Our results suggest, using several measures of symptom severity, that the preemptive use of Diclectin mitigated symptoms of severe NVP, as compared to the control group. Significantly less women receiving antiemetics preemptively experienced HG, and significantly more women in the preemptive group were symptom-free before the end of pregnancy, as compared to the control group. On average, women in the preemptive group needed similar doses of Diclectin to those of the control group; synthesizing these results, it appears that the preemptive use may allow early prevention of a vicious cycle of nausea and vomiting, possibly by preventing metabolic derangement and dehydration.
Women with NVP commonly report feeling unsupported by the medical community [20
]. Due to fears of teratogenicity, many physicians and pharmacists are hesitant to prescribe antiemetics to pregnant women, and even when they do, they often opt to use minimal doses rather than minimally-effective doses. Moreover, many physicians do not recognize the need to individualize therapy as per women's specific symptomatology. For example, large numbers of women exhibit symptoms of gastroesophageal reflux/indigestion, which are associated with more severe forms of NVP/HG and react favorably to H2 blockers or proton pump inhibitors [13
Acknowledging this void, in 1995 The Motherisk program established the first helpline dedicated to NVP, to ensure that women receive personalized evidence-based counseling. Through our experience with the NVP Helpline, we have realized unmet needs of women after experiencing severe forms of NVP, including HG. Typically, these women exhibit high levels of anxiety and great fear that they would repeat a similar adverse experience [1
The idea of using preemptive antiemetics for NVP stemmed from proven effectiveness of similar approaches in chemotherapy-induced nausea and vomiting, motion sickness, and cyclic vomiting [8
]. The present study aimed to test the hypothesis that preemptive use of antiemetics can mitigate the symptoms in women who have experienced severe NVP in their previous pregnancy.
In a prospective, nonrandomized study, 25 women who reported severe symptoms of NVP with or without HG in their previous pregnancy were recruited and counseled to commence the use of antiemetics as soon as they became aware of the present pregnancy and no later than the beginning of symptoms. They were followed up prospectively through the index pregnancy for symptoms of NVP and frequently counseled as to how to modify antiemetic doses based on symptoms. The comparison group consisted of randomly selected women also counseled by us for NVP, who had also had severe NVP in the previous pregnancy but who did not call before a planned pregnancy and thus could not be offered a preemptive therapy. The recruited women commenced the preemptive drug therapy for NVP before conception or up to 7 weeks' gestation, before the appearance of NVP symptoms. In comparison to the previous pregnancy, only eight of these 18 women experienced an HG again in the index pregnancy (P
= 0.01). In the comparison group (n
= 35), symptoms in the index pregnancy remained severe in 28 cases (80%), decreased to moderate in six (16.6%), and decreased to mild in five cases (13.9%). The preemptive group improved significantly compared to the control group (P
= 0.01). However, the two groups did not differ only in preemptive use of antiemetics, but also in the intensity and content of counseling, which was far superior in the preemptive prospective group. Moreover, patients could be treated with any antiemetic drug [7
Unlike our previous study [7
], we ensured that both arms of the study (those with and without preemptive use) receive identical counseling from the NVP Helpline counselors. We have selected the combination of delayed release doxylamine and pyridoxine (Diclectin), as its fetal safety has been proven in over 200,000 pregnant women [1
], and its effectiveness has been documented (originally in the 1970s, and reaffirmed in a recent randomized, blinded placebo control study) [23
It is conceivable that, by preemptively mitigating nausea and vomiting, this approach prevents the slippery slope of metabolic effects, including starvation, dehydration, acidosis, and electrolyte imbalance [24
]. Moreover, it is possible that it also prevents the conditioning of severe nausea and vomiting on subsequent symptoms, which is well described in chemotherapy-induced nausea and vomiting [25
] and in chronic pain [27
The women in the preemptive group tended to have more common HG in the previous pregnancy, making them potentially more recalcitrant to antiemetic therapy, yet they had significantly more reduction in the recurrence of HG in the present pregnancy. The control women reported more common headache and depressive/anxious symptoms in the index pregnancy. These may reflect more severe NVP symptoms due to less effective treatment. Depression by itself has not been shown to increase the likelihood of more common or more severe NVP [28
] and headaches are not uncommon in severe forms of NVP. The significantly longer time till resolution of NVP in the control group and their higher likelihood of HG as compared to their previous pregnancy are consistent with our findings of lower quality of life among women with higher PUQE scores.
This study documents the effectiveness of preemptive treatment of NVP in women who had experienced severe NVP in a previous pregnancy. This study has been extremely challenging in terms of recruitment and execution. Women had to have experienced severe NVP and/or HG in their previous pregnancy, agree to start preemptive antiemetic use, and participate in an intensive counseling and follow-up program. The women in both groups received a mean of 8 follow-up calls. Moreover, the physician caring for the woman had to be a part of the healthcare team. As evidenced by the characteristics of the women, they indeed represented the severe end of this condition.
Beyond the value of this specific protocol, our study highlights the need for personalized clinical approach to NVP, addressing the specific needs of women and the impact on their daily life. Counseling on dietary strategies, nonpharmacological and pharmacological treatment options, as well as treatment of concurrent conditions is essential for optimal management. Although the old approach that NVP may be a psychosomatic condition is fortunately not practiced anymore by most healthcare professionals, this condition is still being trivialized by many physicians, with women commonly feeling abandoned [20
]. It is beneficial for women to receive early treatment to help reduce the severity of symptoms in future pregnancies, hopefully preventing hospitalization and improving quality of life.
This study was performed in a unique clinic that is focused on the management of NVP. As such, we are contacted by women who had experienced severe NVP in their previous pregnancy and who approach us before symptoms started in the present pregnancy. A strength of the study is the standardization of all other aspects of nonpharmacological management, guided by evidence-based counseling. The PUQE score is validated against physical signs of NVP, including ability to swallow pills, urine output, and need for hospitalization [16
]. The study has a few limitations that should be acknowledged: because randomizing women who had had severe NVP in the previous pregnancy to receive placebo was not felt to be ethically acceptable by the research team, this was not a blinded study due to the ethical concerns using placebo in early pregnancy. However, both arms had identical numbers of follow-up encounters, strongly suggesting that lack of blinding did not result in investigators' bias toward one arm or another. This study is a foundation for future studies and discussion on the topic. If allowed by the IRB, future studies may try to randomize women to placebo during the first part of the trial, before symptoms emerge. The study focused on the very severe end of the NVP spectrum, evidenced by the rates of HG and the late gestational age at which the symptoms resolved. Hence, the generalizability of this study to milder forms of NVP will need to be addressed in future studies. However, it is the severely affected pregnant women, whose burden of illness has been poorly managed by the medical community. Despite conducting power calculations based on the primary endpoint, the total randomized numbers were relatively small, which may result in type 1 error in the difference of baseline characteristics between the two arms.
In conclusion, our study documents that the preemptive use of the delayed combination of doxylamine-pyridoxine among women who had experienced severe NVP in the previous pregnancy can mitigate symptom severity. More studies are needed to investigate the preemptive effectiveness of other antiemetic modalities, as well as the effectiveness in less severe cases of NVP.