Drugs of abuse and HIV infection/replication: implications for mother-fetus transmission

Human immunodeficiency virus (HIV) infection and progression of acquired immunodeficiency syndrome (AIDS) can be modulated by a number of cofactors, including drugs of abuse. Opioids, cocaine, cannabinoids, methamphetamine (METH), alcohol, and other substances of abuse have been implicated as risk factors for HIV infection, as they all have the potential to compromise host immunity and facilitate viral replication. Although epidemiologic evidence regarding the impact of drugs of abuse on HIV disease progression is mixed, in vitro studies as well as studies using in vivo animal models have indicated that drugs of abuse have the ability to enhance HIV infection/replication. Drugs of abuse may also be a risk factor for perinatal transmission of HIV. Because high levels of viral load in maternal blood are associated with increased risk of HIV vertical transmission, it is likely that drugs of abuse play an important role in promoting mother-fetus transmission. Furthermore, because the neonatal immune system differs qualitatively from the adult system, it is possible that maternal exposure to drugs of abuse would exacerbate neonatal immunity defects, facilitating HIV infection of neonate immune cells and promoting HIV vertical transmission. The availability and use of antiretroviral therapy for women infected with HIV increase, there is an increasing interest in determining the impact of drug abuse on efficacy of AIDS Clinical Trials Group (ACTG)-standardized treatment regimens for woman infected with HIV in the context of HIV vertical transmission.     

HIV and HTLV-I antibody studies: pregnant women in the 1960s, patients with AIDS, homosexuals, and individuals with tropical spastic paraparesis

To investigate the possible occurrence of human immunodeficiency virus (HIV) or human T-cell lymphotropic virus, type I (HTLV-I) infections in the United States prior to 1979-1981, when acquired immune deficiency syndrome (AIDS) was first recognized, we tested sera from 310 pregnant women who participated in the Collaborative Perinatal Project during the period 1959-1964 for HIV and HTLV-I antibody. These samples included sera from 53 pregnant women who were intravenous drug users. The remainder were from women who had cervical epithelial abnormalities, who developed cervical carcinomas, who had had children with erythroblastosis fetalis, who had had children that developed malignant neoplasms early in life, or normal pregnant women. None of the 310 women had confirmed HIV or HTLV-I antibody. The rate of false-positive reactions with the HIV enzyme-linked immunosorbent assay (ELISA) antibody test in these long-frozen samples was similar to that observed in fresh sera. HIV antibody was detected in homosexual patients with AIDS; HTLV-I antibody was not detected in any of these sera. HTLV-I antibody was detected in 17 of 20 patients with tropical spastic paraparesis (TSP) and in two of seven patients with other neurological diseases diagnosed as transverse myelopathy and multiple sclerosis, and in none of nine normal controls; HIV antibody was not detected in any of these sera patients. Thus, we conclude that there was no serological evidence of infection with HIV or HTLV-I in the pregnant women studied; however, HIV antibody was present in all AIDS patients tested, and HTLV-I antibody was found in the majority of patients with TSP.     

Greater adherence to highly active antiretroviral therapy (HAART) between pregnant versus non-pregnant women living with HIV.

One of the most remarkable advances in the control of the HIV/AIDS pandemic has been the introduction of highly active antiretroviral therapy (HAART). The use of HAART has been associated to reductions in AIDS-related mortality in most countries where HAART is available. Unfortunately, the adherence required to keep good control of viral replication is higher than what is required in other medical conditions. Several studies have shown a relationship between adherence and viral suppression ranging between 90-95% required for complete suppression. Multiple factors have been related to adherence among which are: gender, racial/ethnic distribution, age, personality traits, education, alcohol use and others. For women living with HIV there might be additional difficulties to handle in order to be adherent (i.e. multiple family responsibilities). A group of 165 women living with HIV attending a multidisciplinary clinic were interviewed with a 3-day adherence questionnaire. Correlation with clinical information was obtained from the Clinic Data Base. A total of 37 pregnant and 128 non-pregnant women were included in this analysis, 96% of which were on HAART. Complete adherence (100%) was reported by 91% of the pregnant and 70% of the non-pregnant women. (Fisher's exact test 0.009). The majority, 99% knew the names of their medications. There were no differences among groups in scholarity, history or actual cigarette smoking, history or actual drug use, CD4 lymphocyte counts (median or proportion below 350 cells/mm3), mean HIV RNA viral load or the proportion of patients with HIV RNA < 1,000 copies/ml. The transmission rate for the sample of pregnant women was zero. The reported adherence rates to HAART for women living with HIV were highest among the pregnant women. This difference was statistically significant (Chi Sq 0.05). The great majority (93%) reported knowing the names of the medications. In spite of reported barriers to adherence, pregnant women attending a multidisciplinary clinic for HIV care and research, reported good rates of adherence to HAART. This is also reflected in the good perinatal outcomes. Non-pregnant women with lower adherence rates might need additional interventions to improve adherence.     

Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals

Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV(+) pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects.     

Human teratogens update 2011: can we ensure safety during pregnancy?

Anniversaries of the identification of three human teratogens (i.e., rubella virus in 1941, thalidomide in 1961, and diethylstilbestrol in 1971) occurred in 2011. These experiences highlight the critical role that scientists with an interest in teratology play in the identification of teratogenic exposures as the basis for developing strategies for prevention of those exposures and the adverse outcomes associated with them. However, an equally important responsibility for teratologists is to evaluate whether medications and vaccines are safe for use during pregnancy so informed decisions about disease treatment and prevention during pregnancy can be made. Several recent studies have examined the safety of medications during pregnancy, including antiviral medications used to treat herpes simplex and zoster, proton pump inhibitors used to treat gastroesophageal reflux, and newer-generation antiepileptic medications used to treat seizures and other conditions. Despite the large numbers of pregnant women included in these studies and the relatively reassuring results, the question of whether these medications are teratogens remains. In addition, certain vaccines are recommended during pregnancy to prevent infections in mothers and infants, but clinical trials to test these vaccines typically exclude pregnant women; thus, evaluation of their safety depends on observational studies. For pregnant women to receive optimal care, we need to define the data needed to determine whether a medication or vaccine is "safe" for use during pregnancy. In the absence of adequate, well-controlled data, it will often be necessary to weigh the benefits of medications or vaccines with potential risks to the embryo or fetus.     

Human teratogens update 2011: Can we ensure safety during pregnancy?

Anniversaries of the identification of three human teratogens (i.e., rubella virus in 1941, thalidomide in 1961, and diethylstilbestrol in 1971) occurred in 2011. These experiences highlight the critical role that scientists with an interest in teratology play in the identification of teratogenic exposures as the basis for developing strategies for prevention of those exposures and the adverse outcomes associated with them. However, an equally important responsibility for teratologists is to evaluate whether medications and vaccines are safe for use during pregnancy so informed decisions about disease treatment and prevention during pregnancy can be made. Several recent studies have examined the safety of medications during pregnancy, including antiviral medications used to treat herpes simplex and zoster, proton pump inhibitors used to treat gastroesophageal reflux, and newer‐generation antiepileptic medications used to treat seizures and other conditions. Despite the large numbers of pregnant women included in these studies and the relatively reassuring results, the question of whether these medications are teratogens remains. In addition, certain vaccines are recommended during pregnancy to prevent infections in mothers and infants, but clinical trials to test these vaccines typically exclude pregnant women; thus, evaluation of their safety depends on observational studies. For pregnant women to receive optimal care, we need to define the data needed to determine whether a medication or vaccine is “safe” for use during pregnancy. In the absence of adequate, well‐controlled data, it will often be necessary to weigh the benefits of medications or vaccines with potential risks to the embryo or fetus. Birth Defects Research (Part A), 2012. © Published 2012 Wiley Periodicals, Inc.     

The treatment of perinatal addiction. Identification,intervention, and advocacy.

Women of reproductive age who use and abuse psychoactive drugs and alcohol present a special challenge to primary care physicians. There are compelling medical reasons for identifying and intervening with pregnant women who are addicted or have alcoholism. The teratogenicity of all drugs of abuse and alcohol, the risk of infection with the acquired immunodeficiency syndrome (AIDS), and the potential for full recovery of a pregnant woman from addiction are some of the reasons that identification and intervention in the problem are indicated. Whether encountered in the clinic setting or in private practice, chemically dependent pregnant or postpartum women are usually responsive to appropriate physician interventions that include a detailed and caring confrontation- and advocacy-oriented support. Complex legal and ethical issues surround perinatal addiction including the role of toxicologic screening, reports to child welfare services, issues in noncompliance, and interdisciplinary case management.     

Women's perspectives on counseling about risks for medication‐induced birth defects

PURPOSE : This qualitative study explored women's experiences with counseling about medication‐induced birth defects, as well as how and when they would like to receive information on medication‐induced birth defects from their health care providers (HCPs). METHODS : We conducted four focus groups with 36 women of reproductive age (18–45 years old) in Pittsburgh, Pennsylvania. Twenty‐one women were using medications to treat a chronic health condition, and two were pregnant. Content analysis was performed by three independent coders using a grounded theory approach. Discrepancies were resolved by consensus. RESULTS : Women reported depending on their HCPs for information about the risks of teratogenic effects of medications on a pregnancy, but felt the information they had been provided was not always comprehensive. Women want HCPs to initiate discussions about potentially teratogenic medications at the time the medications are prescribed, regardless of whether the woman is sexually active or planning a pregnancy. Women want clear information about all potential outcomes for a fetus. Factors women reported as being critical to effective teratogenic risk counseling included privacy, sufficient time to discuss the topic, and a trusting relationship with their HCP. CONCLUSIONS : Women of reproductive age think that providing information about the possible teratogenic effects of medications could be improved by routine discussions of teratogenic risks at the time medications are prescribed. Birth Defects Research (Part A), 2010. © 2009 Wiley‐Liss, Inc.     

Hospitalizations for HIV/AIDS: Differences between sexes

Background: Women are especially vulnerable to HIV infection because of biological, social, cultural, and economic factors. In Brazil, AIDS was initially seen predominantly in homosexual men, but the epidemic gradually reached a gender balance as increasing numbers of women became infected with HIV.Objective: The aim of the present study was to identify the clinical and epidemiologic characteristics of hospitalized patients with HIV/AIDS of both sexes and compare the differences between them.Methods: This epidemiologic cross-sectional study evaluated gender differences in demographic, social, clinical, and epidemiologic characteristics of patients diagnosed with HIV/AIDS who were admitted for any reason to the Public Hospital of the Medical School of the Federal University of Triângulo Mineiro, Uberaba, Minas Gerais State, Brazil.Results: A total of 363 patients were included in the analysis, with a male/female ratio of 1.1:1.0. Forty-one percent of women were pregnant. Mean age at hospitalization and duration of hospitalization were significantly greater among men (P<0.05). Men and nonpregnant women were admitted because of infection significantly more often than were pregnant women (P<0.05). Significantly more single men who reported homosexual, bisexual, or heterosexual behavior associated with drug use were admitted compared with women (P<0.05). Women admitted for treatment were significantly more likely than men to be employed (P<0.05). Adherence to antiretroviral treatment and T CD4+ lymphocyte count indicated important differences between the sexes, with better parameters observed among nonpregnant and pregnant women compared with men.Conclusions: In the present study, women with HIV/AIDS who were admitted to the hospital for any reason were in better clinical condition compared with men. This observation may be partially explained by the proportion of pregnant women in the study population. These findings suggest that future studies should examine pregnant women with HIV/AIDS as a separate population group to avoid bias in analysis.     

Representation of Women and Pregnant Women in HIV Research: A Limited Systematic Review

Background

HIV-related outcomes may be affected by biological sex and by pregnancy. Including women in general and pregnant women in particular in HIV-related research is important for generalizability of findings.

Objective

To characterize representation of pregnant and non-pregnant women in HIV-related research conducted in general populations.

Data Sources

All HIV-related articles published in fifteen journals from January to March of 2011. We selected the top five journals by 2010 impact factor, in internal medicine, infectious diseases, and HIV/AIDS.

Study Eligibility Criteria

HIV-related studies reporting original research on questions applicable to both men and women of reproductive age were considered; studies were excluded if they did not include individual-level patient data.

Study appraisal and synthesis methods.

Articles were doubly reviewed and abstracted; discrepancies were resolved through consensus. We recorded proportion of female study participants, whether pregnant women were included or excluded, and other key factors.

Results

In total, 2014 articles were published during this period. After screening, 259 articles were included as original HIV-related research reporting individual-level data; of these, 226 were determined to be articles relevant to both men and women of reproductive age. In these articles, women were adequately represented within geographic region. The vast majority of published articles, 183/226 (81%), did not mention pregnancy (or related issues); still fewer included pregnant women (n=33), reported numbers of pregnant women (n=19), or analyzed using pregnancy status (n=9).

Limitations

Data were missing for some key variables, including pregnancy. The time period over which published works were evaluated was relatively short.

Conclusions and implications of key findings.

The under-reporting and inattention to pregnancy in the HIV literature may reduce policy-makers’ ability to set evidence-based policy around HIV/AIDS care for pregnant women and women of child-bearing age.     

The Cost-Effectiveness of Directly Observed Highly-Active Antiretroviral Therapy in the Third Trimester in HIV-Infected Pregnant Women

Background

In HIV-infected pregnant women, viral suppression prevents mother-to-child HIV transmission. Directly observed highly-active antiretroviral therapy (HAART) enhances virological suppression, and could prevent transmission. Our objective was to project the effectiveness and cost-effectiveness of directly observed administration of antiretroviral drugs in pregnancy.

Methods and Findings

A mathematical model was created to simulate cohorts of one million asymptomatic HIV-infected pregnant women on HAART, with women randomly assigned self-administered or directly observed antiretroviral therapy (DOT), or no HAART, in a series of Monte Carlo simulations. Our primary outcome was the quality-adjusted life expectancy in years (QALY) of infants born to HIV-infected women, with the rates of Caesarean section and HIV-transmission after DOT use as intermediate outcomes. Both self-administered HAART and DOT were associated with decreased costs and increased life-expectancy relative to no HAART. The use of DOT was associated with a relative risk of HIV transmission of 0.39 relative to conventional HAART; was highly cost-effective in the cohort as a whole (cost-utility ratio $14,233 per QALY); and was cost-saving in women whose viral loads on self-administered HAART would have exceeded 1000 copies/ml. Results were stable in wide-ranging sensitivity analyses, with directly observed therapy cost-saving or highly cost-effective in almost all cases.

Conclusions

Based on the best available data, programs that optimize adherence to HAART through direct observation in pregnancy have the potential to diminish mother-to-child HIV transmission in a highly cost-effective manner. Targeted use of DOT in pregnant women with high viral loads, who could otherwise receive self-administered HAART would be a cost-saving intervention. These projections should be tested with randomized clinical trials.     

孕妇不良情绪、生活事件与妊娠结局以及分娩方式的关系研究

目的:探讨孕妇不良情绪、生活事件对妊娠结局以及分娩方式的影响。方法:选择2017年3月至2018年7月在海南省三亚市人民医院进行分娩的孕妇232例,搜集孕妇的基本资料,调查孕妇的生活事件及抑郁、焦虑状态,并记录孕妇的妊娠结局以及分娩方式,分析孕妇不良情绪、生活事件与妊娠结局以及分娩方式之间的关系。结果:在232例孕妇中,焦虑情绪孕妇有24例,占10.34%;抑郁孕妇有86例,占37.07%;发生生活事件的孕妇有69例,占29.74%。受到生活事件刺激、存在抑郁及焦虑的孕妇出现不良妊娠结局的概率均高于正常孕妇(P0.05)。剖宫产孕妇负性生活事件发生次数高于自然分娩的孕妇,而正性生活事件发生次数低于自然分娩的孕妇(P0.05)。剖宫产孕妇焦虑、抑郁的发生率均高于自然分娩的孕妇(P0.05)。结论:孕妇的不良情绪及生活事件普遍存在,可导致不良妊娠结局的发生并且对分娩方式产生一定的影响,应引起家庭及社会的重视。     

Potential impact of drugs of abuse on mother-to-child transmission (MTCT) of HIV in the era of highly active antiretroviral therapy (HAART)

This report is a summary of a symposium entitled "Mother-to-Child Transmission (MTCT) of HIV and Drugs of Abuse in Highly Active Antiretroviral Therapy (HAART) Era," organized by The National Institute on Drug Abuse, National Institutes of Health in Rockville, Maryland, October 13, 2009. In the pre-HAART era, the prevalence of MTCT of HIV was about 25% and exposure of pregnant mothers to drugs of abuse (illicit drugs and tobacco smoking) was a significant factor in MTCT. However, with the introduction of HAART, the rate of MTCT of HIV has decreased to less that 2%. In the Unites States, it is estimated that currently about 5.1% of pregnant women use illicit drugs and 16.4% smoke tobacco. The residual prevalence of MTCT in the HAART era is still of concern and may be related to this continued prevalence of substance use among pregnant mothers. In this report, we review and present evidence that supports the hypothesis that drugs of abuse do have the potential to increase MTCT of HIV in the presence of HAART. Exposure to drugs of abuse during pregnancy may increase MTCT of HIV through a variety of mechanisms including possible damage to the placenta, induction of preterm birth, and increasing maternal plasma viral load through a variety of putative mechanisms such as: a) promoting HIV mutation and replication through non-adherence to HAART; b) impairing the efficacy of HAART through drug-drug interaction; and c) promoting HIV replication in monocyte/macrophages. Drugs of abuse may promote HIV replication by increasing the expression of CCR5 receptors, decreasing the expression of CCR5 receptor ligands, increasing the expression of CXCR4 receptors, increasing the expression of DC-SIGN, and possibly inducing epigenetic changes.     

Sibutramine use in pregnancy: report of two cases

BACKGROUND: Sibutramine is a drug used for the medical treatment of obesity. No data are available on sibutramine use in pregnancy. We report the fetal outcomes of two pregnant women exposed to sibutramine. CASES: The first woman was exposed to 10 mg/day of sibutramine during gestational weeks 4-6. The second woman was exposed to 10 mg/day of sibutramine during gestational weeks 5-8. At weeks 37 and 39, they delivered healthy infants. CONCLUSIONS: To our knowledge, this is the first report of sibutramine exposure in pregnancy. These cases may contribute to the knowledge about sibutramine use during pregnancy.     

Abortion experience among obstetric patients at Korle-Bu Hospital, Accra, Ghana

Hospital admissions for complications of abortion have been increasing in Africa, indicating a rise in the incidence of abortion. In all pregnant women ever admitted to Korle-Bu hospital in Accra, Ghana, the chance that the outcome of their last pregnancy was an induced abortion decreased as the number of previous pregnancies increased. Women with higher levels of education were more likely to have their 1st pregnancy terminated in an induced abortion. Younger women were more likely than older women at each level of education to have an induced abortion terminate a 1st pregnancy. The use of contraceptives during the last pregnancy interval increased with the level of education of the woman and the number of previous pregnancies. Contraceptive use was also highest among women whose last pregnancy outcome was an induced abortion. The mean pregnancy interval decreased with increasing number of previous pregnancies for both women who used and who did not use contraceptives during their last pregnancy interval. But the mean pregnancy interval was higher among women who used contraceptives. It appears that the abortion experience in this region of Africa is most common in lower parity young women with high levels of education who desire to delay a 1st birth or to space births. This is in contrast in Latin America and other developing countries in which abortion is used mainly by older, married, urban women to limit family size. Contraceptive use in this region of Africa is low, indicating the need for more family planning programs and increasing use of existing programs.     

Injection drug use and HIV/AIDS transmission in China

After nearly three decades of being virtually drug free, use of heroin and other illicit drugs has re-emerged in China as a major public health problem. One result is that drug abuse, particularly heroin injection, has come to play a predominant role in fueling China's AIDS epidemic. The first outbreak of HIV among China's IDUs was reported in the border area of Yunnan province between China and Myanmar where drug trafficking is heavy. Since then drug-related HIV has spread to all 31 provinces, autonomous regions and municipalities. This paper provides an overview to HIV/AIDS transmission through injection drug use in China. It begins with a brief history of the illicit drug trade in China, followed by a discussion of the emergence of drug related AIDS, and a profile of drug users and their sexual partners who have contracted the virus or who are vulnerable to infection. It ends by summarizing three national strategies being used by China to address both drug use and AIDS as major health threats.     

Live and Non-Live Pregnancy Outcomes among Women with Depression and Anxiety: A Population-Based Study

Background

Women taking antidepressant or anti-anxiety medications during early pregnancy have high risks of non-live pregnancy outcomes, although the contribution of the underlying illnesses to these risks remains unclear. We examined the impacts of antenatal depression and anxiety and of commonly prescribed treatments on the risks of non-live pregnancy outcomes.

Methods

We identified all pregnancies and their outcome (live birth, perinatal death, miscarriage or termination) among women aged 15–45 years between 1990 and 2009 from a large primary care database in the United Kingdom. Women were grouped according to whether they had no history of depression and anxiety, a diagnosis of such illness prior to pregnancy, illness during pregnancy and illness during pregnancy with use of medication (stratified by medication type). Multinomial logistic regression models were used to compare risks of non-live outcomes among these groups, adjusting for major socio-demographic and lifestyle characteristics.

Results

Among 512,574 pregnancies in 331,414 women, those with antenatal drug exposure showed the greatest increased risks for all non-live pregnancy outcomes, relative to those with no history of depression or anxiety, although women with prior (but not currently medicated) illness also showed modest increased risks. Compared with un-medicated antenatal morbidity, there was weak evidence of an excess risk in women taking tricyclic antidepressants, and stronger evidence for other medications.

Conclusions

Women with depression or anxiety have higher risks of miscarriage, perinatal death and decisions to terminate a pregnancy if prescribed psychotropic medication during early pregnancy than if not. Although underlying disease severity could also play a role, avoiding or reducing use of these drugs during early pregnancy may be advisable.     

Systematic review of exposure to albendazole or mebendazole during pregnancy and effects on maternal and child outcomes,with particular reference to exposure in the first trimester

Soil-transmitted helminth infections cause an important burden of morbidity worldwide, primarily from blood loss and malabsorption of nutrients. Where STH endemicity ≥20%, the World Health Organization (WHO) recommends preventive chemotherapy with single dose anthelminthic drugs: albendazole or mebendazole. Although WHO recommends that women of reproductive age, including pregnant women after the first trimester, be included in large-scale deworming programs, there are concerns related to the use of anthelminthic drugs during pregnancy, especially inadvertent use in the first few weeks when the pregnancy may not yet be confirmed. We therefore conducted a systematic review using the MEDLINE database with the aim of appraising all peer-reviewed evidence, published up to July 1, 2018, on the association between exposure to albendazole or mebendazole and outcomes in pregnant women, including those in the first trimester of pregnancy, and their children. From a yield of 205 papers based on titles alone, 58 papers, reporting results from 46 originator studies conducted in pregnant populations, constituted the initial evidence base. Among the nine originator observational studies which had included women in the first trimester of pregnancy within their study population, five compared birth outcomes between women exposed in the first trimester with women who were not exposed, and none reported higher rates of adverse birth outcomes in the exposed group. Due to heterogeneity in terms of study design, sample size, deworming drug, dosage and outcomes measured, data from these studies could not be pooled. Based on this cumulative evidence, it is unlikely that inadvertent exposure to albendazole or mebendazole in the first trimester carries an additional risk of adverse birth outcomes. To optimize relevance for policy making, future research in pregnant populations should aim to provide data disaggregated by trimester and to report on maternal and child adverse events, whenever possible.