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Concept: Pregnancy


Objectives To evaluate the existing evidence for associations between coffee consumption and multiple health outcomes.Design Umbrella review of the evidence across meta-analyses of observational and interventional studies of coffee consumption and any health outcome.Data sources PubMed, Embase, CINAHL, Cochrane Database of Systematic Reviews, and screening of references.Eligibility criteria for selecting studies Meta-analyses of both observational and interventional studies that examined the associations between coffee consumption and any health outcome in any adult population in all countries and all settings. Studies of genetic polymorphisms for coffee metabolism were excluded.Results The umbrella review identified 201 meta-analyses of observational research with 67 unique health outcomes and 17 meta-analyses of interventional research with nine unique outcomes. Coffee consumption was more often associated with benefit than harm for a range of health outcomes across exposures including high versus low, any versus none, and one extra cup a day. There was evidence of a non-linear association between consumption and some outcomes, with summary estimates indicating largest relative risk reduction at intakes of three to four cups a day versus none, including all cause mortality (relative risk 0.83, 95% confidence interval 0.83 to 0.88), cardiovascular mortality (0.81, 0.72 to 0.90), and cardiovascular disease (0.85, 0.80 to 0.90). High versus low consumption was associated with an 18% lower risk of incident cancer (0.82, 0.74 to 0.89). Consumption was also associated with a lower risk of several specific cancers and neurological, metabolic, and liver conditions. Harmful associations were largely nullified by adequate adjustment for smoking, except in pregnancy, where high versus low/no consumption was associated with low birth weight (odds ratio 1.31, 95% confidence interval 1.03 to 1.67), preterm birth in the first (1.22, 1.00 to 1.49) and second (1.12, 1.02 to 1.22) trimester, and pregnancy loss (1.46, 1.06 to 1.99). There was also an association between coffee drinking and risk of fracture in women but not in men.Conclusion Coffee consumption seems generally safe within usual levels of intake, with summary estimates indicating largest risk reduction for various health outcomes at three to four cups a day, and more likely to benefit health than harm. Robust randomised controlled trials are needed to understand whether the observed associations are causal. Importantly, outside of pregnancy, existing evidence suggests that coffee could be tested as an intervention without significant risk of causing harm. Women at increased risk of fracture should possibly be excluded.

Concepts: Pregnancy, Epidemiology, Medical statistics, Evidence-based medicine, Systematic review, Randomized controlled trial, Relative risk, Obstetrics


A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain.

Concepts: Pregnancy, Embryo, Fetus, Uterus, Infection, Cerebral cortex, Cerebellum, Gestational age


Background Zika virus (ZIKV) has been linked to neonatal microcephaly. To characterize the spectrum of ZIKV disease in pregnancy, we followed patients in Rio de Janeiro to describe clinical manifestations in mothers and repercussions of acute ZIKV infection in fetuses. Methods We enrolled pregnant women in whom a rash had developed within the previous 5 days and tested blood and urine specimens for ZIKV by reverse-transcriptase-polymerase-chain-reaction assays. We followed the women prospectively and collected clinical and ultrasonographic data. Results A total of 88 women were enrolled from September 2015 through February 2016; of these 88 women, 72 (82%) tested positive for ZIKV in blood, urine, or both. The timing of acute ZIKV infection ranged from 5 to 38 weeks of gestation. Predominant clinical features included pruritic descending macular or maculopapular rash, arthralgias, conjunctival injection, and headache; 28% had fever (short-term and low-grade). Women who were positive for ZIKV were more likely than those who were negative for the virus to have maculopapular rash (44% vs. 12%, P=0.02), conjunctival involvement (58% vs. 13%, P=0.002), and lymphadenopathy (40% vs. 7%, P=0.02). Fetal ultrasonography was performed in 42 ZIKV-positive women (58%) and in all ZIKV-negative women. Fetal abnormalities were detected by Doppler ultrasonography in 12 of the 42 ZIKV-positive women (29%) and in none of the 16 ZIKV-negative women. Adverse findings included fetal deaths at 36 and 38 weeks of gestation (2 fetuses), in utero growth restriction with or without microcephaly (5 fetuses), ventricular calcifications or other central nervous system (CNS) lesions (7 fetuses), and abnormal amniotic fluid volume or cerebral or umbilical artery flow (7 fetuses). To date, 8 of the 42 women in whom fetal ultrasonography was performed have delivered their babies, and the ultrasonographic findings have been confirmed. Conclusions Despite mild clinical symptoms, ZIKV infection during pregnancy appears to be associated with grave outcomes, including fetal death, placental insufficiency, fetal growth restriction, and CNS injury.

Concepts: Pregnancy, Embryo, Fetus, Uterus, Obstetrics, Medical ultrasonography, Gestational age, Amniotic fluid


Background Texas is one of several states that have barred Planned Parenthood affiliates from providing health care services with the use of public funds. After the federal government refused to allow (and courts blocked) the exclusion of Planned Parenthood affiliates from the Texas Medicaid fee-for-service family-planning program, Texas excluded them from a state-funded replacement program, effective January 1, 2013. We assessed rates of contraceptive-method provision, method continuation through the program, and childbirth covered by Medicaid before and after the Planned Parenthood exclusion. Methods We used all program claims from 2011 through 2014 to examine changes in the number of claims for contraceptives according to method for 2 years before and 2 years after the exclusion. Among women using injectable contraceptives at baseline, we observed rates of contraceptive continuation through the program and of childbirth covered by Medicaid. We used the difference-in-differences method to compare outcomes in counties with Planned Parenthood affiliates with outcomes in those without such affiliates. Results After the Planned Parenthood exclusion, there were estimated reductions in the number of claims from 1042 to 672 (relative reduction, 35.5%) for long-acting, reversible contraceptives and from 6832 to 4708 (relative reduction, 31.1%) for injectable contraceptives (P<0.001 for both comparisons). There was no significant change in the number of claims for short-acting hormonal contraceptive methods during this period. Among women using injectable contraceptives, the percentage of women who returned for a subsequent on-time contraceptive injection decreased from 56.9% among those whose subsequent injections were due before the exclusion to 37.7% among those whose subsequent injections were due after the exclusion in the counties with Planned Parenthood affiliates but increased from 54.9% to 58.5% in the counties without such affiliates (estimated difference in differences in counties with affiliates as compared with those without affiliates, -22.9 percentage points; P<0.001). During this period in counties with Planned Parenthood affiliates, the rate of childbirth covered by Medicaid increased by 1.9 percentage points (a relative increase of 27.1% from baseline) within 18 months after the claim (P=0.01). Conclusions The exclusion of Planned Parenthood affiliates from a state-funded replacement for a Medicaid fee-for-service program in Texas was associated with adverse changes in the provision of contraception. For women using injectable contraceptives, there was a reduction in the rate of contraceptive continuation and an increase in the rate of childbirth covered by Medicaid. (Funded by the Susan T. Buffett Foundation.).

Concepts: Pregnancy, Birth control, Emergency contraception, Hormonal contraception, Combined oral contraceptive pill, Menstrual cycle, Sex education, Combined injectable contraceptive


CDC has developed interim guidelines for health care providers in the United States caring for pregnant women during a Zika virus outbreak. These guidelines include recommendations for pregnant women considering travel to an area with Zika virus transmission and recommendations for screening, testing, and management of pregnant returning travelers. Updates on areas with ongoing Zika virus transmission are available online ( Health care providers should ask all pregnant women about recent travel. Pregnant women with a history of travel to an area with Zika virus transmission and who report two or more symptoms consistent with Zika virus disease (acute onset of fever, maculopapular rash, arthralgia, or conjunctivitis) during or within 2 weeks of travel, or who have ultrasound findings of fetal microcephaly or intracranial calcifications, should be tested for Zika virus infection in consultation with their state or local health department. Testing is not indicated for women without a travel history to an area with Zika virus transmission. In pregnant women with laboratory evidence of Zika virus infection, serial ultrasound examination should be considered to monitor fetal growth and anatomy and referral to a maternal-fetal medicine or infectious disease specialist with expertise in pregnancy management is recommended. There is no specific antiviral treatment for Zika virus; supportive care is recommended.

Concepts: Health care, Medicine, Pregnancy, Epidemiology, Disease, Infectious disease, Infection, Measles


This study compared fetal response to musical stimuli applied intravaginally (intravaginal music [IVM]) with application via emitters placed on the mother’s abdomen (abdominal music [ABM]). Responses were quantified by recording facial movements identified on 3D/4D ultrasound. One hundred and six normal pregnancies between 14 and 39 weeks of gestation were randomized to 3D/4D ultrasound with: (a) ABM with standard headphones (flute monody at 98.6 dB); (b) IVM with a specially designed device emitting the same monody at 53.7 dB; or © intravaginal vibration (IVV; 125 Hz) at 68 dB with the same device. Facial movements were quantified at baseline, during stimulation, and for 5 minutes after stimulation was discontinued. In fetuses at a gestational age of >16 weeks, IVM-elicited mouthing (MT) and tongue expulsion (TE) in 86.7% and 46.6% of fetuses, respectively, with significant differences when compared with ABM and IVV (p = 0.002 and p = 0.004, respectively). There were no changes from baseline in ABM and IVV. TE occurred ≥5 times in 5 minutes in 13.3% with IVM. IVM was related with higher occurrence of MT (odds ratio = 10.980; 95% confidence interval = 3.105-47.546) and TE (odds ratio = 10.943; 95% confidence interval = 2.568-77.037). The frequency of TE with IVM increased significantly with gestational age (p = 0.024). Fetuses at 16-39 weeks of gestation respond to intravaginally emitted music with repetitive MT and TE movements not observed with ABM or IVV. Our findings suggest that neural pathways participating in the auditory-motor system are developed as early as gestational week 16. These findings might contribute to diagnostic methods for prenatal hearing screening, and research into fetal neurological stimulation.

Concepts: Pregnancy, Embryo, Prenatal development, Fetus, Uterus, Obstetrics, Gestation, Gestational age


Zika virus is a cause of microcephaly and brain abnormalities (1), and it is the first known mosquito-borne infection to cause congenital anomalies in humans. The establishment of a comprehensive surveillance system to monitor pregnant women with Zika virus infection will provide data to further elucidate the full range of potential outcomes for fetuses and infants of mothers with asymptomatic and symptomatic Zika virus infection during pregnancy. In February 2016, Zika virus disease and congenital Zika virus infections became nationally notifiable conditions in the United States (2). Cases in pregnant women with laboratory evidence of Zika virus infection who have either 1) symptomatic infection or 2) asymptomatic infection with diagnosed complications of pregnancy can be reported as cases of Zika virus disease to ArboNET* (2), CDC’s national arboviral diseases surveillance system. Under existing interim guidelines from the Council for State and Territorial Epidemiologists (CSTE), asymptomatic Zika virus infections in pregnant women who do not have known pregnancy complications are not reportable. ArboNET does not currently include pregnancy surveillance information (e.g., gestational age or pregnancy exposures) or pregnancy outcomes. To understand the full impact of infection on the fetus and neonate, other systems are needed for reporting and active monitoring of pregnant women with laboratory evidence of possible Zika virus infection during pregnancy. Thus, in collaboration with state, local, tribal, and territorial health departments, CDC established two surveillance systems to monitor pregnancies and congenital outcomes among women with laboratory evidence of Zika virus infection(†) in the United States and territories: 1) the U.S. Zika Pregnancy Registry (USZPR),(§) which monitors pregnant women residing in U.S. states and all U.S. territories except Puerto Rico, and 2) the Zika Active Pregnancy Surveillance System (ZAPSS), which monitors pregnant women residing in Puerto Rico. As of May 12, 2016, the surveillance systems were monitoring 157 and 122 pregnant women with laboratory evidence of possible Zika virus infection from participating U.S. states and territories, respectively. Tracking and monitoring clinical presentation of Zika virus infection, all prenatal testing, and adverse consequences of Zika virus infection during pregnancy are critical to better characterize the risk for congenital infection, the performance of prenatal diagnostic testing, and the spectrum of adverse congenital outcomes. These data will improve clinical guidance, inform counseling messages for pregnant women, and facilitate planning for clinical and public health services for affected families.

Concepts: Pregnancy, Embryo, Fetus, United States, Obstetrics, U.S. state, Gestational age, Territories of the United States


Zika virus is causally linked with congenital microcephaly and may be associated with pregnancy loss. However, the mechanisms of Zika virus intrauterine transmission and replication and its tropism and persistence in tissues are poorly understood. We tested tissues from 52 case-patients: 8 infants with microcephaly who died and 44 women suspected of being infected with Zika virus during pregnancy. By reverse transcription PCR, tissues from 32 (62%) case-patients (brains from 8 infants with microcephaly and placental/fetal tissues from 24 women) were positive for Zika virus. In situ hybridization localized replicative Zika virus RNA in brains of 7 infants and in placentas of 9 women who had pregnancy losses during the first or second trimester. These findings demonstrate that Zika virus replicates and persists in fetal brains and placentas, providing direct evidence of its association with microcephaly. Tissue-based reverse transcription PCR extends the time frame of Zika virus detection in congenital and pregnancy-associated infections.

Concepts: DNA, Pregnancy, Molecular biology, Virus, RNA


In the third trimester of pregnancy, the human fetus has the capacity to process perceptual information [1-3]. With advances in 4D ultrasound technology, detailed assessment of fetal behavior [4] is now possible. Furthermore, modeling of intrauterine conditions has indicated a substantially greater luminance within the uterus than previously thought [5]. Consequently, light conveying perceptual content could be projected through the uterine wall and perceived by the fetus, dependent on how light interfaces with maternal tissue. We do know that human infants at birth show a preference to engage with a top-heavy, face-like stimulus when contrasted with all other forms of stimuli [6, 7]. However, the viability of performing such an experiment based on visual stimuli projected through the uterine wall with fetal participants is not currently known. We examined fetal head turns to visually presented upright and inverted face-like stimuli. Here we show that the fetus in the third trimester of pregnancy is more likely to engage with upright configural stimuli when contrasted to inverted visual stimuli, in a manner similar to results with newborn participants. The current study suggests that postnatal experience is not required for this preference. In addition, we describe a new method whereby it is possible to deliver specific visual stimuli to the fetus. This new technique provides an important new pathway for the assessment of prenatal visual perceptual capacities.

Concepts: Pregnancy, Childbirth, Infant, Embryo, Fetus, Uterus, Abortion, 3D ultrasound


In early 2015, an outbreak of Zika virus, a flavivirus transmitted by Aedes mosquitoes, was identified in northeast Brazil, an area where dengue virus was also circulating. By September, reports of an increase in the number of infants born with microcephaly in Zika virus-affected areas began to emerge, and Zika virus RNA was identified in the amniotic fluid of two women whose fetuses had been found to have microcephaly by prenatal ultrasound. The Brazil Ministry of Health (MoH) established a task force to investigate the possible association of microcephaly with Zika virus infection during pregnancy and a registry for incident microcephaly cases (head circumference ≥2 standard deviations [SD] below the mean for sex and gestational age at birth) and pregnancy outcomes among women suspected to have had Zika virus infection during pregnancy. Among a cohort of 35 infants with microcephaly born during August-October 2015 in eight of Brazil’s 26 states and reported to the registry, the mothers of all 35 had lived in or visited Zika virus-affected areas during pregnancy, 25 (71%) infants had severe microcephaly (head circumference >3 SD below the mean for sex and gestational age), 17 (49%) had at least one neurologic abnormality, and among 27 infants who had neuroimaging studies, all had abnormalities. Tests for other congenital infections were negative. All infants had a lumbar puncture as part of the evaluation and cerebrospinal fluid (CSF) samples were sent to a reference laboratory in Brazil for Zika virus testing; results are not yet available. Further studies are needed to confirm the association of microcephaly with Zika virus infection during pregnancy and to understand any other adverse pregnancy outcomes associated with Zika virus infection. Pregnant women in Zika virus-affected areas should protect themselves from mosquito bites by using air conditioning, screens, or nets when indoors, wearing long sleeves and pants, using permethrin-treated clothing and gear, and using insect repellents when outdoors. Pregnant and lactating women can use all U.S. Environmental Protection Agency (EPA)-registered insect repellents according to the product label.

Concepts: Pregnancy, Childbirth, Embryo, Fetus, Mosquito, Obstetrics, Dengue fever, Gestational age