Introduction
Four trials65,84,95,117 assessed the effectiveness of vitamin B6 in combination with doxylamine for the treatment of NVP in comparison with a placebo (Koren and colleagues84), ondansetron (Capp and colleagues65 and Oliveira and colleagues95) or when administered pre-emptively versus following symptom onset (Maltepe and Koren117). In the Koren and colleagues84 and Maltepe and Koren117 studies this took the form of Diclectin (delayed-release doxylamine/pyridoxine combination), while Oliveira and colleagues95 and Capp and colleagues65 gave pyridoxine and doxylamine as separate preparations.
One of the trials95 was only available in abstract form and risk of bias was unclear, whereas the trial of Koren and colleagues84 was at a low risk of bias. Another trial117 examined pre-emptive treatment with Diclectin and this trial appeared to be at low risk of bias but some items were unclear. Capp and colleagues65 was at unclear risk of bias due to lack of provided details across a number of measures.65 The reporting of severity of symptoms was not possible for the Maltepe and Koren117 pre-emptive study, poor for the Oliveira and colleagues95 study and unclear for the Capp and colleagues65 study, but in the Koren and colleagues84 study, severity appeared to range from mild to moderate. As previously described (see Chapter 3, Meta-analysis of included randomised controlled trials), given the differences between trials in patient populations, settings, interventions and, in particular, the heterogeneous nature of the reported outcomes across trials, we did not attempt to perform meta-analyses, and have thus reported a narrative summary only for each intervention and comparator set.
We also identified a non-randomised prospective observational study (Ashkenazi-Hoffnung and colleagues36) which compared a combination regimen of doxylamine and pyridoxine versus metoclopramide only (control group). This study is prone to extreme selection bias and there was a noticeable difference at baseline: moderate to severe symptoms were present in 97% of the intervention group women versus 69% of control group women (p < 0.01). A summary of study conduct and results is depicted in for completeness.
Results for pyridoxine-doxylamine interventions for NVP
Doxylamine/pyridoxine versus placebo
One double-blind, multicentre placebo-controlled trial84 compared treatment with Diclectin, a combination preparation of doxylamine succinate (10 mg) and pyridoxine hydrochloride (10 mg), to placebo in women with symptoms of NVP and a PUQE score ≥ 7. Women in the trial had not previously responded to conservative management.
Pregnancy-Unique Quantification of Emesis and Nausea scale
Diclectin led to significantly greater improvement in NVP symptoms as compared with placebo (PUQE score: –4.8 ± 2.7 vs. 3.9 ± 2.6; p = 0.006). The mean area under the curve of the change in PUQE from baseline as measured day-by-day was significantly larger with Diclectin compared with placebo (61.5 ± 36.9 in the Diclectin group vs. 53.5 ± 37.5 in the placebo group; p < 0.001).
Nausea outcomes
No independent nausea outcomes reported.
Vomiting outcomes
No independent vomiting outcomes reported.
Retching outcomes
No independent retching outcomes reported.
Safety outcomes
Koren and colleagues84 did not report on pregnancy outcomes or adverse events. UKTIS data on doxylamine/pyridoxine combination treatment are provided in Appendix 7.
Doxylamine/pyridoxine versus ondansetron
The double-blind RCT of Oliveira and colleagues95 was in abstract form only and randomised women in the first trimester of pregnancy requesting treatment for NVP to either one tablet of ondansetron (4 mg) plus a second (placebo) tablet or one tablet of pyridoxine (25 mg) plus one tablet of doxylamine (12.5 mg) administered every 8 hours for 5 days.95 All study medications were identical in appearance. Capp and colleagues65 also compared 4-mg ondansetron plus a placebo tablet administered every 8 hours for 5 days against 25-mg pyridoxine plus 12.5-mg doxylamine.65
Combined severity score
No combined score reported.
Nausea outcomes
Oliveira and colleagues95 found a significantly greater mean reduction in nausea (p = 0.02) using the VAS in patients using ondansetron (56 ± 15 mm) compared with those taking pyridoxine plus doxylamine (27 ± 29 mm). A significant difference in favour of ondansetron was also reported by Capp and colleagues.65 However, no detailed scores were provided as the paper was in abstract form only (p < 0.05).
Vomiting outcomes
There was no significant difference in vomiting between the two groups reported by Oliveira and colleagues95 (28 ± 25 mm for ondansetron vs. 10 ± 31 mm for pyridoxine plus doxylamine; p = 0.38). However, Capp and colleagues65 found a significant improvement in the ondansetron groups in terms of reduction in vomiting using the VAS (p < 0.05), although, as with nausea scores, no exact values were reported in the abstract.
Retching outcomes
No independent retching outcomes reported.
Safety outcomes
Oliveira and colleagues95 did not report on pregnancy outcomes or adverse events. The trial of Capp and colleagues65 did not report on pregnancy outcomes either but found no statistically significant difference between groups with respect to sedation or constipation (p > 0.05) (see Appendix 8). UKTIS data on doxylamine/pyridoxine combination treatment are provided in Appendix 7.
Pre-emptive doxylamine/pyridoxine
One RCT117 compared pre-emptive treatment with Diclectin before the onset of symptoms of NVP, versus when the symptoms first began in patients at high risk for recurrence of severe NVP.
Pregnancy-Unique Quantification of Emesis and Nausea scale
In the pre-emptive group there were 70% fewer cases of moderate–severe NVP (PUQE score of ≥ 11) compared with the control group [4/26 (15.4%) vs. 9/23 (39.13%)] during the first 3 weeks of NVP (p = 0.05). In addition, in the pre-emptive group there was a 43% reduction in HG between the previous pregnancy (19/30) and the present one (6/30) compared with a 17% reduction (from 11/29 to 6/29) in the control group (p = 0.047).
Nausea outcomes
No independent nausea outcomes reported.
Vomiting outcomes
No independent vomiting outcomes reported.
Retching outcomes
No independent retching outcomes reported.
Safety outcomes
The trial of Maltepe and Koren117 did not report either pregnancy outcomes or adverse events. UKTIS data on doxylamine/pyridoxine combination treatment are provided in Appendix 7.
Summary
The evidence available for pyridoxine/doxylamine combinations is varied, but two trials appeared to be at low risk of bias
84,117 with the other two having an unclear risk of bias profile.
65,95The quality of the evidence is low and was downgraded due to clinical heterogeneity and sparseness of data in most comparisons. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates.
Diclectin appears to be more effective at relieving symptoms of NVP than placebo.
Ondansetron appears more effective at reducing nausea than pyridoxine plus doxylamine but there was no difference for vomiting.
Limited data from a single small study
36 showed no difference in efficacy between pyridoxine plus vitamin B6 versus metoclopramide but was subject to selection bias.
Pre-emptive treatment with Diclectin appears to result in a reduced risk of moderate/severe NVP compared with treatment initiation once symptoms begin.
Further larger, well-conducted trials are required to test the effectiveness of Diclectin or pyridoxine/doxylamine in combination compared with other treatment options.
