scholarly journals In utero exposure to protease inhibitor-based antiretroviral regimens delays growth and developmental milestones in mice

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242513
Author(s):  
Ambalika Sarkar ◽  
Kayode Balogun ◽  
Monica S. Guzman Lenis ◽  
Sebastian Acosta ◽  
Howard T. Mount ◽  
...  
Keyword(s):  
Open Field ◽  
Somatic Growth ◽  
In Utero ◽  
Developmental Milestones ◽  
Human Infants ◽  
Developmental Milestone ◽  
Negative Geotaxis ◽  
Primitive Reflexes ◽  
Olfactory Test ◽  
In Pregnancy

Antiretroviral therapy (ART) in pregnancy has dramatically reduced HIV vertical transmission rates. Consequently, there is a growing number of children that are HIV exposed uninfected (CHEUs). Studies suggest that CHEUs exposed in utero to ART may experience developmental delays compared to their peers. We investigated the effects of in utero ART exposure on perinatal neurodevelopment in mice, through assessment of developmental milestones. Developmental milestone tests (parallel to reflex testing in human infants) are reflective of brain maturity and useful in predicting later behavioral outcomes. We hypothesized that ART in pregnancy alters the in utero environment and thereby alters developmental milestone outcomes in pups. Throughout pregnancy, dams were treated with boosted-atazanavir combined with either abacavir/lamivudine (ATV/r/ABC/3TC), or tenofovir/emtricitabine (ATV/r/TDF/FTC), or water as control. Pups were assessed daily for general somatic growth and on a battery of tests for primitive reflexes including surface-righting, negative-geotaxis, cliff-aversion, rooting, ear-twitch, auditory-reflex, forelimb-grasp, air-righting, behaviors in the neonatal open field, and olfactory test. In utero exposure to either ART regimen delayed somatic growth in offspring and evoked significant delays in the development of negative geotaxis, cliff-aversion, and ear-twitch reflexes. Exposure to ATV/r/ABC/3TC was also associated with olfactory deficits in male and forelimb grasp deficits in female pups. To explore whether delays persisted into adulthood we assessed performance in the open field test. We observed no significant differences between treatment arm for males. In females, ATV/r/TDF/FTC exposure was associated with lower total distance travelled and less ambulatory time in the centre, while ATV/r/ABC/3TC exposure was associated with higher resting times compared to controls. In utero PI-based ART exposure delays the appearance of primitive reflexes that involve vestibular and sensory-motor pathways in a mouse model. Our findings suggest that ART could be disrupting the normal progress/maturation of the underlying neurocircuits and encourage further investigation for underlying mechanisms.

scholarly journals Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat

2004 ◽  
Vol 287 (2) ◽  
pp. R375-R385 ◽  
Author(s):  
Charles R. Neal ◽  
Gabrielle Weidemann ◽  
Mohamed Kabbaj ◽  
Delia M. Vázquez
Keyword(s):  
Open Field ◽  
Neonatal Intensive Care ◽  
Somatic Growth ◽  
Stress Axis ◽  
Human Infants ◽  
Neurodevelopmental Delay ◽  
Adult Rat ◽  
Physical Maturation ◽  
Corticosterone Response

Until recently, the synthetic glucocorticoid dexamethasone was commonly used to lessen the morbidity of chronic lung disease in premature infants. This practice diminished as dexamethasone use was linked to an increased incidence of cerebral palsy and short-term neurodevelopmental delay. Of more concern is the fact that we know little regarding dexamethasone effects on long-term neurodevelopment. To study the effects of neonatal dexamethasone exposure on long-term neurodevelopment, we have developed a rat model where newborn pups are exposed to tapering doses of dexamethasone at time points corresponding to the neurodevelopmental age when human infants are traditionally exposed to this drug in the neonatal intensive care unit. Using a within-litter design, pups were assigned to one of three groups on postnatal day 2 (P2): handled controls, saline-injected controls, and animals receiving intramuscular dexamethasone between P3 and P6. Somatic growth was decreased in dexamethasone-treated animals. Dexamethasone-treated animals demonstrated slight delays in indexes of neurodevelopment and physical maturation at P7 and P14, but not P20. In adolescence (P45), there was no difference between groups in an open field test. However, as adult dexamethasone-treated animals were less active in the open field and spent more time in closed arms of the elevated plus maze. The serum corticosterone response to crowding stress in dexamethasone-treated animals was no different from controls, but they demonstrate a delay in return of corticosterone levels to baseline. These differences in behavior and hormonal stress responsiveness suggest that neonatal dexamethasone exposure may permanently alter function of the neuroendocrine stress axis.

Vertebral malformation in the mouse foetus caused by X-radiation of the mother during pregnancy

Development ◽  
1964 ◽  
Vol 12 (4) ◽  
pp. 841-850
Author(s):  
Ujihiro Murakami ◽  
Yoshiro Kameyama
Keyword(s):  
Early Pregnancy ◽  
Vertebral Column ◽  
Strain Differences ◽  
In Utero ◽  
Oxygen Deprivation ◽  
Experimental Animals ◽  
Vertebral Malformation ◽  
Pregnant Mice ◽  
Maternal Hypoxia ◽  
In Pregnancy

Maternal hypoxia in early pregnancy can result in malformations of the vertebrae of mouse foetuses, and there is a tendency for more posterior vertebrae to be affected the later in pregnancy the oxygen deprivation occurs (Murakami & Kameyama, 1963). Ingalls et al. (1957) and Degenhardt (1954, 1959) had earlier obtained similar results. We have also exposed pregnant mice to X-radiation and studied the consequent malformations. The effects on the extremities have already been described (Murakami, Kameyama & Nogami, 1963), and in the present paper we shall describe the effects on the vertebral column. Vertebral malformations in animals irradiated in utero have been described by Job, Leibold & Fitzmaurice (1935), Warkany and Schraffenberger (1947), Russell. (1950, 1954), and Russell & Russell (1954). In order to obtain results comparable with those of our experiments with hypoxia, no less than to detect inter-strain differences, we used mice of the ddN and CF1 strains originally supplied by the Central Laboratories for Experimental Animals, Tokyo (Zikkendobutsu Chuo Kenkyujo).

Neurodevelopment following exposure to antiseizure medications in utero: a review

2021 ◽  
Vol 19 ◽  
Author(s):  
Rebecca L Bromley ◽  
Matthew Bluett-Duncan
Keyword(s):  
Lower Risk ◽  
In Utero ◽  
Neurodevelopmental Outcomes ◽  
Unexposed Control ◽  
Long Period ◽  
Risks And Benefits ◽  
Limited Experience ◽  
Potential Impact ◽  
Child's Brain ◽  
In Pregnancy

: Exposure in the womb to antiseizure medications and their potential impact on the developing child's brain has long been researched. Despite this long period of interest, this review highlights above the well-known risks associated with valproate exposure; more data is required for conclusions regarding all other antiseizure medications. Limited experience with phenytoin and phenobarbital in monotherapy clearly defines the risk to later child postnatal functioning difficult. However, the evidence of an impact is stronger for phenobarbital than for phenytoin. The widely prescribed lamotrigine is limited in its investigation compared to unexposed control children. It has been demonstrated to carry a lower risk than valproate for specific outcomes; whether associated with a more moderate impact on broader aspects of neurodevelopmental functioning is still to be understood. Data for levetiracetam, topiramate, and oxcarbazepine are too limited to conclude most neurodevelopmental outcomes confidently. This slow accumulation of evidence impacts the safest use of medications in pregnancy and makes counseling women regarding the risks and benefits of specific antiseizure drugs difficult. Improved focus, funding, and research methodologies are urgently needed.

Coronal Craniostenosis: Fetal Head Constraint as One Possible Cause

PEDIATRICS ◽  
1980 ◽  
Vol 65 (5) ◽  
pp. 995-999 ◽  
Author(s):  
John M. Graham ◽  
Richard J. Badura ◽  
David W. Smith
Keyword(s):  
Retrospective Study ◽  
In Utero ◽  
Foot Deformities ◽  
Coronal Suture ◽  
Fetal Head ◽  
Normal Children ◽  
Possible Cause ◽  
In Pregnancy

A retrospective study of 11 instances of idiopathic coronal craniostenosis in otherwise normal children revealed that early lightening, prolonged moderate to severe pelvic discomfort late in pregnancy, and/or an abnormal fetal lie were unusual gestational features indicative of intrauterine constraint for eight of these patients. The impression of unusual constraint in utero was futher implied by finding associated positional foot deformities in four of these latter eight children. We hypothesize that prolonged constraint of the fetal head may limit anteroposterior growth stretch at the coronal suture and thereby predispose toward early sutural fusion.

scholarly journals Gadolinium Chelate Safety in Pregnancy: Barely Detectable Gadolinium Levels in the Juvenile Nonhuman Primate after in Utero Exposure

Radiology ◽  
2018 ◽  
Vol 286 (1) ◽  
pp. 122-128 ◽  
Author(s):  
Joao Prola-Netto ◽  
Mark Woods ◽  
Victoria H. J. Roberts ◽  
Elinor L. Sullivan ◽  
Christina Ann Miller ◽  
...  
Keyword(s):  
Nonhuman Primate ◽  
In Utero ◽  
In Utero Exposure ◽  
Gadolinium Chelate ◽  
In Pregnancy

Cancer in pregnancy: To treat or not?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e12533-e12533
Author(s):  
Elaine Walsh ◽  
Grainne O'Kane ◽  
Karen Anne Cadoo ◽  
Donna M. Graham ◽  
Grzegorz Korpanty ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Post Partum ◽  
In Utero ◽  
Adverse Outcomes ◽  
Cytotoxic Agents ◽  
Normal Delivery ◽  
Cancer In Pregnancy ◽  
Disease Free ◽  
In Pregnancy

e12533 Background: Cancer in pregnancy accounts for ~1 in 1,000 pregnancies. Studies show that cytotoxic agents are safe from the second trimester. Long-term follow up has not shown increased malformations or malignancies in children exposed to chemotherapy in utero. There is no evidence of worse outcomes among women diagnosed in pregnancy. Methods: We retrospectively identified women diagnosed with cancer in pregnancy over a 25-year period. Medical records were reviewed for demographics, diagnosis, gestation, timing of treatment and outcomes. We assessed if all cancers need to be treated in pregnancy or if treatment could be safely deferred to allow normal delivery. Results: Twenty-five women were diagnosed with cancer in pregnancy and referred to medical oncology. Of 25 women, 16 (64%) received chemotherapy during pregnancy. These included 13 cases of breast cancer, one Ewing’s sarcoma, one ovarian cancer, and one small cell of cervix. All 16 women received doxorubicin and cyclophosphamide. There were 15 live births and no abnormalities seen in children who received chemotherapy in utero. At a median follow-up of 6 years 11 mothers (69%) are disease free and 4 (25%) have recurrent disease. Of nine mothers who did not receive chemotherapy in pregnancy, seven received chemotherapy immediately post-partum. Six (86%) were diagnosed in early pregnancy (median gestation 13 weeks). There were three cases of Hodgkin lymphoma, two breast cancers, and one ovarian cancer. At a median follow-up of 12 years, all mothers remain disease free. There were no abnormalities seen in these children. Conclusions: We did not identify any adverse outcomes in mothers or infants exposed to chemotherapy during pregnancy. We identified a cohort of patients that do not need immediate treatment during pregnancy. In selected cases, it is safe and appropriate to delay chemotherapy until delivery of the baby. There were no adverse outcomes to mothers due to delayed treatment and no adverse outcomes to babies not exposed to chemotherapy in utero. A multi-disciplinary team is essential to individualize treatment planning. [Table: see text]

scholarly journals Effects of in utero heat stress on subsequent reproduction performance of first-calf Holstein heifers

2020 ◽  
Vol 18 (2) ◽  
pp. e0404
Author(s):  
María I. Chavez ◽  
José E. García ◽  
Francisco G. Véliz ◽  
Leticia R. Gaytán ◽  
Ángeles De Santiago ◽  
...  
Keyword(s):  
Heat Stress ◽  
Pregnancy Rate ◽  
Reproductive Performance ◽  
Fold Increase ◽  
In Utero ◽  
Northern Mexico ◽  
Reproduction Performance ◽  
In Pregnancy

Aim of study: To determine the reproductive performance of heifers gestated under maternal conditions of heat stress in late gestation.Area of study: Northern Mexico (25° 32’ N, 103° 23’ W).Material and methods: The study included reproductive records of 4976 first-calf Holstein heifers in a hot environment.Main results: Heifers born to cows experiencing no heat stress three months before parturition but with a THI >83 at calving were older (p<0.05) at first calving (743 ± 67 vs. 729 ± 55 days) than heifers gestated under maternal conditions of heat stress. A two-fold increase (p<0.01) in pregnancy rate occurred in heifers gestated under maternal conditions of no heat stress during two or three months before pregnancy and no heat stress at parturition, compared with heifers gestated under maternal conditions of no heat stress. Overall, across in utero heat stress one, two or three months before calving, pregnancy rate to all services was higher (p<0.05) for first-calf heifers gestated under maternal conditions of no heat stress during delivery, compared with heifers gestated under maternal conditions of heat stress (66.7 vs. 51.1%). Median days for getting pregnant was higher (140 d) for heifers whose dams were exposed to THI >83 at calving than heifers whose mothers were exposed to <76 or 76-83 (117 and 114 d) at calving.Research highlights: These data suggest that in utero heat stress during the last three months of gestation negatively affects the reproductive performance of first-calf Holstein heifers.

scholarly journals Lower Birth Weight-for-age and Length-for-age Z-scores in Infants With in-utero HIV and ART Exposure: A Prospective Study in Cape Town, South Africa

2020 ◽  
Author(s):  
Dorothy Chiwoniso Nyemba ◽  
Emma Kalk ◽  
Hlengiwe P. Madlala ◽  
Thokozile R. Malaba ◽  
Amy L. Slogrove ◽  
...  
Keyword(s):  
South Africa ◽  
Scale Up ◽  
Cape Town ◽  
In Utero ◽  
Women Living With Hiv ◽  
Z Scores ◽  
Hiv Exposed ◽  
Hiv Acquisition ◽  
Weight For Age ◽  
In Pregnancy

Abstract Background: Successful scale-up of antiretroviral therapy (ART) during pregnancy has minimized infant HIV acquisition, and over 1 million infants are born HIV-exposed but uninfected (HEU), with an increasing proportion also exposed in utero to maternal ART. While benefits of ART in pregnancy outweigh risks, some studies have reported associations between in utero ART exposure and impaired fetal growth, highlighting the need to identify the safest ART regimens for use in pregnancy. Methods: We compared birth anthropometrics of infants who were HEU with those HIV-unexposed (HU) in Cape Town, South Africa. Pregnant women had gestational age assessed by ultrasound at enrolment. Women living with HIV were on ART (predominately tenofovir-emtricitabine-efavirenz) either prior to conception or initiated during pregnancy. Birth weights and lengths were converted to weight-for-age (WAZ) and length-for-age (LAZ) z-scores using Intergrowth-21st software. Linear regression was used to compare mean z-scores adjusting for maternal and pregnancy characteristics. Results: Among 888 infants, 49% (n=431) were HEU and 51% (n=457) HU. Of 431 HEU infants, 62% (n=268) were exposed to HIV and antiretroviral (ARVs) from conception and 38% (n=163) were exposed to ARVs during gestation but after conception (median fetal ARV exposure of 21 weeks [IQR; 17-26]). In univariable analysis, infants who were HEU had lower mean WAZ compared with HU [β= -0.15 (95% Confidence Interval (CI): -0.28, -0.020)]. After adjustment for maternal age, gravidity, alcohol use, marital and employment status the effect remained [adjusted β -0.14 (95%CI: -0.28, -0.01]. Similar differences were noted for mean LAZ in univariable [β -0.20 (95%CI: -0.42, -0.01] but not multivariable analyses [adjusted β -0.18 (95%CI: -0.41, +0.04] after adjusting for the same variables. Mean WAZ and LAZ did not vary by in utero ARV exposure duration among infants who were HEU. Conclusion: In a cohort with high prevalence of ART exposure in pregnancy, infants who were HEU had lower birth WAZ compared with those HU. Studies designed to identify the mechanisms and clinical significance of these disparities, and to establish the safest ART for use in pregnancy are urgently needed.

scholarly journals Elevated Anthropometric and Metabolic Indicators among Young Adult Offspring of Mothers with Pregestational Diabetes: Early Results from the Transgenerational Effect on Adult Morbidity Study (the TEAM Study)

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Katherine Bowers ◽  
Shelley Ehrlich ◽  
Lawrence M. Dolan ◽  
Resmi Gupta ◽  
Mekibib Altaye ◽  
...  
Keyword(s):  
Young Adult ◽  
In Utero ◽  
Adult Offspring ◽  
Diabetes In Pregnancy ◽  
Pregestational Diabetes ◽  
Metabolic Outcomes ◽  
Early Results ◽  
Increased Risk ◽  
Maternal Glucose ◽  
In Pregnancy

Exposure to maternal diabetes in utero increases the risk in the offspring for a range of metabolic disturbances. However, the timing and variability of in utero hyperglycemic exposure necessary to cause impairment have not been elucidated. The TEAM Study was initiated to evaluate young adult offspring of mothers with pregestational diabetes mellitus. This paper outlines the unique enrollment challenges of the TEAM Study and preliminary analysis of the association between exposure to diabetes in pregnancy and adverse metabolic outcomes. The TEAM Study enrolls offspring of women who participated in a Diabetes in Pregnancy (DiP) Program Project Grant between 1978 and 1995. The DiP Study collected medical and obstetric data across pregnancy. The first 96 eligible offspring of women with pregestational diabetes were age-, sex-, and race-matched to adults from the National Health and Nutrition Examination Survey (NHANES) 2015-2016 with an OGTT. Descriptive and regression analyses were employed to compare TEAM participants to NHANES participants. Among a subset of TEAM participants, we compared the metabolic outcomes across maternal glucose profiles using a longitudinal data clustering technique that characterizes level and variability, in maternal glucose across pregnancy. By comparing categories of BMI, TEAM Study participants had over 2.0 times the odds of being obese compared to matched NHANES participants (for class III obesity, OR = 2.81 ; 95% confidence interval (CI): 1.15, 6.87). Increasing levels of two-hour glucose were also associated with in utero exposure to pregestational diabetes in matched analyses. Exposure to pregestational diabetes in utero may be associated with an increased risk of metabolic impairment in the offspring with clinical implications.

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