Is Dolutegravir Safe for Use During Pregnancy

Is Dolutegravir safe for use during pregnancy?

Introduction

While avoidance of medications in pregnant women may be desirable, certain diseases and conditions such as HIV necessitate drug treatment during the gestational period. As women of reproductive age account for over half the 38 million people living with HIV worldwide [1], evaluating the safety of anti-retro viral (ARV) drugs in the mother, as well as the foetus is imperative. This includes careful evaluation of potential foetal drug exposure and subsequent harm, particularly when considering first trimester exposure when teratogenic drugs most frequently result in structural defects.[2] Furthermore, a mother’s body is subject to many physiological and anatomical changes during the gestational period that can influence drug pharmacokinetics and pharmacodynamics. As a result, dose adjustments or drug avoidance may be recommended for pregnant patients.

In 2018, the updated WHO interim guidelines [3] recommend dolutegravir (DTG)-based regimens as the preferred first- and second- line treatment for people initiating anti-retro viral therapy (ART). However, following a preliminary data review of the Tsepamo surveillance study,[4] caution for the use of DTG in women of reproductive age was advised due to a potential early signal for neural-tube defects associated with DTG exposure at conception. In light of such findings, there is urgent need for safety evaluations of DTG use during the preconception and gestational period.

The aim of this review is to determine if DTG is safe for use in pregnant women via assessment of (1) potential adverse effects on prenatal complications and (2) the effects on neonatal outcomes, embryo-foetal and postnatal development of the children born to mothers exposed to DTG during their pregnancy.

Search strategy

Following PRISMA guidelines for systematic reviews, electronic literature searches of the PubMed and Cochrane databases were conducted by a single author. This consisted of an advanced search utilising applicable medical subject headings (MeSH) terms and key words (see Appendix, Figure 1 and 2). Inclusion criteria, outlined in Appendix Table 1, were designed to reflect the PICO framework underpinning the research question. Results were limited to (1) human studies and reviews originally published in the English language and (2) publications dating from January 1st, 2014 to December 31st, 2019. No methodological limitations were applied due to the limited studies and reviews that have been conducted on the topic. Titles and abstracts were screened for relevance and duplicates removed before full text articles were obtained. If full text access was denied, papers were subsequently excluded from this review. A summary of the study selection process is displayed in Figure 1.

Figure 1. Study selection process

Findings

• Of the 49 papers meeting the inclusion criteria, based on their quality and relevancy, 5 were selected for use in this review. These consisted of 3 studies [5-7] reporting on a total of 5,676 pregnancies, a review [8] and a systematic review.[9] One paper was not identified via database searches but was identified from the reference list of a surveillance study included in this review. Table 1 summarises the main findings from each paper, while the main trends identified are discussed below.
• Despite a modest number of women exposed to DTG being included from studies in this review,[5-7] no increase in the rate of non-chromosomal congenital anomalies or major external structural malformations were observed. Their prevalence was not reported to differ from that in the general population or among mothers exposed to alternative ARV drugs e.g. efavirenz. These findings are consistent with the systematic review evaluating DTG use in pregnancy which showed no evidence of increased risk of adverse birth outcomes.[9]
• DTG treatment at the time of conception was associated with a higher incidence of major external structural abnormalities (9 per 1000 births) than with DTG treatment that was started during pregnancy (4 per 1000 births).[6]
• 40% higher median DTG concentrations were recorded in cord blood compared to maternal blood providing evidence of transplacental passage.[9]
• One study [5] reported a higher incidence of preeclampsia (8.3%) among their study population than was expected (3-4%), however, due to the small sample size no conclusions can be drawn from this. No other adverse maternofoetal outcomes that were reported deviated from the expected prevalence among the study populations.[5-7]
• All papers have relative risk of malformation values ≤1 indicating that the risk of malformation is not increased by exposure to DTG during pregnancy.[5-9]

Table 1. Papers reporting obstetric, neonatal and postnatal outcomes associated with DTG administration during pregnancy.

Paper/ study type	Number of deliveries/ pregnancies exposed to DTG	Timing of maternal DTG exposure	Number of deliveries with follow up data	Spontaneous abortions % (n)	Preterm deliveries % (n)	LBW % (n)	Malformations/ live-born children (%)	RR of malfor-mation	Prenatal complications	Additional notes
Retrospective cohort study [5]	36/ 36	At time of conception n=14. Initiated during pregnancy n=22.	35	0.11% (4)	0.03% (1)	0.03% (1)	0/ 30 (0.00%)	0.00	Maternal liver function was normal. Preterm delivery attributable to maternal preeclampsia and myelitis.	No gross malformations were reported. No increased maternal or infant morbidity. 1 termination was carried out and 1 lost to follow up.
Surveillance study [6]	5,523/ N/A	At time of conception n=1,683. Initiated during pregnancy n=3,840.	5,523	N/A	N/A	N/A	33/ 5,523 (0.01%)	0.00	N/A	6 neural tube defects reported. Prevalence of adverse birth outcomes associated with continuous dolutegravir exposure (33.2%) was comparable with continuous efavirenz exposure (35.0%)
Surveillance study [7]	117/ 117	At time of conception n=69. Initiated during pregnancy n=48.	117	0.00% (0)	N/A	N/A	4/ 117 (0.03%)	0.01	N/A	No neural tube defects reported among neonates born to mothers exposed to DTG at time of conception or during pregnancy.
Review [8]	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	DTG has high placental transfer. Insufficient data due to lack of completed studies to evaluate teratogenicity, dosing and efficacy during pregnancy.
Systematic review [9]	N/A/ 1,200	At time of conception n=. Initiated during pregnancy n=.	1,180	N/A	N/A	N/A	16/ 1,180 (1.36%)	0.62	N/A	No reported increase in risks of stillbirth, preterm birth, SGA or congenital anomalies, compared to historical control studies of ARV-treated pregnant women.

N/A= not available, DTG= Dolutegravir, LBW= low birth weight <2500g, RR= relative risk compared to European population, preterm delivery= <37 weeks.

Conclusion

No evidence of increased risk of negative maternal-foetal outcomes or negative effects on postnatal development of children born to mothers exposed DTG during pregnancy was observed. This, in combination with all papers having relative risk of malformation values ≤1 indicating that the risk of malformation is not increased by exposure to DTG during pregnancy, provides reassurance that DTG is not teratogenic. Thus, based on our review, DTG appears to be appropriate for use during pregnancy.

These preliminary findings should be interpreted with caution due to the small cumulative cohorts. Additionally, none of the papers included in this review were randomised clinical trials evaluating pregnancy outcomes of mothers taking DTG compared to other ARVs. This is attributable to pregnant women bring excluded from randomised DTG trials, so outcome data is not yet available. Furthermore, discrepancies between study designs result in different outcomes being reported in varying detail.

With WHO interim guidelines recommending DTG based first- and second- line ART regimens and the large proportion of women initiating ART being of reproductive age, continued pharmacovigilance is essential. However, it is reassuring that no further possible or clear safety signals have been detected, to date, for pregnant women treated with DTG in terms of birth outcomes or congenital anomalies. The evidence of transplacental transfer enhances the need to ensure foetal safety. Further studies are required to do this and to fully evaluate the safety profile for use of DTG during and/or throughout the gestational period.

References

1. Mirochnick M, Capparelli E. Pharmacokinetics of antiretrovirals in pregnant women. Clinical pharmacokinetics 2004; 43(15): 1071-87.
2. Gilbert-Barness, E. Teratogenic causes of malformations. Annals of Clinical & Laboratory Science 2010; 40(2): 99-11
3. 
   https://apps.who.int/iris/bitstream/handle/10665/277395/WHO-CDS-HIV-18.51-eng.pdf?ua=1
   
4. Zash R, Makhema J, Shapiro RL. Neural-Tube Defects with Dolutegravir Treatment from the Time of Conception. The New England journal of medicine 2018; 379(10): 979-981
5. Bornhede R, Soeria-Atmadja S, Westling K, Pettersson K, Navér L. Dolutegravir in pregnancy—effects on HIV-positive women and their infants. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology 2018; 37(3): 495-500
6. Zash R, Holmes L, Diseko M, Jacobson DL, Brummel S, Mayondi G et al. Neural-Tube Defects and Antiretroviral Treatment Regimens in Botswana. The New England journal of medicine 2019; 381(9): 827-840
7. Money D, Lee T, O’Brien C, Brophy J, Bitnun A, Kakkar F, et al. Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study. BJOG : an international journal of obstetrics and gynaecology 2019; 126(11): 1338-1345
8. Slogrove AL, Clayden P, Abrams EJ. Toward a universal antiretroviral regimen: special considerations of pregnancy and breast feeding. Current opinion in HIV and AIDS 2017; 12(4): 359-368
9. Hill A, Clayden P, Thorne C, Christie R, Zash R. Safety and pharmacokinetics of dolutegravir in HIV-positive pregnant women: a systematic review. Journal of virus eradication 2018; 4(2): 66-71

Appendix

Figure 1

. PubMed search criteria and number of hits.

Figure 2

. Cochrane search criteria and number of hits.

Table 1

. PICO framework for the inclusion criteria of literature review

	Inclusion criteria
Population	HIV positive pregnant women
Intervention	DTG administration during the gestational period. DTG as part of combination ART was accepted for inclusion
Comparison	Relative risk of malformation in population
Outcome	Adverse maternofoetal outcomes