing the adolescent dams to promote rapid maternal growth throughout pregnancy results in a major restriction in placental mass and leads to a significant decrease in birth weight relative to moderately-fed adolescents of equivalent gynaecological age. High maternal feed intakes are also associated with an increased incidence of non-infectious spontaneous abortion, a reduction in gestation length and colostrum production, and a higher incidence of neonatal mortality. The present paper examines the putative role of a variety of endocrine regulators of nutrient partitioning in this unusual model system, where the dam is overnourished while the stunted placenta restricts nutrient supply to the fetus. The central role of nutritionally-mediated alterations in placental growth and development in setting the subsequent pattern of nutrient partitioning between the maternal body, placenta and fetus is examined, and critical periods of sensitivity to alterations in maternal nutritional status are defined. Finally, the consequences of this form of inappropriate nutrient partitioning on the growth and development of the fetus and neonate are described with particular emphasis on the reproductive axis.

Transplacental pharmacokinetics of the antituberculosis drugs.

Information concerning passage of the antituberculosis drugs across the human placenta is sparse and scattered throughout the medical literature. Little mention was made of this subject in recent reviews of the clinical pharmacokinetics of these agents (Holdiness 1984, 1985a). However, a detailed survey indicates 6 of the 12 compounds commonly used have documented transplacental passage in humans (table I). If pregnancy occurs during the treatment of tuberculosis, the risk to the developing fetus must be considered in advising the expectant mother and her obstetrician. The indications for chemotherapy and the basic principles of management of the pregnant women with active tuberculosis are essentially no different from those in the non-pregnant patient (Snider 1984). Therapy with 2 drugs is instituted at standard doses, and the duration of treatment should not be altered by the patient's pregnancy. Retrospective studies by Snider et al. (1980) have revealed a reasonable margin of safety for isoniazid, rifampicin, and ethambutol when utilised during pregnancy; questionable results have precluded the administration of streptomycin. From their research of the literature, these authors showed that 94% of all gestations terminated in delivery of apparently normal term infants. In utero exposure of fetuses to antituberculosis therapy revealed 2.8% with classified birth defects. It was suggested that with the exception of women on streptomycin, the risk of adverse gestational outcomes is no greater among pregnant women on antituberculosis regimens than among healthy pregnant females. Caution must be exercised when considering the teratogenic effects of these drugs as spontaneous abortions, stillbirths, birth defects and prematurity are common even in normal pregnancy. The possible teratogenic effects of this class of antibiotics in animal models and humans have recently been reviewed (Holdiness 1987a) and the reader is referred to this article. Snider (1984) indicated that preventive therapy should be given during the second and third trimesters of pregnancy to selected patients at high risk of development of progressive disease. Treatment should be instituted promptly when a tuberculous infection is detected. Preferred regimens are isoniazid-ethambutol, isoniazid-rifampicin, or isoniazid-ethambutol-rifampicin, although other drugs may be needed if the disease is recurrent or if there is resistance to these primary drugs.