Use Of Drugs In Early Pregnancy Research Articles

Polypharmacy in polymorbid pregnancies and the risk of congenital malformations-A systematic review.

With an increased prevalence of concurrent morbidities during pregnancy, polypharmacy has become increasingly common in pregnant women. The risks associated with polypharmacy may exceed those of individual medication because of drug-drug interactions. This systematic review aims to evaluate the risk of congenital malformations in polymorbid pregnancies exposed to first-trimester polypharmacy. PubMed, Embase and Scopus were searched to identify original human studies with first- trimester polypharmacy due to polymorbidity as the exposure and congenital malformations as the outcome. After screening of 4034 identified records, seven studies fulfilled the inclusion criteria. Four of the seven studies reported an increased risk of congenital malformations compared with unexposed or monotherapy, odds ratios ranging from 1.1 to >10.0. Particularly, short-term anti-infective treatment combined with other drugs and P-glycoprotein substrates were associated with increased malformation risks. In conclusion, knowledge is limited on risks associated with first-trimester polypharmacy due to polymorbidity with the underlying evidence of low quantity and quality. Therefore, an increased focus on pharmacovigilance to enable safe drug use in early pregnancy is needed. Large-scale register-based studies and better knowledge of placental biology are needed to support the clinical management of polymorbid pregnancies that require polypharmacy.

Maternal employment and pregnancy outcomes in a large European maternity hospital

ObjectiveEpidemiological studies have previously reported that maternal socioeconomic disadvantage is associated with adverse feto-maternal outcomes. However, little attention has been paid to the question of the woman’s employment status. The aim of this observational study was to examine the relationship between maternal employment status at the first antenatal visit and pregnancy outcomes. Study designThe study was confined to women with a singleton pregnancy who attended for maternity care between the years 2010 and 2017 and delivered a baby weighing ≥500 g. Self-reported sociodemographic and clinical details were recorded at the first antenatal visit by a trained midwife and updated before hospital discharge. The hospital is one of the largest in Europe and accepts women from all socioeconomic groups, including women in the public system and those with private health insurance, across the rural-urban spectrum. ResultsOf the 62,395 women, the mean age was 31.5 years (SD 5.4), 39.3% were nulliparas and 70.7% were Irish born. Compared with the 45,028 (72.2%) women who reported as being in paid employment, the 4984 (8.0%) women who were unemployed had a higher rate of stillbirth (8/4984 vs. 27/45,028, p = 0.005) and homemakers had a higher incidence of neonatal death (31/12,383 vs. 73/45,028, p = 0.02). On multivariable analysis, women who were unemployed or homemakers had increased adjusted odds ratios for neonatal unit (NNU) admissions, preterm birth, low birth weight, and small-for-gestational-age. Compared to women in paid employment, women who were unemployed or homemakers were associated with younger age (<30 years) in pregnancy, multiparity, unplanned pregnancy, no or postconceptional only folic acid supplementation, anxiolytic/antidepressant use, as well as persistent smoking and illicit drug use during pregnancy. ConclusionsIn a high-income European country, women who reported as unemployed or homemakers were associated with higher rates of adverse pregnancy outcomes. Furthermore, these women were associated with suboptimal lifestyle behaviours such as smoking and illicit drug use in early pregnancy. This highlights the need for long term public policies on female unemployment and retaining women with children in employment.

Use of nonsteroidal antiinflammatory drugs during pregnancy and the risk of miscarriage

Nonsteroidal antiinflammatory drugs are among the medications most widely used by pregnant women, and previous studies have reported an increased risk of miscarriage that is associated with nonsteroidal antiinflammatory drug use during pregnancy. Although the findings have not always been consistent, there is a well-established mechanism for the association: nonsteroidal antiinflammatory drugs inhibit the production of prostaglandin, which is essential for successful embryonic implantation. Abnormal implantation increases the risk of miscarriage. The purpose of this study was to examine the impact of nonsteroidal antiinflammatory drug use in early pregnancy on the risk of miscarriage, especially regarding the timing and duration of use. We conducted a cohort study among pregnant members of Kaiser Permanente Northern California, an integrated healthcare delivery system. Pregnant Kaiser Permanente Northern California members (N=1097) were recruited very early in pregnancy (median gestational age at enrollment, 39 days) to achieve optimal ascertainment of miscarriage, including early miscarriages, which are often missed in studies of miscarriages. Based on the use of nonsteroidal antiinflammatory drugs and acetaminophen, which has similar indication as nonsteroidal antiinflammatory drugs, 3 cohorts were formed: (1) women who used nonsteroidal antiinflammatory drugs only, (2) women who used acetaminophen only (to control for indication), and (3) women who used neither nonsteroidal antiinflammatory drugs nor acetaminophen (unexposed control subjects). Among all eligible women contacted, 63% participated in the study. Miscarriages were ascertained from both electronic medical record data and directly from interviews with participants. The Cox proportional hazards model with accommodation for left truncation was used to examine the risk of miscarriage associated with the use of nonsteroidal antiinflammatory drugs and acetaminophen during pregnancy; we controlled for potential confounders. After an adjustment for multiple confounders that included maternal age, previous miscarriage, multivitamin use, caffeine drinking, and smoking during pregnancy, we found that nonsteroidal antiinflammatory drug use during pregnancy was associated with a statistically significant increased risk of miscarriage compared with both unexposed control subjects (adjusted hazard ratio, 1.59; 95% confidence interval, 1.13-2.24) and acetaminophen users (indication control subjects; adjusted hazard ratio, 1.45; 95% confidence interval, 1.01-2.08). The risk was largely due to nonsteroidal antiinflammatory drug use around conception (adjusted hazard ratio, 1.89; 95% confidence interval, 1.31-2.71) with a statistically significant dose-response relationship: adjusted hazard ratio, 1.37 (95% confidence interval, 0.70-2.71) for nonsteroidal antiinflammatory drug use of ≤14 days; adjusted hazard ratio, 1.85 (95% confidence interval, 1.24-2.78) for nonsteroidal antiinflammatory drug use of ≥15 days. The association was stronger for early miscarriage (<8 weeks gestational age): adjusted hazard ratio, 4.08 (95% confidence interval, 2.25-7.41). Women with lower body mass index (<25 kg/m2) appeared to be more susceptible to the effect of nonsteroidal antiinflammatory drug use around conception (adjusted hazard ratio, 3.78; 95% confidence interval, 2.04-6.99) than women with high body mass index (≥25 kg/m2; adjusted hazard ratio, 1.03; 95% confidence interval, 0.61-1.72). After we controlled for confounding by indication, nonsteroidal antiinflammatory drug use around conception was associated with an increased risk of miscarriage with a dose-response relationship. In addition, women with lower body mass index could be especially vulnerable to the effects of nonsteroidal antiinflammatory drug use around the time of embryonic implantation, although this new observation must be confirmed in future studies.

Drug use during early pregnancy: Cross-sectional analysis from the Childbirth and Health Study in Primary Care in Iceland

Objective. To analyse drug use in early pregnancy with special focus on socio-demographic factors associated with psychotropic and analgesic drug use. Design. Cross-sectional study. Setting and subjects. A total of 1765 women were invited via their local health care centres, and 1111 participated at 11–16 weeks of pregnancy by filling out a postal questionnaire concerning socio-demographic and obstetric background, stressful life events, and drug use. Main outcome measures. Drug use prior to and early on in pregnancy, socio-demographic factors, smoking, and adverse life events were investigated. Drug categories screened for were psychotropics (collective term for antidepressants, relaxants, and sleep medication), analgesics, hormones, nicotine, vitamins/minerals, and homeopathic medicine. Results. Drug use from the aforementioned drug categories, excluding vitamins/minerals and homeopathic medicine, was reduced by 18% during early pregnancy, compared with six months prior to conception (49% vs. 60%). Psychotropic drug use during early pregnancy was associated with elementary maternal education (p < 0.5), being unemployed (p < 0.001), being single/divorced/separated (p < 0.01), smoking prior to or during pregnancy (p < 0.01), forced to change job/move house (p < 0.001), and psychotropic drug use six months prior to pregnancy (p < 0.001). No items on the stressful life events scale were associated with increased analgesic use, which increased only with multiparity. Conclusions. Use of analgesics and psychotropic drugs seems common in pregnancy. Our results indicate that lack of a support network, stressful life events, and lower status in society may predispose women to more drug use. GPs and midwives responsible for maternity care could take this into account when evaluating risk and gain for women and foetuses in the primary care setting.

Is there such thing as safe drug use in pregnancy?

British Journal of Midwifery • June 2014 • Vol 22, No 6 From nausea and sickness to depression, it is universally acknowledged that pregnant women get ill. However, drug taking in pregnancy is a contentious issue and most midwives and doctors steer clear of prescribing medication for pregnant women. This is because women, pregnant or otherwise, are grossly underrepresented in clinical trials (Mullin, 2014). It simply isn’t considered ethical to test drugs on pregnant women or women of childbearing age. Yet a woman may take a drug without it having a longor short-term effect on the baby but, unlike using the Yellow Card for adverse drug reactions, its ‘safety’ wont be reported. Drug use in early pregnancy (from the third to the eleventh week) can produce congenital malformations, and should be avoided if possible. During the second and third trimester medications can affect the growth or functional development of the baby (Joint Formulary Committee, 2014). But what happens when a sick woman becomes pregnant? It is not always advisable to stop treatment. An untreated illness such as depression may be more harmful to the baby, especially if the mother chooses to hurt herself or her unborn child. In these cases common sense must prevail. We often only hear about drugs that have an adverse effect on the baby, but not taking antidepressants in this case may do more damage. The thalidomide scandal of the late 1950s, ensured that doctors and midwives were more likely to recommend women try alternative or complementary therapies, such as ginger and acupressure, for nausea and sickness in pregnancy. However, the National Institute for Health and Care Excellence (NICE, 2008) discourages the use of complementary therapies due to insufficient evidence. Just because it is natural, doesn’t mean it is safe. Earlier this month, at Primary Care & Public Health 2014, Denise Tiran discussed the use of alternative therapies for nausea and sickness in pregnancy. She highlighted that ginger, although often recommended, may do more harm than good at the wrong dose. Ginger acts like a pharmacological and has an anticoagulant effect, and so it may not be advisable to be taken before birth or in a history of bleeding (WebMD, 2014). Tiran did point out that the amount of ginger in ginger biscuits is too small to have any affect on nausea and its perceived benefits are due to a sugar surge temporarily alleviating the symptoms. The Joint Formulary Committee (2014) recommends that if drugs are to be prescribed, they should be ones which have been extensively used and appear to be safe rather than new or untrialled drugs. The most important thing to remember is that the benefits to the woman should always outweigh the risks to the baby. But, what good is a mother who is too sick to look after her baby? BJM

THERAPY OF ENDOCRINE DISEASE: Antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk?

Antithyroid drugs (ATDs) may have teratogenic effects when used in early pregnancy. To review the association between the time period of ATD exposure in early pregnancy and the development of birth defects. We identified publications on birth defects after early pregnancy exposure to the ATDs methimazole (MMI; and its prodrug carbimazole (CMZ)) and propylthiouracil (PTU). Cases of birth defects after ATD treatment had been initiated or terminated within the first 10 weeks of pregnancy were identified and studied in detail. A total of 92 publications were read in detail. Two recent large controlled studies showed ATD-associated birth defects in 2-3% of exposed children, and MMI/CMZ-associated defects were often severe. Out of the total number of publications, 17 included cases of birth defects with early pregnancy stop/start of ATD treatment, and these cases suggested that the high risk was confined to gestational weeks 6-10, which is the major period of organogenesis. Thus, the cases reported suggest that the risk of birth defects could be minimized if pregnant women terminate ATD intake before gestational week 6. Both MMI and PTU use in early pregnancy may lead to birth defects in 2-3% of the exposed children. MMI-associated defects are often severe. Proposals are given on how to minimize the risk of birth defects in fertile women treated for hyperthyroidism with ATDs.

Drug safety in pregnancy - monitoring congenital anomalies

This paper outlines research into the causes of congenital anomalies, and introduces a pan-European study. The potential roles of nurses and midwives in this area are illustrated by a case report. Since the thalidomide disaster, use of drugs in pregnancy has been carefully monitored to prevent anything similar happening again. However, monitoring is incomplete and questions remain unanswered. Many medicines are essential for the health of pregnant women. However, drug use in pregnancy requires surveillance. Methods include spontaneous reporting of adverse events, cohort studies and case control studies. It is hoped that a Europe-wide study, combining data from several congenital anomaly registers, will provide a sufficiently large population to assess the impact of selected drugs on congenital anomalies. However, this work depends on the consistency of reporting by nurses and midwives. Drug safety in pregnancy remains undetermined. Collaboration across Europe has the potential to provide a framework for safety evaluation. Prescribers should consider the possibility of pregnancy in women of child-bearing age. Careful review of maternal drug use in early pregnancy is essential. Midwives and nurses should be aware of adverse event drug reporting systems, including congenital anomaly registers.

Maternal drug use in early pregnancy and risk of cardiovascular defect in infant—A follow-up study

Maternal drug use in early pregnancy and risk of cardiovascular defect in infant—A follow-up study

Maternal use of selective serotonin re‐uptake inhibitors and persistent pulmonary hypertension of the newborn

In order to evaluate the previously published association between maternal use of selective serotonin re-uptake inhibitors (SSRI) and persistent pulmonary hypertension in the neonate (PPHN), we used data from the Swedish Medical Birth Register for the years 1997-2005. Infants were identified from discharge diagnoses, and maternal exposure to drugs from interviews performed in early pregnancy and from prescriptions from the antenatal care service. Putative confounders were studied: an increased risk for PPHN was indicated for high maternal age, for first parity, for maternal BMI, and possibly for maternal smoking. Adjusting for these variables and year of birth, an association between maternal use of SSRI and PPHN in births after 34 completed weeks was identified with a risk ratio of 2.4, 95%CI 1.2-4.3 when based on women who reported the drug use in early pregnancy. When a subgroup of the women were studied who also had prescriptions for SSRI from the antenatal care later in pregnancy, the risk estimate was 3.6, 95%CI 1.2-8.3. The risk estimates were lower than that described previously in the literature, but both estimates could come from the same about 4-5 times increased risk. The mechanism behind the association between SSRI and PPHN is unclear but an increased risk for respiratory problems after maternal use of SSRI is well known, and PPHN could be a rare part of this association.

Medication use in early pregnancy: a study in a teaching hospital in Western Nepal

This study explored the extent of drug use in early pregnancy (first trimester of pregnancy) in Nepalese women in the setting of a large teaching hospital in western Nepal.

Maternal drug use and infant cleft lip/palate with special reference to corticoids.

To study the association between maternal drug use in early pregnancy and orofacial cleft in the infant. Register analysis based on prospectively collected information. All delivered women in Sweden July 1, 1995, through December 31, 2001. Presence of orofacial cleft in infant. Prospective information on maternal drug use during the first trimester, as reported in early pregnancy, was studied in 1142 infants with orofacial clefts, isolated or with other malformations, excluding chromosome anomalies. Any drug use was not associated with clefts (odds ratio [OR] = 0.98, 95% confidence interval [95% CI] = 0.85 to 1.13), with isolated clefts (OR = 0.92) with isolated median cleft palate (OR = 1.03, 95% CI = 0.79 to 1.36) or with isolated cleft lip with or without cleft palate (OR = 0.86, 95% CI = 0.71 to 1.05). Reported use of multivitamins, folic acid, or B(12) was not associated with a decrease in orofacial cleft risk (OR = 1.00, 95% CI = 0.63 to 1.52). ORs above 2 were seen for some drugs: sulfasalazine, naproxen, and anticonvulsants, but only a few exposed cases occurred. An association between glucocorticoid use and infant cleft was indicated and seemed to be strongest for median cleft palate. Maternal drug use seems to play only a small role for the origin of orofacial clefts, at least in Sweden.

Maternal drug use in early pregnancy and infant cardiovascular defect

The purpose of the paper is to identify maternal drug use that may be associated with an increased risk for cardiac defects in the offspring. A case-control study was performed with cases (cardiovascular defects without known chromosome anomalies) being identified from three Swedish health registers ( n=5015) and controls being all infants born in Sweden during the period 1 July 1995–2001 ( n=577,730). Information on drug exposure was obtained by interview in early pregnancy. Associations between maternal drug use and infant cardiovascular defect were identified for insulin, antihypertensives, fertility drugs, erythromycin, naproxen, anticonvulsants, nitrofurantoin, clomipramine, and budesonide in nasal preparations. Some of these associations are probably due to confounding from underlying disease or complaint, some may be due to multiple testing, some may be true drug effects. Further studies are needed to verify or reject these associations.

Use of antihistamine drugs in early pregnancy and delivery outcome

Objective: To study the impact of antihistamine use in early pregnancy on delivery outcome. Methods: Using prospectively collected information on drug use in early pregnancy, delivery outcome was studied among 17 266 women with 17 776 deliveries and 18 197 infants. The analysis was performed according to the main reason for antihistamine use: nausea and vomiting in pregnancy and allergy. Results: In the nausea and vomiting in pregnancy group, we found a significant increase in twin births and a significant reduction in preterm births, low birth weight and being small-for-gestational age among singletons. The perinatal death rate was reduced and the rate of congenital malformations was normal. A reduction was seen in the occurrence of congenital cardiovascular defects after the use of antihistamines. The odds ratio for specified cardiac defects, with the exception of ventricular and atrium septal defects, after the use of antihistamines for nausea and vomiting in pregnancy (0.54) was significantly lower than that for non-cardiovascular congenital malformations (0.95). No statistically significant effects on delivery outcome were seen after the use of antihistamine drugs for allergy. However, there was a non-significant tendency for a reduced risk for cardiovascular defects (odds ratio 0.71). Conclusions: The beneficial effects on delivery outcome observed are most probably related to the underlying nausea and vomiting in pregnancy. There is no clear teratogenic effect of the antihistamines studied.

Use of antihistamine drugs in early pregnancy and delivery outcome

Objective: To study the impact of antihistamine use in early pregnancy on delivery outcome.Methods: Using prospectively collected information on drug use in early pregnancy, deliveryoutcome was studied among 17 266 women with 17 776 deliveries and 18 197 infants. The analysis was performed according to the main reason for antihistamine use: nausea and vomiting in pregnancy and allergy.Results: In the nausea and vomiting in pregnancy group, we found a significant increase in twin births and a significant reduction in preterm births, low birth weight and being small-for-gestationalage among singletons. The perinatal death rate was reduced and the rate of congenital malformations was normal. A reduction was seen in the occurrence of congenital cardiovascular defects after the useof antihistamines. The odds ratio for specified cardiac defects, with the exception of ventricular and atrium septal defects, after the use of antihistamines for nausea and vomiting in pregnancy (0.54)was significantly lower than that for non-cardiovascular congenital malformations (0.95). No statistically significant effects on delivery outcome were seen after the use of antihistamine drugs for allergy.However, there was a non-significant tendency for a reduced risk for cardiovascular defects (odds ratio 0.71).Conclusions: The beneficial effects on delivery outcome observed are most probablyrelated to the underlying nausea and vomiting in pregnancy. There is no clear teratogenic effect of the antihistamines studied.

Drug use during early pregnancy. The impact of maternal illness, outcome of prior pregnancies and socio-demographic factors.

Socio-demographic factors have been associated with drug use in pregnancy. However, information on maternal illness has rarely been included in previous studies. The aim of this study was therefore to estimate the impact of maternal illness and prior pregnancy outcome on the use of analgesics/antipyretics, anti-infectives and antihistamines in early pregnancy controlling for socio-demographic factors. One thousand nine-hundred and forty-five parous pregnant women from Norway and Sweden were included in an interview study. Information on drug use, obstetric history, maternal illness and socio-demographic factors was collected by specially trained midwives at gestational week 17 and form the basis for the present analyses. After control for socio-demographic factors, reported illness was associated with the use of analgesics/antipyretics, anti-infectives and antihistamines during early pregnancy. The use of analgesic/antipyretic and anti-infective drugs differed between study sites. Sociodemographic factors such as age, parity, marital status, education, occupation and smoking habits did not influence drug use in the multivariate analysis. Maternal illness during pregnancy was associated with drug use in early pregnancy. When studying factors related to drug use during pregnancy, it is important to include information on maternal illness. Socio-demographic factors may be confounders and lead to erroneous conclusions about the factors related to drug use.

Drugs in Pregnancy — The Dilemma of Labeling

The paper discusses the problems with pregnancy labeling of drugs. The Swedish, United States, and Australian labeling systems are briefly summarized. Data on drug use in early pregnancy in Sweden (1996) are presented according to pregnancy labeling category and with details on drugs thought to be teratogenic or where animal data suggest hazards. The various situations when drug teratogenicity are of interest are reviewed and the difficulties in presenting detailed pregnancy warnings valid for all situations are stressed. The amount of data needed for information in the different situations is discussed and exemplified. Finally, suggestions are made on how texts referring to drug use during pregnancy can be structured for different drug categories.

Delivery outcome after the use of antidepressants in early pregnancy.

To investigate delivery outcome after the use of antidepressants in early pregnancy. Using an ongoing prospective recording of drug use in early pregnancy, 969 women were identified who reported the use of antidepressants: 531 used only SSRI (selective serotonin re-uptake inhibitor) drugs (mostly citalopram, 375 exposures), 423 used only other antidepressants, and 15 used both. Outcome was compared with all births in the population. Women using these drugs were older and smoked more than three times as often as other women. There seemed to be an excess of high parity women. The frequency of multiple births was lower than expected, resulting from too few twin births in women who had used SSRI. Gestational duration among singletons was shorter but it did not affect infant survival and was similar after the use of SSRI or non-SSRI antidepressants, perhaps the result of uncompensated for confounding or related to the underlying disease. Infants were somewhat heavier than expected, notably after non-SSRI treatment. No increase was seen in congenital abnormalities, observable in the perinatal period. Based on this database, the use of antidepressants in early pregnancy does not seem to carry any significant risk for the infant that is detectable during the newborn period.

The teratogenicity of antirheumatic drugs—what is the evidence?

This review adresses on various methods used in the detection of human teratogenic effects of drug use in early pregnancy. Data are presented from the new Swedish ongoing recording of drug use in early pregnancy. These data do not indicate a teratogenic effect of the main antirheumatic drugs used in Sweden.