treatment of acute migraine attacks, 1,000 mg of paracetamol (acetaminophen), preferably as a suppository, is considered the first-choice drug treatment. The risks associated with use of aspirin and NSAIDs are considered to be small when the agents are taken episodically and if they are avoided during the last trimester of pregnancy (risks of maternal or fetal bleeding and premature closure of the fetal ductus arterio- sus). There is limited evidence about triptan safety during pregnancy, therefore they should be avoided in these patients. DHE and ergotamine are contraindicated in women who are pregnant. Prochlorperazine and promethazine hydrochloride for treatment of nausea are unlikely to be harmful during pregnancy. Metoclopramide is probably acceptable to use during the second and third trimesters. Domperidone is also safe in pregnant women. Prophylactic treatment is rarely indicated because of potential teratogenicity. When pro- phylactic treatment is used, beta-blockers are the preferred treatment (stopping 2 weeks before partum). 77–79 Ondanse-
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Nausea and vomiting are the most prevalent and prob- ably the most unpleasant complications in pregnancy. It is reported by 50% to 80% of pregnant women (1). There is no known cause for this problem; however, hormonal changes as well as psychological factors may play a role in this con- dition (2). Approximately, a quarter of all pregnant women have to leave their work because of this problem (3). In less than 2% of cases, this problem escalates to severe nausea and vomiting (hyperemesis gravidarum), and that leads to an im- balance of water and electrolytes, malnutrition, and loss of 5% of body weight (4). This condition may result in the mal- function of different body systems and organs, including the kidneys, and an imbalance of water and electrolytes. In addi- tion, it may also have adverse effects on the fetus (5). Nausea and vomiting in pregnancy (NVP) may lead to depression, feelings of incompetence, loss of work hours, hospitalization and termination of the pregnancy (6). For this reason, an ef-
and all seem to be safe for use in pregnancy [7-10]. How- ever, response to these medications in the treatment of NVP is highly variable [7,11-13]. While pharmacologic intervention may ameliorate symptoms in many women, some women improve dramatically while others continue to experience severe NVP despite treatment. As such, pharmacogenetic polymorphisms become an important consideration in evaluating variability in responsiveness to pharmacologic intervention. Many antiemetics are sub- strates for serotonin receptors and transporters—which are known to have clinically relevant genetic polymor- phisms. Previous studies have shown that variations in the HTR3B gene predict the efficacy of antiemetics in cancer patients  and the occurrence of selective serotonin reuptake inhibitor (SSRI)-induced nausea . However, there have been limited studies which have investigated the effects of the serotonin receptor gene polymorphisms on the efficacy of antiemetics used in the treatment of NVP .
Nausea and vomiting during pregnancy (NVP) is expe- rienced by approximately 70 to 80% of pregnant women . The timing, frequency, and duration of NVP varies between women and, in its most extreme form (hyper- emesis gravidarum), is characterized by severe and per- sistent nausea and vomiting that results in a significant loss in body weight . While NVP is known to involve a heritable component [15, 16], the biological mecha- nisms underpinning the maternal experience of severe NVP are thought to involve the dysregulation of mater- nal human chorionic gonadotropin (hCG), thyroid hor- mones (particularly thyroxine and thyroid-stimulating hormone), and estrogens [14, 17]. There are a number of reasons to hypothesize a link between NVP and the ASD phenotype among offspring. First, women who ex- perience hyperemesis gravidarum have a greater risk of having a child with behavioral and neurodevelopmental conditions [18, 19]. While no study has been sufficiently powered to investigate offspring risk for ASD, an in- creased risk has been observed for common neurodeve- lopmental comorbidities for ASD, such as intellectual disability, developmental language disorder, and atten- tional deficit hyperactivity disorder . Second, differ- ential levels of hCG during pregnancy have been associated with later ASD in offspring. A recent study of Californian state records examined the association be- tween hCG levels during pregnancy (collected for rou- tine screening between 15 and 20 weeks ’ pregnancy) and the prevalence of ASD among offspring . An in- creased risk of offspring ASD was identified for women with the highest and lowest decile of hCG concentration distribution, suggesting a link between atypical hCG regula- tion and offspring ASD. Third, a number of large studies have identified an association between maternal auto- immune thyroid disease during pregnancy and risk for ASD [22, 23], with a recent meta-analysis reporting a pooled odds ratio of 1.29 (95% confidence interval 1.14 – 1.45) .
commonly used for NVP and was the only drug ap- proved by the FDA until the manufacturer’s voluntary removal of it from the market in 1983 . In 1983  and 1999 , the FDA determined that this drug com- bination was not withdrawn from sale for reasons of safety and effectiveness. In fact, its removal from the American market was temporally associated with a 2- fold increase in rates of hospitalization of pregnant women for the most severe form of NVP, hyperemesis gravidarum [6,7]. Over the last 3 decades a large body of evidence corroborated the fetal safety of this drug com- bination [8,9].
Dealing with the significance of this issue is because women with mild to moderate NVP experience suffer depression, reduced function of employment, home activity, parental roles, and other physical and social activities. NVP increases the cost and use of health care resources. In addition, in some cases, pregnant women decide to terminate their pregnancy due to the complications of these symptoms . It has been shown that preterm birth in the group with severe longing is clearly more prevalent than the patients with mild longing . The risk factors for NVP include low maternal age, first pregnancy, female embryo, and twins . In other studies, fetal abnormalities, history of nausea and vomiting in the previous pregnancy are related to mental and psychological conditions of the individuals, and the increase and decrease in BMI before pregnancy and the economic and social status associated with NVP . Overall, the most important and commonly used NVP treatments include non-pharmaceutical treatments, such as special diets and the use of medication treatments. The popularity of complementary and alternative medicine, such as non-pharmaceutical treatments and herbal extracts has grown significantly in recent years, and the prevalence of using complementary and alternative therapies during pregnancy have been significant. In Iranian traditional medicine, one of the common treatments for NVP has been the use of ginger . Ginger is an herb used in traditional medicine to treat all types of nausea and vomiting, such as NVP . The precise mechanism of ginger as an anti-nausea and vomiting agent has not been completely known. Ginger seems to control the mechanism of the transmission of serotonin messages at the gastrointestinal system  that can be due to its direct effect on the intestinal duct. Its antiemetic effect through the central nervous system is debatable because there are compounds in ginger that inhibit type 3 serotonin receptors that have not been known well .
This randomized, single-center, open, crossover study was conducted in Wunstorf, Germany, from November 2013 to March 2015 (trial registration no DRKS00009679 in the German Clinical Trials Register). Pregnant women aged 18 years and with mild to moderate NVP were eligible to participate. Exclusion criteria included severe hyperem- esis; a history of thrombosis, edema, or skin changes typical of chronic venous insufficiency; no palpable arterial pulses, deep, or superficial reflux on ultrasound; requirement for custom-made stockings; regular prior use of compression stockings; and inability to read and complete a questionnaire in German. Women who reported leg pain were referred for specialist medical advice to rule out venous disorders. The study was approved by the Ethics Committee of the Medical Chamber of Lower Saxony (BO/28/2013), and all participants provided written informed consent.
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Demographic data were collected for all of the survey re- spondents including the number of previous children, previous experience with NVP, pregnancy-related medica- tion as well as any adverse experiences related to pregnan- cy-related medication. In addition, all respondents were asked to describe the severity of their NVP on a scale of 0– 10, with 10 being the most severe, as well as whether or not they had previously used CAM. Survey respondents who reported non-use of CAM to alleviate NVP were asked to agree or disagree with a series of possible reasons why they did not use CAM to alleviate their NVP. The level of agreement was measured by a 5-point Likert Scale, where 1 = strongly disagree, 2 = disagree somewhat, 3 = undecided, 4 = somewhat agree and 5 = strongly agree. Re- spondents who reported using CAM to alleviate their NVP were asked which CAM therapies they had used. They were also asked how they found out about CAM therapies, and whether or not their CAM use was supervised by a li- censed health care practitioner who practiced CAM either as part of their practice or in whole. Users of CAM were also asked 9 possible reasons why they chose to use CAM to alleviate their NVP, using the same Likert Scale used for non-CAM users.
It is also worth noting that among women with severe symptoms, 76% reported that they considered never to get pregnant again, 84% reported that the NVP had major ad- verse effects on the ability to care for their children, and 43% reported major impact on the relationship with their partner, reflecting substantial effects on family life func- tioning. In total 94% reported major impact on their work capacity and over 90% had been on sick leave due to NVP, illustrating that occupational functioning is affected for most women with severe NVP. However, considerable ad- verse effects were also seen among women with moderate symptoms, and even some women with mild symptoms reported major impact on different aspects of daily life functioning. This is in line with other studies describing that even mild NVP affected important part of the women’s daily lives, such as caring for children, rela- tionship with partner, work productivity and intent to become pregnant again [13, 30].
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nausea and vomiting during pregnancy requiring hospi- talisation before week 25 of gestation. Q3 also provided data regarding history of high blood pressure prior to pregnancy (yes or no), PGP (defined as self-reported mild or severe pain in the anterior and bilateral poster- ior pelvis, experiences of ≥3 weeks; yes or no), severe PGP (defined as PGP in addition to the pubic bone region with severe pain reported in all three pelvic lo- cations), high blood pressure in pregnancy (≥3 weeks; yes or no), and proteinuria (≥3 weeks with protein in urine; yes or no). Women answering Q3 also had an option to report their highest recorded systolic and dia- stolic pressure readings. We included one question, an- swered 6 months postpartum in questionnaire four (Q4), regarding reasons for caesarean delivery (breech, previous caesarean delivery, pregnancy complication/ill mother, poor growth/fetus complication, own prefer- ence, or other).
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The NVPQOL questionnaire has been previously reported to be suitable for all women with mild to severe NVP as well as having a good external validity . Our study population is comparable to the Montreal population of pregnant women. The majority of women in our study cohort were Caucasians, which consequently improves the external validity of our results to Canadian popula- tion. Indeed, in 2001 less than 15% of the Canadian pop- ulation belonged to a visible minority group . Conclusion
The overall rate of preterm births (< 37 weeks) was 4.6% (4397/96,056). Rates of extremely (26–27 weeks), very (28–31 weeks), and moderately (32–36 weeks) preterm births were 0.09% (88/96,056), 0.38% (364/96,056), and 4.1% (3929/96,056), respectively. Median gestational age was not statistically influenced by NVP status. However, the prevalence of preterm birth was slightly higher in women without NVP (Table 2). When compared to women without NVP, women with mild or moderate NVP had lower odds for overall preterm births (aOR 0.87, 95% CI 0.80–0.95 and aOR 0.85, 95% CI 0.78–0.93, respect- ively), and women with severe NVP had the lowest odds (aOR 0.84, 95% CI 0.74–0.95; Table 3). Differences be- tween women with and without NVP were more obvious when the risk of very preterm birth and extremely pre- term birth was analyzed. When compared to women with- out NVP, women with mild or moderate NVP had lower
most commonly used 5-HT 3 antagonist for the treatment of severe NVP, usually when other types of therapy prove ineffective. A limited number of case series and one study from Motherisk which included 176 women exposed to ondansetron in the 1st trimester, failed to find an association between exposure in first trimester and increased risk for major malformations. 38,42,43 Although it may help with reduc-
This is a secondary analysis of a double-blind, random- ized, multicenter, placebo-controlled study of the delayed-release combination of doxylamine succinate (10 mg) and pyridoxine hydrochloride (10 mg) (Dicle- gis®) for the treatment of NVP]. The full details of the study have been previously published . Briefly, the subjects were at least 18 years of age, pregnant in the gestational age range of 7–14 weeks, suffered from NVP, and had a PUQE score ≥6 [20–22]. The PUQE score in- corporates the number of daily vomiting episodes, num- ber of daily retching, and length of daily nausea in hours, for an overall score of symptoms rated from 3 (no symptoms) to 15 (most severe). Score of 1 on each of the 3 symptoms-nausea, vomiting and retching, de- notes “no symptoms”, and goes as high as 15 (5, or max- imum for each symptom). Scores of 4–6 denote mild NVP. Scores of 7–11 denote moderate NVP, and scores of 12–15 denote severe NVP.
It is important to emphasize that early assessment of nausea and vomiting in pregnancy is essential to prevent delay in diagnosis and management of HG. Apart from HG, consid- eration should be given to other underlying complications associated with persistent vomiting, such as gastrointes- tinal conditions (eg, hepatitis, pancreatitis, or biliary tract disease), pyelonephritis, and metabolic disorders (eg, diabetic ketoacidosis, porphyria, or Addison’s disease). 55 If such
SPA or EDA. In addition, CSE analgesia is frequently used. Established medications used for an SPA or EDA (local anesthetics and opioids) have a regional effect; they do not pass the placenta to a large extent and presumably do not cause major unintended (adverse) effects to the fetus. But there are also disadvantages regarding neuraxial techniques: The injected local anesthetic does not only specifically block the pain fibers but also leads to a vasodilatation by affecting sympathetic efferences. Due to the induced temporary sym- pathicolysis, blood pressure fluctuation in terms of significant hypotension can occur. On top of that, the increased vagal tone entails bradycardia which is often accompanied with nausea and vomiting. 11,12
A large percentage of pregnant women will experience some degree of the medical conditions outlined in this paper. Health conditions affecting day-to-day life can range from mild discomfort to placing a major burden on both the pregnant patient and her family members. The goal in managing these conditions is to discuss the medical condition with the patient and inform her of the treatment options available. Most patients will respond well to the first line treatment which includes lifestyle modifications and dietary advice. With worsening symptoms, pharmacological treatment may be warranted. Literature pertaining to effective treatment for these conditions is limited and based on data captured in pregnancy registries. Hence, it is important to discuss the risks versus benefits with the patient. Evidence-based guidelines as available are required to manage these conditions and provide good quality healthcare during maternity.
Official obstetric guidelines need to adequately emphasize the oral health issues related to nausea and vomiting in pregnancy and ways to reduce the effect. This study sug- gests that the use of a solution of a teaspoon of baking soda (sodium bicarbonate) in a cup of water for mouth rinses, one of the non-pharmacological methods of deal- ing with nausea and vomiting is not popular. The need to neutralize the acid from the vomitus is highlighted with respondents advising pregnant women to rinse with clean water only after vomiting. Tooth brushing immediately after vomiting is not recommended, how- ever resident obstetricians were giving pregnant women incorrect advice.
providing detailed access to maternal health during preg- nancy. The MoBa cohort specifically addressed NVP- related issues, providing the opportunity to differentiate between NP and NVP women [5, 24, 33]. Likewise, the detailed questions regarding PGP formed a basis for the robust definition of PGP used . As this is a large cohort, numerous significant associations tend to appear, yet the merit of these in the clinical setting are not always relevant. Furthermore, the responses in the MoBa ques- tionnaires do not allow for an easy assessment of the severity of NVP symptoms. Retrospective evaluation of NVP symptoms has previously been reported as a possible source of bias . We attempted to address this by excluding cases with inconsistencies in NVP symptoms reported between questionnaires (n = 15,791) to have as much confidence as possible in the remaining study sample. When we performed sensitivity analyses with the excluded cases included in the sample, the results were mostly unaffected. Women excluded from the present study had similar ages at delivery, BMI and energy intake, while there tended to be more women with a lower educa- tion (29.2% vs 30.5%) as well as a higher parity (48.4% vs 52.7%), findings consistent with non-compliance present in other studies [34, 51, 52]. The slightly higher number of daily smokers in the excluded group (5.7% vs 5.1%) is most likely a product of the high number of missing values for this variable. Other weaknesses include the reli- ance on self-reports of PGP, nausea, and vomiting. The diagnosis of PGP in our study would have benefited from a clinical assessment, as has been suggested elsewhere , in order to support the women’s self-reports. How- ever, this is not feasible in a large cohort study. Categoris- ing the difference between retching and actual vomiting (defining NP and NVP) may also have led to misclassifica- tions and affected the results. Another weakness is the lack of information on biomarkers (e.g. hormones).
without publication in peer-reviewed literature. In 2010, a randomized, double-blind, multicenter, placebo-controlled trial in the US enrolled 261 patients in the gestational age range of 7–14 weeks. The study used a two-part pregnancy- unique quantification of emesis (PUQE) score, which is the only validated scoring system that incorporates both the physi- cal (nausea, vomiting, retching) and quality-of-life aspects of NVP. The PUQE scoring system has been widely used and has been validated for use in both English and Spanish. In this study, Diclectin use resulted in a significantly larger improvement in symptoms of NVP compared with placebo over 15 days based on both the clinical PUQE score (scale 3–15) ( - 4.8 ± 2.7 PUQE score versus - 3.9 ± 2.6; P= 0.006) and global assessment of well-being (scale 1–10) (2.8 ± 2.8 versus 1.8 ± 2.2; P= 0.005). 17 At the end of the 15-day trial, 48.9% of